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Chagas YW, Vaz de Castro PAS, Simões-E-Silva AC. Neuroinflammation in kidney disease and dialysis. Behav Brain Res 2025; 483:115465. [PMID: 39922385 DOI: 10.1016/j.bbr.2025.115465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 01/19/2025] [Accepted: 01/30/2025] [Indexed: 02/10/2025]
Abstract
The complex relationship between chronic kidney disease (CKD) and neuroinflammation shows how important immunological processes are in mediating cognitive dysfunction and psychiatric symptoms in this disease. Proinflammatory cytokines and chemokines, such as IL-1β and IL-6, are capable of crossing the blood-brain barrier, and, consequently, may contribute to neuropsychiatric symptoms including anxiety, depression, and cognitive impairment in CKD patients. The peptides of the renin-angiotensin system (RAS), with their dual functions in inflammation and neuroprotection, also highlight the intricate immunological mechanisms operating within the kidney-brain axis. Understanding these immunological pathways is essential for developing targeted interventions to modulate neuroinflammation and improve cognitive outcomes in individuals with CKD. Further research in renal immunology and neuroinflammation holds promise for advancing our understanding of the intricate connections between kidney health, brain function, and immune responses in the context of CKD. This review summarizes the critical role of immunological factors in the pathophysiology of CKD-related cognitive impairment and psychiatric disorders.
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Affiliation(s)
- Yumi Watanabe Chagas
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Brazil
| | - Pedro Alves S Vaz de Castro
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Brazil
| | - Ana Cristina Simões-E-Silva
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Brazil.
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2
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Boyle AK, Tetorou K, Suff N, Beecroft L, Mazzaschi M, Karda R, Hristova M, Waddington SN, Peebles D. Ascending Vaginal Infection in Mice Induces Preterm Birth and Neonatal Morbidity. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00040-9. [PMID: 39892780 DOI: 10.1016/j.ajpath.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 12/06/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025]
Abstract
Preterm birth (PTB; delivery before 37 weeks), the main cause of neonatal death worldwide, can lead to adverse neurodevelopmental outcomes, as well as lung and gut pathology. PTB can be associated with ascending vaginal infection. Previously, it was shown that ascending Escherichia coli infection in pregnant mice induces PTB and reduces pup survival. Here, it is demonstrated that this model recapitulates the pathology observed in human preterm neonates (namely, neuroinflammation, lung injury, and gut inflammation). In neonatal brains, there is widespread cell death, microglial activation, astrogliosis, and reduced neuronal density. The utility of this model is also validated by assessing the efficacy of maternal cervical gene therapy with an adeno-associated viral vector containing human β defensin 3; this improves pup survival and reduces Tnfa mRNA expression in perinatal pup brains exposed to E. coli. This model provides a unique opportunity to evaluate the therapeutic benefit of preterm labor interventions on perinatal pathology.
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Affiliation(s)
- Ashley K Boyle
- EGA Institute for Women's Health, University College London, London, United Kingdom.
| | - Konstantina Tetorou
- EGA Institute for Women's Health, University College London, London, United Kingdom
| | - Natalie Suff
- Department of Women and Children's Health, St Thomas' Hospital, King's College London, London, United Kingdom
| | - Laura Beecroft
- EGA Institute for Women's Health, University College London, London, United Kingdom
| | - Margherita Mazzaschi
- EGA Institute for Women's Health, University College London, London, United Kingdom
| | - Rajvinder Karda
- EGA Institute for Women's Health, University College London, London, United Kingdom
| | - Mariya Hristova
- EGA Institute for Women's Health, University College London, London, United Kingdom
| | - Simon N Waddington
- EGA Institute for Women's Health, University College London, London, United Kingdom; Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, Johannesburg, South Africa
| | - Donald Peebles
- EGA Institute for Women's Health, University College London, London, United Kingdom
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3
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Mohammad ZB, Yudin SCY, Goldberg BJ, Serra KL, Klegeris A. Exploring neuroglial signaling: diversity of molecules implicated in microglia-to-astrocyte neuroimmune communication. Rev Neurosci 2025; 36:91-117. [PMID: 39240134 PMCID: PMC11717358 DOI: 10.1515/revneuro-2024-0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024]
Abstract
Effective communication between different cell types is essential for brain health, and dysregulation of this process leads to neuropathologies. Brain glial cells, including microglia and astrocytes, orchestrate immune defense and neuroimmune responses under pathological conditions during which interglial communication is indispensable. Our appreciation of the complexity of these processes is rapidly increasing due to recent advances in molecular biology techniques, which have identified numerous phenotypic states of both microglia and astrocytes. This review focuses on microglia-to-astrocyte communication facilitated by secreted neuroimmune modulators. The combinations of interleukin (IL)-1α, tumor necrosis factor (TNF), plus complement component C1q as well as IL-1β plus TNF are already well-established microglia-derived stimuli that induce reactive phenotypes in astrocytes. However, given the large number of inflammatory mediators secreted by microglia and the rapidly increasing number of distinct functional states recognized in astrocytes, it can be hypothesized that many more intercellular signaling molecules exist. This review identifies the following group of cytokines and gliotransmitters that, while not established as interglial mediators yet, are known to be released by microglia and elicit functional responses in astrocytes: IL-10, IL-12, IL-18, transforming growth factor (TGF)-β, interferon (IFN)-γ, C-C motif chemokine ligand (CCL)5, adenosine triphosphate (ATP), l-glutamate, and prostaglandin E2 (PGE2). The review of molecular mechanisms engaged by these mediators reveals complex, partially overlapping signaling pathways implicated in numerous neuropathologies. Additionally, lack of human-specific studies is identified as a significant knowledge gap. Further research on microglia-to-astrocyte communication is warranted, as it could discover novel interglial signaling-targeted therapies for diverse neurological disorders.
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Affiliation(s)
- Zainab B. Mohammad
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, V1V 1V7, Canada
| | - Samantha C. Y. Yudin
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, V1V 1V7, Canada
| | - Benjamin J. Goldberg
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, V1V 1V7, Canada
| | - Kursti L. Serra
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, V1V 1V7, Canada
| | - Andis Klegeris
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, V1V 1V7, Canada
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Timofeeva AV, Akhmetzyanova ER, Rizvanov AA, Mukhamedshina YO. Interaction of microglia with the microenvironment in spinal cord injury. Neuroscience 2025; 565:594-603. [PMID: 39622381 DOI: 10.1016/j.neuroscience.2024.11.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 12/28/2024]
Abstract
This article discusses the peculiarities of microglia behaviour and their interaction with other cells of the central nervous system (CNS) during neural tissue injury with a focus on spinal cord injury (SCI). Taking into account the plasticity of microglia, the influence of the microenvironment should be taken into account to establish the mechanisms determining the polarization pathways of these cells. Determination of the system of microglia interactions with other CNS cells during injury will reveal the patterns of post-traumatic microglia responses, in particular, determining both pro-inflammatory and anti-inflammatory responses. This review compiles information on changes in microglia activation, migration and phagocytosis, as well as their reciprocal effects on other CNS cells, such as neurons, astrocytes and oligodendrocytes, in the background of SCI. The information contained in this article may be of interest not only to scientists studying traumatic injuries of the central nervous system, but also to specialists in the field of studying and treating neurodegenerative diseases, since the mechanisms occurring in the injured spinal cord may also be characteristic of pathological events in degenerative processes.
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Affiliation(s)
- A V Timofeeva
- Kazan (Volga Region) Federal University, Kazan, Russia
| | | | - A A Rizvanov
- Kazan (Volga Region) Federal University, Kazan, Russia; Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, Russia
| | - Y O Mukhamedshina
- Kazan (Volga Region) Federal University, Kazan, Russia; Kazan State Medical University, Kazan, Russia
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5
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Heesbeen EJ, Bijlsma EY, Risseeuw TA, Hessel EVS, Groenink L. A systematic approach to identify gaps in neuroimmunology: TNF-α and fear learning deficits, a worked example. Brain Behav Immun 2025; 123:752-764. [PMID: 39442635 DOI: 10.1016/j.bbi.2024.10.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND The pathophysiology of several neurodegenerative and neuropsychiatric disorders is linked to an altered immune system. However, it is often unclear how the immune system specifically affects these disorders since neuroimmune interactions are very complex. In this paper, we introduce an adjusted version of the adverse outcome pathway (AOP) approach from toxicology to the field of neuroimmunology. A review of the effect of TNF-α on fear learning deficits is used as a worked example to demonstrate how an AOP approach can help identify gaps of knowledge and crucial steps in the pathophysiology of neuroimmunological disorders. METHODS The AOP was constructed in five steps. First, the adverse outcome was formulated clearly and specifically. Second, the link between the molecular initiating event and the adverse outcome was established with a preliminary literature search in the Medline database. Third, a systematic literature search was performed in which we identified 95 relevant articles. Fourth, the main biological processes and relevant key events were identified. Fifth, the links between key events were determined and an AOP network was constructed. RESULTS We identified three pathways through which TNF-α may affect fear learning. First, TNF-α receptor activation increases NF-κB levels which increases oxidative stress levels and reduces the activity of glutamate transporters. This alters the synaptic plasticity which is associated with impaired fear acquisition, consolidation, and fear extinction. Second, activation of TNF-α receptors increases the expression and capacity of the serotonin transporter which is linked to impaired fear acquisition, expression, and extinction. Third, TNF-α receptor 1 activation can induce necroptosis, leading to neuroinflammation which is linked to fear learning deficits. CONCLUSION To successfully apply the AOP approach in neuroimmunology we recommend defining adverse outcomes more precisely, establishing stronger connections between key events from various biological processes, incorporating feedforward and feedback loops, and identifying more mechanistic knowledge in later key events. These adjustments are needed to map the complex processes within the field of neuroimmunology and to identify gaps of knowledge.
