|
1
|
Kandy AT, Chand J, Baba MZ, Subramanian G. Is SIRT3 and Mitochondria a Reliable Target for Parkinson's Disease and Aging? A Narrative Review. Mol Neurobiol 2025; 62:6898-6912. [PMID: 39287746 DOI: 10.1007/s12035-024-04486-w] [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: 03/13/2024] [Accepted: 09/09/2024] [Indexed: 09/19/2024]
Abstract
Aging is a complicated degenerative process that has been thoroughly researched in a variety of taxa, including mammals, worms, yeast, and flies. One important controller of organismal lifetime is the conserved deacetylase protein known as silencing information regulator 2 (SIR2). It has been demonstrated that overexpressing SIR2 lengthens the life span in worms, flies, and yeast, demonstrating its function in enhancing longevity. SIRT3 is a member of the sirtuin protein family, identified as a major regulator of longevity and aging. Sirtuin 3 (SIRT3), a possible mitochondrial tumor suppressor, has been explicitly linked to the control of cellular reactive oxygen species (ROS) levels, the Warburg effect, and carcinogenesis. SIRT3 plays a significant part in neurodegenerative illnesses such as Parkinson's and Alzheimer's disease by decreasing the oxidative stress in mitochondria and reducing the ROS levels. Furthermore, SIRT3 has been linked to metabolic and cardiovascular disorders, indicating its wider role in the pathophysiology of disease and possible therapeutic applications.
Collapse
Affiliation(s)
- Amarjith Thiyyar Kandy
- Department of Pharmaceutical Chemistry, JSS College Of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu-643001, India
| | - Jagdish Chand
- Department of Pharmaceutical Chemistry, JSS College Of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu-643001, India
| | - Mohammad Zubair Baba
- Department of Pharmaceutical Chemistry, JSS College Of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu-643001, India
| | - Gomathy Subramanian
- Department of Pharmaceutical Chemistry, JSS College Of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu-643001, India.
| |
Collapse
|
|
2
|
Gruenbaum BF, Merchant KS, Zlotnik A, Boyko M. Gut Microbiome Modulation of Glutamate Dynamics: Implications for Brain Health and Neurotoxicity. Nutrients 2024; 16:4405. [PMID: 39771027 PMCID: PMC11677762 DOI: 10.3390/nu16244405] [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: 11/22/2024] [Revised: 12/07/2024] [Accepted: 12/20/2024] [Indexed: 01/05/2025] Open
Abstract
The gut-brain axis plays an integral role in maintaining overall health, with growing evidence suggesting its impact on the development of various neuropsychiatric disorders, including depression. This review explores the complex relationship between gut microbiota and glutamate (Glu) regulation, highlighting its effect on brain health, particularly in the context of depression following certain neurological insults. We discuss how microbial populations can either facilitate or limit Glu uptake, influencing its bioavailability and predisposing to neuroinflammation and neurotoxicity. Additionally, we examine the role of gut metabolites and their influence on the blood-brain barrier and neurotransmitter systems involved in mood regulation. The therapeutic potential of microbiome-targeted interventions, such as fecal microbiota transplantation, is also highlighted. While much research has explored the role of Glu in major depressive disorders and other neurological diseases, the contribution of gut microbiota in post-neurological depression remains underexplored. Future research should focus on explaining the mechanisms linking the gut microbiota to neuropsychiatric outcomes, particularly in conditions such as post-stroke depression, post-traumatic brain-injury depression, and epilepsy-associated depression. Systematic reviews and human clinical studies are needed to establish causal relationships and assess the efficacy of microbiome-targeted therapies in improving the neuropsychiatric sequalae after neurological insults.
Collapse
Affiliation(s)
- Benjamin F. Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Kiran S. Merchant
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel; (A.Z.); (M.B.)
| | - Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel; (A.Z.); (M.B.)
| |
Collapse
|
|
3
|
Wart M, Edwards TH, Rizzo JA, Peitz GW, Pigott A, Levine JM, Jeffery ND. Traumatic brain injury in companion animals: Pathophysiology and treatment. Top Companion Anim Med 2024; 63:100927. [PMID: 39461414 DOI: 10.1016/j.tcam.2024.100927] [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: 06/14/2024] [Revised: 10/01/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Abstract
Traumatic brain injuries (TBI) are common in dogs and cats that have sustained head trauma from a variety of causes. In moderate to severe TBI, damage from both the primary and secondary injuries can be life-threatening. TBI management may be further complicated by concurrent injuries in polytrauma patients. Thorough initial and serial examinations are key in detecting neurologic changes quickly and guiding treatment. Intensive treatments such as nursing care, fluid therapy, hyperosmolar agents, analgesia, sedation, anticonvulsants, oxygen supplementation, surgery, and rehabilitation may be employed in TBI management. Prognostication resources for an individual patient are limited and a perceived poor prognosis may worsen clinical outcomes. In this paper, we review the pathophysiology of TBI, identification, injury stratification and prognosis of patients with TBI as well as propose treatment and monitoring recommendations for companion animals based on severity of TBI.