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Affiliation(s)
- Elise J Heesbeen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands (the).
| | - Elisabeth Y Bijlsma
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands (the)
| | - Tristan A Risseeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands (the)
| | - Ellen V S Hessel
- Public Health and Health Services, RIVM National Institute for Public Health and the Environment, Bilthoven, Netherlands (the)
| | - Lucianne Groenink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands (the)
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Bahaaeldin M, Bülte C, Luelsberg F, Kumar S, Kappler J, Völker C, Schilling K, Baader SL. Engrailed-2 and inflammation convergently and independently impinge on cerebellar Purkinje cell differentiation. J Neuroinflammation 2024; 21:306. [PMID: 39609827 PMCID: PMC11603920 DOI: 10.1186/s12974-024-03301-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/17/2024] [Indexed: 11/30/2024] Open
Abstract
Autism spectrum disorders (ASD) have a complex pathogenesis thought to include both genetic and extrinsic factors. Among the latter, inflammation of the developing brain has recently gained growing attention. However, how genetic predisposition and inflammation might converge to precipitate autistic behavior remains elusive. Cerebellar structure and function are well known to be affected in autism. We therefore used cerebellar slice cultures to probe whether inflammatory stimulation and (over)expression of the autism susceptibility gene Engrailed-2 interact in shaping differentiation of Purkinje cells, key organizers of cerebellar histogenesis and function. We show that lipopolysaccharide treatment reduces Purkinje cell dendritogenesis and that this effect is enhanced by over-expression of Engrailed-2 in these cells. The effects of lipopolysaccharide can be blocked by inhibiting microglia proliferation and also by blocking tumor necrosis factor alpha receptor signaling, suggesting microglia and tumor necrosis factor alpha are major players in this scenario. These findings identify Purkinje cells as a potential integrator of genetic and environmental signals that lead to an autism-associated morphology.
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Affiliation(s)
- Mohammed Bahaaeldin
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany
| | - Carolin Bülte
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany
| | - Fabienne Luelsberg
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany
| | - Sujeet Kumar
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany
- National Reference Laboratory for Tuberculosis, ICMR-RMRC, Bhubaneswar, Odisha, India
| | - Joachim Kappler
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, 53125, Bonn, Germany
| | - Christof Völker
- Institute of Biochemistry and Molecular Biology, University of Bonn, Nussallee 11, 53125, Bonn, Germany
| | - Karl Schilling
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany
| | - Stephan L Baader
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany.
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Perdaens O, van Pesch V. Should We Consider Neurodegeneration by Itself or in a Triangulation with Neuroinflammation and Demyelination? The Example of Multiple Sclerosis and Beyond. Int J Mol Sci 2024; 25:12637. [PMID: 39684351 PMCID: PMC11641818 DOI: 10.3390/ijms252312637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Neurodegeneration is preeminent in many neurological diseases, and still a major burden we fail to manage in patient's care. Its pathogenesis is complicated, intricate, and far from being completely understood. Taking multiple sclerosis as an example, we propose that neurodegeneration is neither a cause nor a consequence by itself. Mitochondrial dysfunction, leading to energy deficiency and ion imbalance, plays a key role in neurodegeneration, and is partly caused by the oxidative stress generated by microglia and astrocytes. Nodal and paranodal disruption, with or without myelin alteration, is further involved. Myelin loss exposes the axons directly to the inflammatory and oxidative environment. Moreover, oligodendrocytes provide a singular metabolic and trophic support to axons, but do not emerge unscathed from the pathological events, by primary myelin defects and cell apoptosis or secondary to neuroinflammation or axonal damage. Hereby, trophic failure might be an overlooked contributor to neurodegeneration. Thus, a complex interplay between neuroinflammation, demyelination, and neurodegeneration, wherein each is primarily and secondarily involved, might offer a more comprehensive understanding of the pathogenesis and help establishing novel therapeutic strategies for many neurological diseases and beyond.
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Affiliation(s)
- Océane Perdaens
- Neurochemistry Group, Institute of NeuroScience, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium;
| | - Vincent van Pesch
- Neurochemistry Group, Institute of NeuroScience, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium;
- Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium
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8
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Althammer F, Roy RK, Kirchner MK, Podpecan Y, Helen J, McGrath S, Lira EC, Stern JE. Angiotensin-II drives changes in microglia-vascular interactions in rats with heart failure. Commun Biol 2024; 7:1537. [PMID: 39562706 PMCID: PMC11577102 DOI: 10.1038/s42003-024-07229-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 11/07/2024] [Indexed: 11/21/2024] Open
Abstract
Activation of microglia, the resident immune cells of the central nervous system, leading to the subsequent release of pro-inflammatory cytokines, has been linked to cardiac remodeling, autonomic disbalance, and cognitive deficits in heart failure (HF). While previous studies emphasized the role of hippocampal Angiotensin II (AngII) signaling in HF-induced microglial activation, unanswered mechanistic questions persist. Evidence suggests significant interactions between microglia and local microvasculature, potentially affecting blood-brain barrier integrity and cerebral blood flow regulation. Still, whether the microglial-vascular interface is affected in the brain during HF remains unknown. Using a well-established ischemic HF rat model, we demonstrate the increased abundance of vessel-associated microglia (VAM) in HF rat hippocampi, along with an increased expression of AngII AT1a receptors. Acute AngII administration to sham rats induced microglia recruitment to brain capillaries, along with increased expression of TNFα. Conversely, administering an AT1aR blocker to HF rats prevented the recruitment of microglia to blood vessels, normalizing their levels to those in healthy rats. These results highlight the critical importance of a rather understudied phenomenon (i.e., microglia-vascular interactions in the brain) in the context of the pathophysiology of a highly prevalent cardiovascular disease, and unveil novel potential therapeutic avenues aimed at mitigating neuroinflammation in cardiovascular diseases.
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Affiliation(s)
- Ferdinand Althammer
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA
- Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Ranjan K Roy
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA
| | - Matthew K Kirchner
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA
| | - Yuval Podpecan
- Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Jemima Helen
- Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Shaina McGrath
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA
| | - Elba Campos Lira
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA
| | - Javier E Stern
- Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta, GA, USA.
- Neuroscience Institute, Georgia State University, Atlanta, GA, USA.
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9
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Tobinick E, Ucci D, Bermudo K, Asseraf S. Perispinal etanercept stroke trial design: PESTO and beyond. Expert Opin Biol Ther 2024; 24:1095-1108. [PMID: 39177653 DOI: 10.1080/14712598.2024.2390636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 08/06/2024] [Indexed: 08/24/2024]
Abstract
INTRODUCTION Perispinal etanercept (PSE) is an innovative treatment designed to improve stroke recovery by addressing chronic post-stroke neuroinflammation. Basic science evidence, randomized clinical trial (RCT) evidence and 14 years of favorable clinical experience support the use of PSE to treat chronic stroke. This article provides guidance for the design of future PSE RCTs in accordance with current FDA recommendations. AREAS COVERED Scientific background and essential elements of PSE RCT design. EXPERT OPINION Intimate familiarity with PSE, its novel method of drug delivery, and the characteristics of ideal enriched study populations are necessary for those designing future PSE stroke trials. The design elements needed to enable a PSE RCT to generate valid results include a suitable research question; a homogeneous study population selected using a prospective enrichment strategy; a primary outcome measure responsive to the neurological improvements that result from PSE; trialists with expertise in perispinal delivery; optimal etanercept dosing; and steps taken to minimize the number of placebo responders. RCTs failing to incorporate these elements, such as the PESTO trial, are incapable of reaching reliable conclusions regarding PSE efficacy. SF-36 has not been validated in PSE trials and is unsuitable for use as a primary outcome measure in PSE RCTs.
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Affiliation(s)
| | - Danielle Ucci
- Institute of Neurological Recovery, Boca Raton, FL, USA
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10
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Pramanik S, Devi M H, Chakrabarty S, Paylar B, Pradhan A, Thaker M, Ayyadhury S, Manavalan A, Olsson PE, Pramanik G, Heese K. Microglia signaling in health and disease - Implications in sex-specific brain development and plasticity. Neurosci Biobehav Rev 2024; 165:105834. [PMID: 39084583 DOI: 10.1016/j.neubiorev.2024.105834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/21/2024] [Accepted: 07/27/2024] [Indexed: 08/02/2024]
Abstract
Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.
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Affiliation(s)
- Subrata Pramanik
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
| | - Harini Devi M
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Saswata Chakrabarty
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Berkay Paylar
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Ajay Pradhan
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Manisha Thaker
- Eurofins Lancaster Laboratories, Inc., 2425 New Holland Pike, Lancaster, PA 17601, USA
| | - Shamini Ayyadhury
- The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Arulmani Manavalan
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India
| | - Per-Erik Olsson
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Gopal Pramanik
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133791, the Republic of Korea.
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11
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Chmielarz M, Bromke MA, Olbromski M, Środa-Pomianek K, Frej-Mądrzak M, Dzięgiel P, Sobieszczańska B. Lipidomics Analysis of Human HMC3 Microglial Cells in an In Vitro Model of Metabolic Syndrome. Biomolecules 2024; 14:1238. [PMID: 39456170 PMCID: PMC11506612 DOI: 10.3390/biom14101238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/28/2024] Open
Abstract
Metabolic endotoxemia (ME) is associated with bacterial lipopolysaccharide (LPS, endotoxin) and increased levels of saturated fatty acids (SFAs) in the bloodstream, causing systemic inflammation. ME usually accompanies obesity and a diet rich in fats, especially SFAs. Numerous studies confirm the effect of ME-related endotoxin on microglial activation. Our study aimed to assess lipid metabolism and immune response in microglia pre-stimulated with TNFα (Tumor Necrosis Factor α) and then with endotoxin and palmitic acid (PA). Using ELISA, we determined cytokines IL-1β, IL-10, IL-13 (interleukin-1β, -10, -13, and TGFβ (Transforming Growth Factor β) in the culture medium from microglial cells stimulated for 24 h with TNFα and then treated with LPS (10 ng/mL) and PA (200 µM) for 24 h. HMC3 (Human Microglial Cells clone 3) cells produced negligible amounts of IL-1β, IL-10, and IL-13 after stimulation but secreted moderate levels of TGFβ. Changes in lipid metabolism accompanied changes in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) expression. HMC3 stimulation with endotoxin increased TREM2 expression, while PA treatment decreased it. Endotoxin increased ceramide levels, while PA increased triglyceride levels. These results indicated that pre-stimulation of microglia with TNFα significantly affects its interactions with LPS and PA and modulates lipid metabolism, which may lead to microglial activation silencing and neurodegeneration.
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Affiliation(s)
- Mateusz Chmielarz
- Department of Clinical Microbiology, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 4, 50-368 Wroclaw, Poland; (M.C.); (M.F.-M.)
| | - Mariusz Aleksander Bromke
- Department of Biochemistry and Immunochemistry, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland;
| | - Mateusz Olbromski
- Department of Human Morphology and Embryology, Faculty of Medicine, Division of Histology and Embryology, Wroclaw Medical University, Chalubinskiego 6a, 50-368 Wrocław, Poland; (M.O.); (P.D.)
| | - Kamila Środa-Pomianek
- Department of Biophysics and Neuroscience, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 3a, 50-368 Wroclaw, Poland;
| | - Magdalena Frej-Mądrzak
- Department of Clinical Microbiology, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 4, 50-368 Wroclaw, Poland; (M.C.); (M.F.-M.)
| | - Piotr Dzięgiel
- Department of Human Morphology and Embryology, Faculty of Medicine, Division of Histology and Embryology, Wroclaw Medical University, Chalubinskiego 6a, 50-368 Wrocław, Poland; (M.O.); (P.D.)
| | - Beata Sobieszczańska
- Department of Clinical Microbiology, Faculty of Medicine, Wroclaw Medical University, Chalubinskiego 4, 50-368 Wroclaw, Poland; (M.C.); (M.F.-M.)
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12
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Thijs V, Cloud GC, Gilchrist N, Parsons B, Tilvawala F, Ho J, Ruthnam L, Stanislaus V, Sprigg N, Walker M, Bath PM, Churilov L, Bernhardt J. Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial. Eur Stroke J 2024; 9:789-795. [PMID: 38676623 PMCID: PMC11418453 DOI: 10.1177/23969873241249248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/01/2024] [Indexed: 04/29/2024] Open
Abstract
RATIONALE A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.
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Affiliation(s)
- Vincent Thijs
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
- Department of Neurology, Austin Health, Heidelberg, VIC, Australia
- Department of Medicine, Melbourne Medical School, University of Melbourne, Heidelberg/Parkville, VIC Australia
| | - Geoffrey C Cloud
- Department of Neuroscience, Central Clinical School, Monash University Melbourne, Melbourne, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | | | - Brooke Parsons
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
| | - Forum Tilvawala
- Department of Neurology, Austin Health, Heidelberg, VIC, Australia
| | - Jan Ho
- Department of Neurology, Austin Health, Heidelberg, VIC, Australia
| | - Lara Ruthnam
- Department of Neurology, Austin Health, Heidelberg, VIC, Australia
| | - Vimal Stanislaus
- Department of Neuroscience, Central Clinical School, Monash University Melbourne, Melbourne, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Nikola Sprigg
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Marion Walker
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Philip M Bath
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Leonid Churilov
- Department of Medicine, Melbourne Medical School, University of Melbourne, Heidelberg/Parkville, VIC Australia
| | - Julie Bernhardt
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
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13
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Zhang X, Zhang F, Xu X. Single-cell RNA sequencing in exploring the pathogenesis of diabetic retinopathy. Clin Transl Med 2024; 14:e1751. [PMID: 38946005 PMCID: PMC11214886 DOI: 10.1002/ctm2.1751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/10/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024] Open
Abstract
Diabetic retinopathy (DR) is a leading cause of irreversible blindness in the working-age populations. Despite decades of research on the pathogenesis of DR for clinical care, a comprehensive understanding of the condition is still lacking due to the intricate cellular diversity and molecular heterogeneity involved. Single-cell RNA sequencing (scRNA-seq) has made the high-throughput molecular profiling of cells across modalities possible which has provided valuable insights into complex biological systems. In this review, we summarise the application of scRNA-seq in investigating the pathogenesis of DR, focusing on four aspects. These include the identification of differentially expressed genes, characterisation of key cell subpopulations and reconstruction of developmental 'trajectories' to unveil their state transition, exploration of complex cell‒cell communication in DR and integration of scRNA-seq with genome-wide association studies to identify cell types that are most closely related to DR risk genetic loci. Finally, we discuss the future challenges and expectations associated with studying DR using scRNA-seq. We anticipate that scRNA-seq will facilitate the discovery of mechanisms and new treatment targets in the clinical care landscape for patients with DR. KEY POINTS: Progress in scRNA-seq for diabetic retinopathy (DR) research includes studies on DR patients, non-human primates, and the prevalent mouse models. scRNA-seq facilitates the identification of differentially expressed genes, pivotal cell subpopulations, and complex cell-cell interactions in DR at single-cell level. Future scRNA-seq applications in DR should target specific patient subsets and integrate with single-cell and spatial multi-omics approaches.
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Affiliation(s)
- Xinzi Zhang
- National Clinical Research Center for Eye DiseasesDepartment of OphthalmologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Eye Institute of Shanghai Jiao Tong University SchoolShanghaiChina
- Shanghai Key Laboratory of Ocular Fundus DiseasesShanghaiChina
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina
| | - Fang Zhang
- National Clinical Research Center for Eye DiseasesDepartment of OphthalmologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Eye Institute of Shanghai Jiao Tong University SchoolShanghaiChina
- Shanghai Key Laboratory of Ocular Fundus DiseasesShanghaiChina
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina
| | - Xun Xu
- National Clinical Research Center for Eye DiseasesDepartment of OphthalmologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Eye Institute of Shanghai Jiao Tong University SchoolShanghaiChina
- Shanghai Key Laboratory of Ocular Fundus DiseasesShanghaiChina
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina
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14
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Khan MM, Khan ZA, Khan MA. Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration. World J Psychiatry 2024; 14:767-783. [PMID: 38984346 PMCID: PMC11230099 DOI: 10.5498/wjp.v14.i6.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024] Open
Abstract
Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
| | - Zaw Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
| | - Mohsin Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
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15
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Gao R, Ali T, Liu Z, Li A, He K, Yang C, Feng J, Li S. NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression. Int Immunopharmacol 2024; 132:111964. [PMID: 38603856 DOI: 10.1016/j.intimp.2024.111964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/16/2024] [Accepted: 03/26/2024] [Indexed: 04/13/2024]
Abstract
The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.
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Affiliation(s)
- Ruyan Gao
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055.
| | - Tahir Ali
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055; Institute of Chemical Biology, Shenzhen Bay Laboratory Shenzhen 518132 China.
| | - Zizhen Liu
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055.
| | - Axiang Li
- Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Kaiwu He
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055.
| | - Canyu Yang
- Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Jinxing Feng
- Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China.
| | - Shupeng Li
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055; Institute of Chemical Biology, Shenzhen Bay Laboratory Shenzhen 518132 China; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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16
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Mayer MG, Fischer T. Microglia at the blood brain barrier in health and disease. Front Cell Neurosci 2024; 18:1360195. [PMID: 38550920 PMCID: PMC10976855 DOI: 10.3389/fncel.2024.1360195] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/23/2024] [Indexed: 01/24/2025] Open
Abstract
The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain's vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.
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Affiliation(s)
- Meredith G. Mayer
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
| | - Tracy Fischer
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, United States
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
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17
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Augusto-Oliveira M, Tremblay MÈ, Verkhratsky A. Receptors on Microglia. ADVANCES IN NEUROBIOLOGY 2024; 37:83-121. [PMID: 39207688 DOI: 10.1007/978-3-031-55529-9_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Microglial cells are the most receptive cells in the central nervous system (CNS), expressing several classes of receptors reflecting their immune heritage and newly acquired neural specialisation. Microglia possess, depending on the particular context, receptors to neurotransmitters and neuromodulators as well as immunocompetent receptors. This rich complement allows microglial cells to monitor the functional status of the nervous system, contribute actively to the regulation of neural activity and plasticity and homeostasis, and guard against pathogens as well as other challenges to the CNS's integrity and function.
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Affiliation(s)
- Marcus Augusto-Oliveira
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil
- Programa de Pós-Graduação em Farmacologia e Bioquímica, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil
| | - Marie-Ève Tremblay
- Division of Medical Sciences, Medical Sciences Building, University of Victoria, Victoria, BC, Canada
- Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada
- Department of Molecular Medicine, Université Laval, Pavillon Ferdinand-Vandry, Québec City, QC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Life Sciences Center, Vancouver, BC, Canada
| | - Alexei Verkhratsky
- Faculty of Life Sciences, The University of Manchester, Manchester, UK.
- Department of Neurosciences, University of the Basque Country, Leioa, Spain.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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18
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Husseini L, Geladaris A, Weber MS. Toward identifying key mechanisms of progression in multiple sclerosis. Trends Neurosci 2024; 47:58-70. [PMID: 38102058 DOI: 10.1016/j.tins.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/16/2023] [Accepted: 11/14/2023] [Indexed: 12/17/2023]
Abstract
A major therapeutic goal in the treatment of multiple sclerosis (MS) is to prevent the accumulation of disability over an often decades-long disease course. Disability progression can result from acute relapses as well as from CNS intrinsic parenchymal disintegration without de novo CNS lesion formation. Research focus has shifted to progression not associated with acute inflammation, as it is not sufficiently controlled by currently available treatments. This review outlines how recent advances in the understanding of the pathogenesis of progressive MS have been facilitated by the development of more precise, less static pathogenetic concepts of progressive MS, as well as by new techniques for the analysis of region-specific proteomic and transcriptomic signatures in the human CNS. We highlight key drivers of MS disease progression and potential targets in its treatment.
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Affiliation(s)
- Leila Husseini
- Department of Neurology, University Medical Center, Göttingen, Germany
| | - Anastasia Geladaris
- Institute of Neuropathology, University Medical Center, Göttingen, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology, 37073 Göttingen, Germany
| | - Martin S Weber
- Department of Neurology, University Medical Center, Göttingen, Germany; Institute of Neuropathology, University Medical Center, Göttingen, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology, 37073 Göttingen, Germany.
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19
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Cabral LM, Oliveira LM, Miranda NC, Kawamoto EM, K P Costa S, Moreira TS, Takakura AC. TNFR1-mediated neuroinflammation is necessary for respiratory deficits observed in 6-hydroxydopamine mouse model of Parkinsońs Disease. Brain Res 2024; 1822:148586. [PMID: 37757967 DOI: 10.1016/j.brainres.2023.148586] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/17/2023] [Accepted: 09/17/2023] [Indexed: 09/29/2023]
Abstract
Parkinson's Disease (PD) is characterized by classic motor symptoms related to movement, but PD patients can experience symptoms associated with impaired autonomic function, such as respiratory disturbances. Functional respiratory deficits are known to be associated with brainstem neurodegeneration in the mice model of PD induced by 6-hydroxydopamine (6-OHDA). Understanding the causes of neuronal death is essential for identifying specific targets to prevent degeneration. Many mechanisms can explain why neurons die in PD, and neuroinflammation is one of them. To test the influence of inflammation, mediated by microglia and astrocytes cells, in the respiratory disturbances associated with brainstem neurons death, we submitted wild-type (WT) and TNF receptor 1 (TNFR1) knockout male mice to the 6-OHDA model of PD. Also, male C57BL/6 animals were induced using the same PD model and treated with minocycline (45 mg/kg), a tetracycline antibiotic with anti-inflammatory properties. We show that degeneration of brainstem areas such as the retrotrapezoid nucleus (RTN) and the pre-Botzinger Complex (preBotC) were prevented in both protocols. Notably, respiratory disturbances were no longer observed in the animals where inflammation was suppressed. Thus, the data demonstrate that inflammation is responsible for the breathing impairment in the 6-OHDA-induced PD mouse model.
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Affiliation(s)
- Laís M Cabral
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Luiz M Oliveira
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Nicole C Miranda
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Elisa M Kawamoto
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Soraia K P Costa
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Thiago S Moreira
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil
| | - Ana C Takakura
- Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP 05508-000, Brazil.
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20
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Thougaard E, Nielsen PV, Forsberg A, Phuong V, Velasco AM, Wlodarczyk A, Wajant H, Lang I, Mikkelsen JD, Clausen BH, Brambilla R, Lambertsen KL. Systemic treatment with a selective TNFR2 agonist alters the central and peripheral immune responses and transiently improves functional outcome after experimental ischemic stroke. J Neuroimmunol 2023; 385:578246. [PMID: 37988839 DOI: 10.1016/j.jneuroim.2023.578246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/27/2023] [Accepted: 11/13/2023] [Indexed: 11/23/2023]
Abstract
Ischemic stroke often leaves survivors with permanent disabilities and therapies aimed at limiting detrimental inflammation and improving functional outcome are still needed. Tumor necrosis factor (TNF) levels increase rapidly after ischemic stroke, and while signaling through TNF receptor 1 (TNFR1) is primarily detrimental, TNFR2 signaling mainly has protective functions. We therefore investigated how systemic stimulation of TNFR2 with the TNFR2 agonist NewSTAR2 affects ischemic stroke in mice. We found that NewSTAR2 treatment induced changes in peripheral immune cell numbers and transiently affected microglial numbers and neuroinflammation. However, this was not sufficient to improve long-term functional outcome after stroke in mice.
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Affiliation(s)
- Estrid Thougaard
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark.
| | - Pernille Vinther Nielsen
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsløwsvej 4, 5000 Odense C, Denmark.
| | - Amalie Forsberg
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark.
| | - Victoria Phuong
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark.
| | - Aitana Martínez Velasco
- Neurobiology Research Unit, University Hospital Rigshospitalet, Inge Lehmanns Vej 6, 2100 Copenhagen, Denmark
| | - Agnieszka Wlodarczyk
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark.
| | - Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, Würzburg 97080, Germany.
| | - Isabell Lang
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, Würzburg 97080, Germany.
| | - Jens D Mikkelsen
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; Neurobiology Research Unit, University Hospital Rigshospitalet, Inge Lehmanns Vej 6, 2100 Copenhagen, Denmark; Department of Neuroscience, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
| | - Bettina Hjelm Clausen
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark.
| | - Roberta Brambilla
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Lois Pope LIFE Center, Miami, FL 33136, USA.
| | - Kate Lykke Lambertsen
- Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsløwsvej 4, 5000 Odense C, Denmark.
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21
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Lei L, Wang YT, Hu D, Gai C, Zhang Y. Astroglial Connexin 43-Mediated Gap Junctions and Hemichannels: Potential Antidepressant Mechanisms and the Link to Neuroinflammation. Cell Mol Neurobiol 2023; 43:4023-4040. [PMID: 37875763 PMCID: PMC11407732 DOI: 10.1007/s10571-023-01426-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/14/2023] [Indexed: 10/26/2023]
Abstract
Major depression disorder (MDD) is a neuropsychiatric disorder associated with a high suicide rate and a higher disability rate than any other disease. Evidence suggests that the pathological mechanism of MDD is related to astrocyte dysfunction. Depression is mainly associated with the expression of connexin 43 (Cx43) and the function of Cx43-mediated gap junctions and hemichannels in astrocytes. Moreover, neuroinflammation has been a hotspot in research on the pathology of depression, and Cx43-mediated functions are thought to be involved in neuroinflammation-related depression. However, the specific mechanism of Cx43-mediated functions in neuroinflammation-related depression pathology remains unclear. Therefore, this review summarizes and discusses Cx43 expression, the role of gap junction intercellular communication, and its relationship with neuroinflammation in depression. This review also focuses on the effects of antidepressant drugs (e.g., monoamine antidepressants, psychotropic drugs, and N-methyl-D-aspartate receptor antagonists) on Cx43-mediated function and provides evidence for Cx43 as a novel target for the treatment of MDD. The pathogenesis of MDD is related to astrocyte dysfunction, with reduced Cx43 expression, GJ dysfunction, decreased GJIC and reduced BDNF expression in the depressed brain. The effect of Cx43 on neuroinflammation-related depression involving inflammatory cytokines, glutamate excitotoxicity, and HPA axis dysregulation. Antidepressant drugs targeting Cx43 can effectively relieve depressive symptoms.
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Affiliation(s)
- Lan Lei
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Sunshine Southern Avenue, Fang-Shan District, Beijing, 102488, China
| | - Ya-Ting Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Sunshine Southern Avenue, Fang-Shan District, Beijing, 102488, China
| | - Die Hu
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Sunshine Southern Avenue, Fang-Shan District, Beijing, 102488, China
| | - Cong Gai
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Sunshine Southern Avenue, Fang-Shan District, Beijing, 102488, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Sunshine Southern Avenue, Fang-Shan District, Beijing, 102488, China.
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22
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Clark IA, Vissel B. Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease. Pharmacol Res Perspect 2023; 11:e01136. [PMID: 37750203 PMCID: PMC10520644 DOI: 10.1002/prp2.1136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/27/2023] Open
Abstract
Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.
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Affiliation(s)
- Ian A. Clark
- Research School of Biology, Australian National UniversityCanberraAustralian Capital TerritoryAustralia
| | - Bryce Vissel
- St Vincent's Hospital Centre for Applied Medical ResearchSt Vincent's HospitalDarlinghurstAustralia
- UNSW Medicine & Health, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and HealthSchool of Clinical Medicine, UNSW SydneySydneyNew South WalesAustralia
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23
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Ocañas SR, Pham KD, Cox JEJ, Keck AW, Ko S, Ampadu FA, Porter HL, Ansere VA, Kulpa A, Kellogg CM, Machalinski AH, Thomas MA, Wright Z, Chucair-Elliott AJ, Freeman WM. Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease. J Neuroinflammation 2023; 20:188. [PMID: 37587511 PMCID: PMC10433617 DOI: 10.1186/s12974-023-02870-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/03/2023] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. METHODS Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. RESULTS There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. CONCLUSIONS These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.
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Affiliation(s)
- Sarah R Ocañas
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kevin D Pham
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Jillian E J Cox
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Alex W Keck
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Sunghwan Ko
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Felix A Ampadu
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Hunter L Porter
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Victor A Ansere
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Adam Kulpa
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Collyn M Kellogg
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Adeline H Machalinski
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Manu A Thomas
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Zsabre Wright
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Ana J Chucair-Elliott
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA
| | - Willard M Freeman
- Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA.
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA.
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24
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Park J, Lee C, Kim YT. Effects of Natural Product-Derived Compounds on Inflammatory Pain via Regulation of Microglial Activation. Pharmaceuticals (Basel) 2023; 16:941. [PMID: 37513853 PMCID: PMC10386117 DOI: 10.3390/ph16070941] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Inflammatory pain is a type of pain caused by tissue damage associated with inflammation and is characterized by hypersensitivity to pain and neuroinflammation in the spinal cord. Neuroinflammation is significantly increased by various neurotransmitters and cytokines that are expressed in activated primary afferent neurons, and it plays a pivotal role in the development of inflammatory pain. The activation of microglia and elevated levels of pro-inflammatory cytokines are the hallmark features of neuroinflammation. During the development of neuroinflammation, various intracellular signaling pathways are activated or inhibited in microglia, leading to the regulation of inflammatory proteins and cytokines. Numerous attempts have been conducted to alleviate inflammatory pain by inhibiting microglial activation. Natural products and their compounds have gained attention as potential candidates for suppressing inflammatory pain due to verified safety through centuries of use. Many studies have also shown that natural product-derived compounds have the potential to suppress microglial activation and alleviate inflammatory pain. Herein, we review the literature on inflammatory mediators and intracellular signaling involved in microglial activation in inflammatory pain, as well as natural product-derived compounds that have been found to suppress microglial activation. This review suggests that natural product-derived compounds have the potential to alleviate inflammatory pain through the suppression of microglial activation.
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Affiliation(s)
- Joon Park
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Republic of Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
- Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
| | - Changho Lee
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Republic of Korea
| | - Yun Tai Kim
- Division of Functional Food Research, Korea Food Research Institute, Wanju 55365, Republic of Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
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25
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Ocañas SR, Pham KD, Cox JEJ, Keck AW, Ko S, Ampadu FA, Porter HL, Ansere VA, Kulpa A, Kellogg CM, Machalinski AH, Chucair-Elliott AJ, Freeman WM. Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.07.531562. [PMID: 36945656 PMCID: PMC10028852 DOI: 10.1101/2023.03.07.531562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Background Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally-and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.
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Affiliation(s)
- Sarah R Ocañas
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Kevin D Pham
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Jillian E J Cox
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Alex W Keck
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Sunghwan Ko
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Felix A Ampadu
- Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Hunter L Porter
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Victor A Ansere
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Adam Kulpa
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Collyn M Kellogg
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
| | - Adeline H Machalinski
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Ana J Chucair-Elliott
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
| | - Willard M Freeman
- Genes & Human Disease Program, Oklahoma Medical Research Foundation, Oklahoma City, OK USA
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK USA
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26
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Caruso G, Di Pietro L, Caraci F. Gap Junctions and Connexins in Microglia-Related Oxidative Stress and Neuroinflammation: Perspectives for Drug Discovery. Biomolecules 2023; 13:biom13030505. [PMID: 36979440 PMCID: PMC10046203 DOI: 10.3390/biom13030505] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/28/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Microglia represent the immune system of the brain. Their role is central in two phenomena, neuroinflammation and oxidative stress, which are at the roots of different pathologies related to the central nervous system (CNS). In order to maintain the homeostasis of the brain and re-establish the equilibrium after a threatening imbalance, microglia communicate with each other and other cells within the CNS by receiving specific signals through membrane-bound receptors and then releasing neurotrophic factors into either the extracellular milieu or directly into the cytoplasm of nearby cells, such as astrocytes and neurons. These last two mechanisms rely on the activity of protein structures that enable the formation of channels in the membrane, namely, connexins and pannexins, that group and form gap junctions, hemichannels, and pannexons. These channels allow the release of gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, together with calcium ion (Ca2+), that seem to play a pivotal role in inter-cellular communication. The aim of the present review is focused on the physiology of channel protein complexes and their contribution to neuroinflammatory and oxidative stress-related phenomena, which play a central role in neurodegenerative disorders. We will then discuss how pharmacological modulation of these channels can impact neuroinflammatory phenomena and hypothesize that currently available nutraceuticals, such as carnosine and N-acetylcysteine, can modulate the activity of connexins and pannexins in microglial cells and reduce oxidative stress in neurodegenerative disorders.
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Affiliation(s)
- Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, 95123 Catania, Italy
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, 94018 Troina, Italy
- Correspondence: ; Tel.: +39-0957385036
| | - Lucia Di Pietro
- Department of Drug and Health Sciences, University of Catania, 95123 Catania, Italy
- Scuola Superiore di Catania, University of Catania, 95123 Catania, Italy
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, 95123 Catania, Italy
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, 94018 Troina, Italy
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27
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Lecca D, Hsueh SC, Luo W, Tweedie D, Kim DS, Baig AM, Vargesson N, Kim YK, Hwang I, Kim S, Hoffer BJ, Chiang YH, Greig NH. Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury. J Biomed Sci 2023; 30:16. [PMID: 36872339 PMCID: PMC9987061 DOI: 10.1186/s12929-023-00907-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/09/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs. METHODS TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions. RESULTS TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice. CONCLUSION TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component.
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Affiliation(s)
- Daniela Lecca
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA
| | - Shih-Chang Hsueh
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA
| | - Weiming Luo
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA
| | - David Tweedie
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA
| | - Dong Seok Kim
- Aevisbio Inc., Gaithersburg, MD, 20878, USA
- Aevis Bio Inc., Daejeon, 34141, Republic of Korea
| | - Abdul Mannan Baig
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, 74800, Pakistan
| | - Neil Vargesson
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK
| | - Yu Kyung Kim
- Aevis Bio Inc., Daejeon, 34141, Republic of Korea
| | - Inho Hwang
- Aevis Bio Inc., Daejeon, 34141, Republic of Korea
| | - Sun Kim
- Aevis Bio Inc., Daejeon, 34141, Republic of Korea
| | - Barry J Hoffer
- Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Yung-Hsiao Chiang
- Neuroscience Research Center, Taipei Medical University, Taipei, 110, Taiwan.
- Department of Neurosurgery, Taipei Medical University Hospital, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
| | - Nigel H Greig
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program National Institute On Aging, NIH, Baltimore, MD, 21224, USA.
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28
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Hamilton J, Nguyen C, McAvoy M, Roeder N, Richardson B, Quattrin T, Hajnal A, Thanos PK. Calorie restriction, but not Roux-en-Y gastric bypass surgery, increases [ 3 H] PK11195 binding in a rat model of obesity. Synapse 2023; 77:e22258. [PMID: 36352528 DOI: 10.1002/syn.22258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 11/11/2022]
Abstract
Roux-en-Y gastric bypass surgery (RYGB) remains an effective weight-loss method used to treat obesity. While it is successful in combating obesity, there are many lingering questions related to the changes in the brain following RYGB surgery, one of them being its effects on neuroinflammation. While it is known that chronic high-fat diet (HFD) contributes to obesity and neuroinflammation, it remains to be understood whether bariatric surgery can ameliorate diet-induced inflammatory responses. To examine this, rats were assigned to either a normal diet (ND) or a HFD for 8 weeks. Rats fed a HFD were split into the following groups: sham surgery with ad libitum access to HFD (sham-HF); sham surgery with calorie-restricted HFD (sham-FR); RYGB surgery with ad libitum access to HFD (RYGB). Following sham or RYGB surgeries, rats were maintained on their diets for 9 weeks before being euthanized. [3 H] PK11195 autoradiography was then performed on fresh-frozen brain tissue in order to measure activated microglia. Sham-FR rats showed increased [3 H] PK11195 binding in the amygdala (63%), perirhinal (60%), and ectorhinal cortex (53%) compared with the ND rats. Obese rats who had the RYGB surgery did not show this increased inflammatory effect. Since the sham-FR and RYGB rats were fed the same amount of HFD, the surgery itself seems responsible for this attenuation in [3 H] PK11195 binding. We speculate that calorie restriction following obese conditions may be seen as a stressor and contribute to inflammation in the brain. Further research is needed to verify this mechanism.
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Affiliation(s)
- John Hamilton
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Cynthia Nguyen
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Margaret McAvoy
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Nicole Roeder
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.,Department of Psychology, University at Buffalo, Buffalo, New York, USA
| | - Brittany Richardson
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.,Department of Psychology, University at Buffalo, Buffalo, New York, USA
| | - Teresa Quattrin
- Department of Pediatrics, University at Buffalo, UBMD Pediatrics, JR Oishei Children's Hospital, Buffalo, New York, USA
| | - Andras Hajnal
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Panayotis K Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.,Department of Psychology, University at Buffalo, Buffalo, New York, USA
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29
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Huang Z, Ding Z, Xu Y, Xi C, He L, Luo H, Guo Q, Huang C. Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve. Front Pharmacol 2023; 14:1069331. [PMID: 36744245 PMCID: PMC9890072 DOI: 10.3389/fphar.2023.1069331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/04/2023] [Indexed: 01/19/2023] Open
Abstract
Regulation of gene transcription in the spinal dorsal horn (SDH) plays a critical role in the pathophysiology of neuropathic pain. In this study, we investigated whether the transcription factor STAT2 affects neuropathic pain and evaluated its possible mechanisms. A proteomic analysis showed that the nuclear fraction of STAT2 protein in the SDH was downregulated after chronic constriction injury of the rat sciatic nerve, which was associated with the development of neuropathic pain. Similarly, siRNA-induced downregulation of STAT2 in the SDH of naïve rats also resulted in pain hypersensitivity. Using RNA-sequencing analysis, we showed that reduction of nuclear STAT2 after chronic constriction injury was associated with increased expression of microglial activation markers, including the class II transactivator and major histocompatibility complex class II proteins. In addition, siRNA-induced downregulation of STAT2 promoted microglial activation and pro-inflammatory cytokine expression in the SDH. Taken together, these results showed that chronic constriction injury caused downregulation of nuclear STAT2 in the SDH, which may result in microglial activation and development of neuropathic pain. Our findings indicate that restoration of nuclear expression of STAT2 could be a potential pathway for the treatment of neuropathic pain.
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Affiliation(s)
- Zhifeng Huang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Zijing Ding
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Yangting Xu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Caiyun Xi
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Liqiong He
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Luo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Changsheng Huang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Changsheng Huang,
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Tobinick E, Spengler RN, Ignatowski TA, Wassel M, Laborde S. Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin 2022; 38:2013-2020. [PMID: 35791687 DOI: 10.1080/03007995.2022.2096351] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. METHODS Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25 mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration. RESULTS Following perispinal etanercept administration there was immediate neurological improvement. At 24 h, there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved. CONCLUSION Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.
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Affiliation(s)
| | | | - Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Manar Wassel
- Institute of Neurological Recovery, Boca Raton, FL, USA
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31
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Yang Y, Zhao X, Zhu Z, Zhang L. Vascular dementia: A microglia's perspective. Ageing Res Rev 2022; 81:101734. [PMID: 36113763 DOI: 10.1016/j.arr.2022.101734] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 08/28/2022] [Accepted: 09/11/2022] [Indexed: 01/31/2023]
Abstract
Vascular dementia (VaD) is a second most common form of age-related dementia. It is characterized by cognitive impairment associated with vascular pathology, symptoms mainly caused by cerebral damage due to inadequate blood flow to the brain. The pathogenesis of VaD is complex, and a growing body of literature emphasizes on the involvement of microglia in disease development and progression. Here, we review the current knowledge on the role of microglia in regulating neuroinflammation under the pathogenesis of VaD. The commonly used animal and cell models for understanding the disease pathogenesis were summarized. The mechanisms by which microglia contribute to VaD are multifactorial, and we specifically focus on some of the predominant functions of microglia, including chemotaxis, secretory property, phagocytosis, and its crosstalk with other neurovascular unit cells. Finally, potential therapeutic strategies targeting microglia-modulated neuroinflammation are discussed.
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Affiliation(s)
- Yi Yang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; Hangzhou Key Laboratory of Medical Neurobiology, Hangzhou Normal University, Hangzhou 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China.
| | - Xinyuan Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; Hangzhou Key Laboratory of Medical Neurobiology, Hangzhou Normal University, Hangzhou 311121, China
| | - Zirui Zhu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; Hangzhou Key Laboratory of Medical Neurobiology, Hangzhou Normal University, Hangzhou 311121, China
| | - Lihui Zhang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; Hangzhou Key Laboratory of Medical Neurobiology, Hangzhou Normal University, Hangzhou 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China.
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32
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Green TRF, Murphy SM, Moreno-Montano MP, Audinat E, Rowe RK. Reactive morphology of dividing microglia following kainic acid administration. Front Neurosci 2022; 16:972138. [PMID: 36248637 PMCID: PMC9556904 DOI: 10.3389/fnins.2022.972138] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
The microglial response to a pathological microenvironment is hallmarked by a change in cellular morphology. Following a pathological stimulus, microglia become reactive and simultaneously divide to create daughter cells. Although a wide array of microglial morphologies has been observed, the exact functions of these distinct morphologies are unknown, as are the morphology and reactivity status of dividing microglia. In this study, we used kainic acid to trigger microglial activation and cell division. Following a cortical kainic acid injection, microglial morphology and proliferation were examined at 3 days post-injection using immunohistochemistry for ionized calcium binding adapter molecule 1 (Iba1) to stain for microglia, and KI67 as a marker of cell division. Individual microglial cells were isolated from photomicrographs and skeletal and fractal analyses were used to examine cell size and spatial complexity. We examined the morphology of microglia in both wildtype and microglia-specific tumor necrosis factor (TNF)-α knockout mice. Data were analyzed using generalized linear mixed models or a two-way ANOVA. We found that dividing microglia had a more reactive morphology (larger cell body area, longer cell perimeter, and less ramification) compared to microglia that were not dividing, regardless of microglial release of TNF-α. However, we also observed dividing microglia with a complex, more ramified morphology. Changes in microglial morphology and division were greatest near the kainic acid injection site. This study uses robust and quantitative techniques to better understand microglial cell division, morphology, and population dynamics, which are essential for the development of novel therapeutics that target microglia.
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Affiliation(s)
- Tabitha R. F. Green
- Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, United States
| | - Sean M. Murphy
- Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, United States
| | - Maria P. Moreno-Montano
- Institute of Functional Genomics (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Etienne Audinat
- Institute of Functional Genomics (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Rachel K. Rowe
- Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, United States
- Department of Integrative Physiology, University of Colorado, Boulder, CO, United States
- *Correspondence: Rachel K. Rowe,
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33
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Gabrielli M, Raffaele S, Fumagalli M, Verderio C. The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after? Front Cell Neurosci 2022; 16:984690. [PMID: 36176630 PMCID: PMC9514840 DOI: 10.3389/fncel.2022.984690] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/23/2022] [Indexed: 11/30/2022] Open
Abstract
As resident component of the innate immunity in the central nervous system (CNS), microglia are key players in pathology. However, they also exert fundamental roles in brain development and homeostasis maintenance. They are extremely sensitive and plastic, as they assiduously monitor the environment, adapting their function in response to stimuli. On consequence, microglia may be defined a heterogeneous community of cells in a dynamic equilibrium. Extracellular vesicles (EVs) released by microglia mirror the dynamic nature of their donor cells, exerting important and versatile functions in the CNS as unbounded conveyors of bioactive signals. In this review, we summarize the current knowledge on EVs released by microglia, highlighting their heterogeneous properties and multifaceted effects.
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Affiliation(s)
- Martina Gabrielli
- CNR Institute of Neuroscience, Vedano al Lambro, Italy
- *Correspondence: Martina Gabrielli,
| | - Stefano Raffaele
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Marta Fumagalli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Claudia Verderio
- CNR Institute of Neuroscience, Vedano al Lambro, Italy
- Claudia Verderio,
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34
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Microglia and microglial-based receptors in the pathogenesis and treatment of Alzheimer’s disease. Int Immunopharmacol 2022; 110:109070. [DOI: 10.1016/j.intimp.2022.109070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/02/2022] [Accepted: 07/14/2022] [Indexed: 11/23/2022]
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Pediaditakis I, Kodella KR, Manatakis DV, Le CY, Barthakur S, Sorets A, Gravanis A, Ewart L, Rubin LL, Manolakos ES, Hinojosa CD, Karalis K. A microengineered Brain-Chip to model neuroinflammation in humans. iScience 2022; 25:104813. [PMID: 35982785 PMCID: PMC9379671 DOI: 10.1016/j.isci.2022.104813] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/10/2022] [Accepted: 07/18/2022] [Indexed: 11/30/2022] Open
Abstract
Species differences in brain and blood-brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding the development of therapeutics for brain diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels. This human Brain-Chip engineered to recapitulate critical aspects of the complex interactions that mediate neuroinflammation and demonstrates significant improvements in clinical mimicry compared to previously reported similar MPS. In comparison to Transwell culture, the transcriptomic profiling of the Brain-Chip displayed significantly advanced similarity to the human adult cortex and enrichment in key neurobiological pathways. Exposure to TNF-α recreated the anticipated inflammatory environment shown by glia activation, increased release of proinflammatory cytokines, and compromised barrier permeability. We report the development of a robust brain MPS for mechanistic understanding of cell-cell interactions and BBB function during neuroinflammation.
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Affiliation(s)
| | - Konstantia R. Kodella
- Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
- University of Crete Medical School, Department of Pharmacology, Heraklion, 71110 Greece
| | | | | | | | | | - Achille Gravanis
- University of Crete Medical School, Department of Pharmacology, Heraklion, 71110 Greece
| | - Lorna Ewart
- Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
| | - Lee L. Rubin
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Elias S. Manolakos
- Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, Greece
- Northeastern University, Bouvé College of Health Sciences, Boston, MA, USA
| | | | - Katia Karalis
- Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
- Endocrine Division, Children’s Hospital, Harvard Medical School, Boston, MA, USA
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36
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The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study. BIOLOGY 2022; 11:biology11060939. [PMID: 35741460 PMCID: PMC9220050 DOI: 10.3390/biology11060939] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/30/2022] [Accepted: 06/17/2022] [Indexed: 11/25/2022]
Abstract
Simple Summary The neuroinflammatory response is a rather complex event in spinal cord injury (SCI) and has the capacity to exacerbate cell damage but also to contribute to the repair of the injury. This complexity is thought to depend on a variety of inflammatory mediators, of which tumor necrosis factor (TNF) plays a key role. Evidence indicates that TNF can be both protective and detrimental in SCI. In the present study, we studied the temporal and cellular expression of TNF and its receptors after SCI in mice. We found TNF to be significantly increased in both the acute and the delayed phases after SCI, alongside a robust neuroinflammatory response. As we could verify some of our results in human postmortem tissue, our results imply that diminishing the detrimental immune signaling after SCI could also enhance recovery in humans. Abstract Spinal cord injury (SCI) initiates detrimental cellular and molecular events that lead to acute and delayed neuroinflammation. Understanding the role of the inflammatory response in SCI requires insight into the temporal and cellular synthesis of inflammatory mediators. We subjected C57BL/6J mice to SCI and investigated inflammatory reactions. We examined activation, recruitment, and polarization of microglia and infiltrating immune cells, focusing specifically on tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2. In the acute phase, TNF expression increased in glial cells and neuron-like cells, followed by infiltrating immune cells. TNFR1 and TNFR2 levels increased in the delayed phase and were found preferentially on neurons and glial cells, respectively. The acute phase was dominated by the infiltration of granulocytes and macrophages. Microglial/macrophage expression of Arg1 increased from 1–7 days after SCI, followed by an increase in Itgam, Cx3cr1, and P2ry12, which remained elevated throughout the study. By 21 and 28 days after SCI, the lesion core was populated by galectin-3+, CD68+, and CD11b+ microglia/macrophages, surrounded by a glial scar consisting of GFAP+ astrocytes. Findings were verified in postmortem tissue from individuals with SCI. Our findings support the consensus that future neuroprotective immunotherapies should aim to selectively neutralize detrimental immune signaling while sustaining pro-regenerative processes.
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia.
AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ.
METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA).
RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = −0.4972, P = 0.001), PANSS-PSS (r = −0.4034, P = 0.028), and PANSS-NSS (r = −0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia.
CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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38
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Liu T, Xu Y, Yi CX, Tong Q, Cai D. The hypothalamus for whole-body physiology: from metabolism to aging. Protein Cell 2022; 13:394-421. [PMID: 33826123 PMCID: PMC9095790 DOI: 10.1007/s13238-021-00834-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/01/2021] [Indexed: 01/05/2023] Open
Abstract
Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.
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Affiliation(s)
- Tiemin Liu
- grid.8547.e0000 0001 0125 2443State Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, Institute of Metabolism and Integrative Biology, Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, 200438 China
| | - Yong Xu
- grid.39382.330000 0001 2160 926XChildren’s Nutrition Research Center, Department of Pediatrics, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
| | - Chun-Xia Yi
- grid.7177.60000000084992262Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, Netherlands
| | - Qingchun Tong
- grid.453726.10000 0004 5906 7293Brown Foundation Institute of Molecular Medicine, Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Graduate Program in Neuroscience of MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030 USA
| | - Dongsheng Cai
- grid.251993.50000000121791997Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 USA
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Clark IA. Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic. Pharmacol Res Perspect 2022; 10:e00926. [PMID: 35174650 PMCID: PMC8850677 DOI: 10.1002/prp2.926] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 12/15/2022] Open
Abstract
The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions. The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.
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Affiliation(s)
- Ian Albert Clark
- Research School of BiologyAustralian National UniversityCanberraACTAustralia
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40
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Wang SK, Cepko CL. Targeting Microglia to Treat Degenerative Eye Diseases. Front Immunol 2022; 13:843558. [PMID: 35251042 PMCID: PMC8891158 DOI: 10.3389/fimmu.2022.843558] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 01/31/2022] [Indexed: 12/29/2022] Open
Abstract
Microglia have been implicated in many degenerative eye disorders, including retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, uveitis, and retinal detachment. While the exact roles of microglia in these conditions are still being discovered, evidence from animal models suggests that they can modulate the course of disease. In this review, we highlight current strategies to target microglia in the eye and their potential as treatments for both rare and common ocular disorders. These approaches include depleting microglia with chemicals or radiation, reprogramming microglia using homeostatic signals or other small molecules, and inhibiting the downstream effects of microglia such as by blocking cytokine activity or phagocytosis. Finally, we describe areas of future research needed to fully exploit the therapeutic value of microglia in eye diseases.
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Affiliation(s)
- Sean K. Wang
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Constance L. Cepko
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
- Howard Hughes Medical Institute, Chevy Chase, MD, United States
- *Correspondence: Constance L. Cepko,
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41
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Miola A, Dal Porto V, Meda N, Perini G, Solmi M, Sambataro F. Secondary Mania induced by TNF-α inhibitors: A systematic review. Psychiatry Clin Neurosci 2022; 76:15-21. [PMID: 34590391 PMCID: PMC9298409 DOI: 10.1111/pcn.13302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/09/2021] [Accepted: 09/13/2021] [Indexed: 12/01/2022]
Abstract
A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor necrosis factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes. PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Out of the initial 75 references, the screening resulted in the inclusion of four case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600-0.53% - experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept. These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.
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Affiliation(s)
- Alessandro Miola
- Department of Neuroscience, University of Padova, Padova, Italy.,Padova Neuroscience Center, University of Padova, Padova, Italy.,Casa di Cura Parco dei Tigli, Padova, Italy
| | | | - Nicola Meda
- Department of Medicine, University of Padova, Padova, Italy
| | - Giulia Perini
- Department of Neuroscience, University of Padova, Padova, Italy.,Padova Neuroscience Center, University of Padova, Padova, Italy.,Casa di Cura Parco dei Tigli, Padova, Italy
| | - Marco Solmi
- Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.,Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute (OHRI), University of Ottawa, Ottawa, ON, Canada
| | - Fabio Sambataro
- Department of Neuroscience, University of Padova, Padova, Italy.,Padova Neuroscience Center, University of Padova, Padova, Italy
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Brás JP, Guillot de Suduiraut I, Zanoletti O, Monari S, Meijer M, Grosse J, Barbosa MA, Santos SG, Sandi C, Almeida MI. Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood. Brain Behav Immun 2022; 99:397-408. [PMID: 34793941 DOI: 10.1016/j.bbi.2021.10.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/22/2021] [Accepted: 10/31/2021] [Indexed: 12/27/2022] Open
Abstract
Neuroinflammation is increasingly recognized as playing a critical role in depression. Early-life stress exposure and constitutive differences in glucocorticoid responsiveness to stressors are two key risk factors for depression, but their impacts on the inflammatory status of the brain is still uncertain. Moreover, there is a need to identify specific molecules involved in these processes with the potential to be used as alternative therapeutic targets in inflammation-related depression. Here, we studied how peripubertal stress (PPS) combined with differential corticosterone (CORT)-stress responsiveness (CSR) influences depressive-like behaviors and brain inflammatory markers in male rats in adulthood, and how these alterations relate to microglia activation and miR-342 expression. We found that high-CORT stress-responsive (H-CSR) male rats that underwent PPS exhibited increased anhedonia and passive coping responses in adulthood. Also, animals exposed to PPS showed increased hippocampal TNF-α expression, which positively correlated with passive coping responses. In addition, PPS caused long-term effects on hippocampal microglia, particularly in H-CSR rats, with increased hippocampal IBA-1 expression and morphological alterations compatible with a higher degree of activation. H-CSR animals also showed upregulation of hippocampal miR-342, a mediator of TNF-α-driven microglial activation, and its expression was positively correlated with TNF-α expression, microglial activation and passive coping responses. Our findings indicate that individuals with constitutive H-CSR are particularly sensitive to developing protracted depression-like behaviors following PPS exposure. In addition, they show neuro-immunological alterations in adulthood, such as increased hippocampal TNF-α expression, microglial activation and miR-342 expression. Our work highlights miR-342 as a potential therapeutic target in inflammation-related depression.
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Affiliation(s)
- João Paulo Brás
- Instituto de Investigação e Inovação em Saúde/Instituto de Engenharia Biomédica (i3S/INEB), University of Porto (UP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
| | | | - Olivia Zanoletti
- Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
| | - Silvia Monari
- Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
| | - Mandy Meijer
- Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jocelyn Grosse
- Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
| | - Mário Adolfo Barbosa
- Instituto de Investigação e Inovação em Saúde/Instituto de Engenharia Biomédica (i3S/INEB), University of Porto (UP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Susana Gomes Santos
- Instituto de Investigação e Inovação em Saúde/Instituto de Engenharia Biomédica (i3S/INEB), University of Porto (UP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Carmen Sandi
- Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
| | - Maria Inês Almeida
- Instituto de Investigação e Inovação em Saúde/Instituto de Engenharia Biomédica (i3S/INEB), University of Porto (UP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
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43
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Murchison AG. Hypothesis: Modulation of microglial phenotype in Alzheimer's disease drives neurodegeneration. Alzheimers Dement 2021; 18:1537-1544. [PMID: 34786841 DOI: 10.1002/alz.12503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 11/11/2022]
Abstract
The pathophysiology of Alzheimer's disease (AD) remains to be elucidated. The amyloid hypothesis holds explanatory power but has limitations. This article suggests that amyloid deposition and increased permeability of the blood-brain barrier are independent early events in the disease process, which together fashion a distinct microglial activation phenotype. Downstream events including, phagocytosis of synapses and persistent glutamate signaling through N-methyl-D-aspartate receptors drive neurodegeneration and tau pathology. This hypothesis draws on several strands of evidence and aims to illuminate several of the unexplained temporal and spatial features of AD.
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44
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Fairless R, Bading H, Diem R. Pathophysiological Ionotropic Glutamate Signalling in Neuroinflammatory Disease as a Therapeutic Target. Front Neurosci 2021; 15:741280. [PMID: 34744612 PMCID: PMC8567076 DOI: 10.3389/fnins.2021.741280] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/30/2021] [Indexed: 01/15/2023] Open
Abstract
Glutamate signalling is an essential aspect of neuronal communication involving many different glutamate receptors, and underlies the processes of memory, learning and synaptic plasticity. Despite neuroinflammatory diseases covering a range of maladies with very different biological causes and pathophysiologies, a central role for dysfunctional glutamate signalling is becoming apparent. This is not just restricted to the well-described role of glutamate in mediating neurodegeneration, but also includes a myriad of other influences that glutamate can exert on the vasculature, as well as immune cell and glial regulation, reflecting the ability of neurons to communicate with these compartments in order to couple their activity with neuronal requirements. Here, we discuss the role of pathophysiological glutamate signalling in neuroinflammatory disease, using both multiple sclerosis and Alzheimer's disease as examples, and how current steps are being made to harness our growing understanding of these processes in the development of neuroprotective strategies. This review focuses in particular on N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisooxazol-4-yl) propionate (AMPA) type ionotropic glutamate receptors, although metabotropic, G-protein-coupled glutamate receptors may also contribute to neuroinflammatory processes. Given the indispensable roles of glutamate-gated ion channels in synaptic communication, means of pharmacologically distinguishing between physiological and pathophysiological actions of glutamate will be discussed that allow deleterious signalling to be inhibited whilst minimising the disturbance of essential neuronal function.
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Affiliation(s)
- Richard Fairless
- Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hilmar Bading
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Ricarda Diem
- Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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45
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Clark IA. How diseases caused by parasites allowed a wider understanding of disease in general: my encounters with parasitology in Australia and elsewhere over the last 50 years. Int J Parasitol 2021; 51:1265-1276. [PMID: 34757090 DOI: 10.1016/j.ijpara.2021.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 09/18/2021] [Accepted: 10/13/2021] [Indexed: 12/18/2022]
Abstract
This is an account of how it can prove possible to carve a reasonable scientific career by following what brought most scientific thrill rather than pursue a safe, institution-directed, path. The fascination began when I noticed, quite unexpectedly, that the normal mouse immune response causes Babesia microti to die, en masse, inside circulating red cells. It eventuated that prior Bacillus Calmette Guerin infection caused the same outcome, even before the protozoal infection became patent. It also rendered mice quite immune, long term. I acquired an obsession about this telling us how little we know. Surrounded by basic immunologists, parasitologists and virologists in London, I had been given, in the days that funding was ample, the opportunity to follow any promising lead with a free hand. Through Bacillus Calmette Guerin, this meant stumbling through a set of phenomena that were in their infancies, and could be explained only through nebulous novel soluble mediators such as TNF, described the following year as causing the in vivo necrosis of tumours in mice. Beginning with malarial disease pathogenesis, I followed TNF wherever it led, into innate immunity, acute and chronic infections, neurophysiology and neurodegenerative diseases, in all of which states awareness of the role of this cytokine is still growing fast. Many of these steps can be illustrated and expanded upon in parasitic diseases. Covering the importance of TNF in the pathogenesis of neurodegenerative disease has proved to be highly illuminating, scientifically and otherwise. But the insights it has given me into understanding the temptations to which patent-owners can succumb when faced with opportunities to put money before people is not for the faint hearted. Clearly, parasitologists inhabit a much more common-good yet science-orientated, civilised, world.
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Affiliation(s)
- Ian A Clark
- Biomedical Sciences and Biochemistry, Research School of Biology, Australian National University, Canberra, ACT 2601, Australia.
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Clark IA. Background to new treatments for COVID-19, including its chronicity, through altering elements of the cytokine storm. Rev Med Virol 2021; 31:1-13. [PMID: 33580566 PMCID: PMC7883210 DOI: 10.1002/rmv.2210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022]
Abstract
Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.
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Affiliation(s)
- Ian A. Clark
- Research School of BiologyAustralian National UniversityCanberraAustralia
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47
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Alexaki VI. The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives. Cells 2021; 10:cells10071584. [PMID: 34201844 PMCID: PMC8307603 DOI: 10.3390/cells10071584] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in it. The present review discusses the effects of obesity, chronic peripheral inflammation and obesity-associated metabolic and endocrine perturbations, including insulin resistance, dyslipidemia and increased glucocorticoid levels, on microglial function.
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Affiliation(s)
- Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
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48
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El-Derany MO, Noureldein MH. Bone marrow mesenchymal stem cells and their derived exosomes resolve doxorubicin-induced chemobrain: critical role of their miRNA cargo. Stem Cell Res Ther 2021; 12:322. [PMID: 34090498 PMCID: PMC8180158 DOI: 10.1186/s13287-021-02384-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Background Doxorubicin (DOX), a widely used chemotherapeutic agent, can cause neurodegeneration in the brain, which leads to a condition known as chemobrain. In fact, chemobrain is a deteriorating condition which adversely affects the lives of cancer survivors. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) and their derived exosomes (BMSCs-Exo) in DOX-induced chemobrain in rat models. Methods Chemobrain was induced by exposing rats to DOX (2 mg/kg, i.p) once weekly for 4 consecutive weeks. After 48 h of the last DOX dose, a subset of rats was supplied with either an intravenous injection of BMSCs (1 × 106) or a single dose of 150 μg of BMSCs-Exo. Behavioral tests were conducted 7 days post injection. Rats were sacrificed after 14 days from BMSCs or BMSCs-Exo injection. Results BMSCs and BMSCs-Exo successfully restored DOX-induced cognitive and behavioral distortion. These actions were mediated via decreasing hippocampal neurodegeneration and neural demyelination through upregulating neural myelination factors (myelin%, Olig2, Opalin expression), neurotropic growth factors (BDNF, FGF-2), synaptic factors (synaptophysin), and fractalkine receptor expression (Cx3cr1). Halting neurodegeneration in DOX-induced chemobrain was achieved through epigenetic induction of key factors in Wnt/β-catenin and hedgehog signaling pathways mediated primarily by the most abundant secreted exosomal miRNAs (miR-21-5p, miR-125b-5p, miR-199a-3p, miR-24-3p, let-7a-5p). Moreover, BMSCs and BMSCs-Exo significantly abrogate the inflammatory state (IL-6, TNF-α), apoptotic state (BAX/Bcl2), astrocyte, and microglia activation (GFAP, IBA-1) in DOX-induced chemobrain with a significant increase in the antioxidant mediators (GSH, GPx, SOD activity). Conclusions BMSCs and their derived exosomes offer neuroprotection against DOX-induced chemobrain via genetic and epigenetic abrogation of hippocampal neurodegeneration through modulating Wnt/β-catenin and hedgehog signaling pathways and through reducing inflammatory, apoptotic, and oxidative stress state. Graphical abstract Proposed mechanisms of the protective effects of bone marrow stem cells (BMSCs) and their exosomes (BMSCs-Exo) in doxorubicin (DOX)-induced chemobrain. Blue arrows: induce. Red arrows: inhibit.
![]() Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02384-9.
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Affiliation(s)
- Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
| | - Mohamed H Noureldein
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,American University of Beirut Diabetes Program, Beirut, Lebanon
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49
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Tang J, Bair M, Descalzi G. Reactive Astrocytes: Critical Players in the Development of Chronic Pain. Front Psychiatry 2021; 12:682056. [PMID: 34122194 PMCID: PMC8192827 DOI: 10.3389/fpsyt.2021.682056] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Chronic pain is associated with long term plasticity of nociceptive pathways in the central nervous system. Astrocytes can profoundly affect synaptic function and increasing evidence has highlighted how altered astrocyte activity may contribute to the pathogenesis of chronic pain. In response to injury, astrocytes undergo a shift in form and function known as reactive astrogliosis, which affects their release of cytokines and gliotransmitters. These neuromodulatory substances have been implicated in driving the persistent changes in central nociceptive activity. Astrocytes also release lactate which neurons can use to produce energy during synaptic plasticity. Furthermore, recent research has provided insight into lactate's emerging role as a signaling molecule in the central nervous system, which may be involved in directly modulating neuronal and astrocytic activity. In this review, we present evidence for the involvement of astrocyte-derived tumor necrosis factor alpha in pain-associated plasticity, in addition to research suggesting the potential involvement of gliotransmitters D-serine and adenosine-5'-triphosphate. We also discuss work implicating astrocyte-neuron metabolic coupling, and the possible role of lactate, which has been sparsely studied in the context of chronic pain, in supporting pathological changes in central nociceptive activity.
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Affiliation(s)
| | | | - Giannina Descalzi
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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50
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Xu JJ, Guo S, Xue R, Xiao L, Kou JN, Liu YQ, Han JY, Fu JJ, Wei N. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging (Albany NY) 2021; 13:14001-14014. [PMID: 34030135 PMCID: PMC8202885 DOI: 10.18632/aging.203009] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/05/2021] [Indexed: 01/31/2023]
Abstract
Vascular dementia (VaD) is the second most common type of dementia worldwide. Although there are five FDA-approved drugs for the treatment of Alzheimer's disease (AD), none of them have been applied to treat VaD. Adalimumab is a TNF-α inhibitor that is used for the treatment of autoimmune diseases such as rheumatoid arthritis. In a recent retrospective case-control study, the application of adalimumab for rheumatoid or psoriasis was shown to decrease the risk of AD. However, whether adalimumab can be used for the treatment of VaD is not clear. In this study, we used 2VO surgery to generate a VaD rat model and treated the rats with adalimumab or vehicle. We demonstrated that VaD rats treated with adalimumab exhibited significant improvements in memory. In addition, adalimumab treatment significantly alleviated neuronal loss in the hippocampi of VaD rats. Moreover, adalimumab significantly reduced microglial activation and reversed M1/M2 polarization in VaD rats. Furthermore, adalimumab treatment suppressed the activity of NF-κB, an important neuroinflammatory transcription factor. Finally, adalimumab displayed a protective role against oxidative stress in VaD rats. Our results indicate that adalimumab may be applied for the treatment of human patients with VaD.
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Affiliation(s)
- Jing-Jing Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou 450002, People’s Republic of China
- Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Si Guo
- Department of Medical Laboratory, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, People’s Republic of China
- Department of Medical Laboratory of Central China Fuwai Hospital, Zhengzhou, Henan 450003, People’s Republic of China
- Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan 450003, People’s Republic of China
| | - Rui Xue
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Lin Xiao
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou 450002, People’s Republic of China
- Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Jun-Na Kou
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou 450002, People’s Republic of China
- Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Yu-Qiong Liu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou 450002, People’s Republic of China
- Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Jun-Ya Han
- Department of Pathology, People’s Hospital of Zhengzhou, Zhengzhou 450000, People’s Republic of China
| | - Jing-Jie Fu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
| | - Na Wei
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou 450002, People’s Republic of China
- Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450002, People’s Republic of China
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