Collapse
Affiliation(s)
- Molly Wart
- School of Veterinary Medicine, Texas A&M University, College Station, TX.
| | - Thomas H Edwards
- School of Veterinary Medicine, Texas A&M University, College Station, TX; US Army Institute of Surgical Research, JBSA Fort Sam Houston, TX
| | - Julie A Rizzo
- Brooke Army Medical Center, JBSA Fort Sam Houston, TX
| | | | - Armi Pigott
- College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Jonathan M Levine
- School of Veterinary Medicine, Texas A&M University, College Station, TX
| | - Nicholas D Jeffery
- School of Veterinary Medicine, Texas A&M University, College Station, TX
| |
Collapse
|
|
4
|
Zima L, Moore AN, Smolen P, Kobori N, Noble B, Robinson D, Hood KN, Homma R, Al Mamun A, Redell JB, Dash PK. The evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies. Neurochem Int 2024; 180:105874. [PMID: 39366429 PMCID: PMC12011104 DOI: 10.1016/j.neuint.2024.105874] [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: 07/24/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024]
Abstract
Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.
Collapse
Affiliation(s)
- Laura Zima
- Departments of Neurosurgery, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Anthony N Moore
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Paul Smolen
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Nobuhide Kobori
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Brian Noble
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Dustin Robinson
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Kimberly N Hood
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Ryota Homma
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Amar Al Mamun
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - John B Redell
- Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Pramod K Dash
- Departments of Neurosurgery, The University of Texas McGovern Medical School, Houston, TX, USA; Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA.
| |
Collapse
|
|
5
|
Bakaeva Z, Goncharov M, Frolov F, Krasilnikova I, Sorokina E, Zgodova A, Smolyarchuk E, Zavadskiy S, Andreeva L, Myasoedov N, Fisenko A, Savostyanov K. Regulatory Peptide Pro-Gly-Pro Accelerates Neuroregeneration of Primary Neuroglial Culture after Mechanical Injury in Scratch Test. Int J Mol Sci 2024; 25:10886. [PMID: 39456669 PMCID: PMC11507231 DOI: 10.3390/ijms252010886] [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: 09/13/2024] [Revised: 09/29/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
The scratch test is used as an experimental in vitro model of mechanical damage to primary neuronal cultures to study the mechanisms of cell death in damaged areas. The involvement of NMDA receptors in processes leading to delayed neuronal death, due to calcium dysregulation and synchronous mitochondrial depolarization, has been previously demonstrated. In this study, we explored the neuroregenerative potential of Pro-Gly-Pro (PGP)-an endogenous regulatory peptide with neuroprotective and anti-inflammatory properties and a mild chemoattractant effect. Mechanical injury to the primary neuroglial culture in the form of a scratch caused acute disruption of calcium homeostasis and mitochondrial functions. This was accompanied by neuronal death alongside changes in the profile of neuronal markers (BDNF, NSE and GFAP). In another series of experiments, under subtoxic doses of glutamate (Glu, 33 μM), delayed changes in [Ca2+]i and ΔΨm, i.e., several days after scratch application, were more pronounced in cells in damaged neuroglial cultures. The percentage of cells that restored the initial level of [Ca2+]i (p < 0.05) and the rate of recovery of ΔΨm (p < 0.01) were decreased compared with undamaged cells. Prophylactic application of PGP (100 μM, once) prevented the increase in [Ca2+]i and the sharp drop in mitochondrial potential [ΔΨm] at the time of scratching. Treatment with PGP (30 μM, three or six days) reduced the delayed Glu-induced disturbances in calcium homeostasis and cell death. In the post-glutamate period, the surviving neurons more effectively restored the initial levels of [Ca2+]i (p < 0.001) and Ψm (p < 0.0001). PGP also increased intracellular levels of BDNF and reduced extracellular NSE. In the context of the peptide's therapeutic effect, the recovery of the damaged neuronal network occurred faster due to reduced astrogliosis and increased migration of neurons to the scratch area. Thus, the peptide PGP has a neuroprotective effect, increasing the survival of neuroglial cells after mechanical trauma in vitro by reducing cellular calcium overload and preventing mitochondrial dysfunction. Additionally, the tripeptide limits the post-traumatic consequences of mechanical damage: it reduces astrogliosis and promotes neuronal regeneration.
Collapse
Affiliation(s)
- Zanda Bakaeva
- National Medical Research Center of Children’s Health, 119296 Moscow, Russia; (I.K.); (E.S.)
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (F.F.); (E.S.)
- Kalmyk State University Named after B.B. Gorodovikov, 358000 Elista, Russia
| | - Mikhail Goncharov
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany;
| | - Fyodor Frolov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (F.F.); (E.S.)
| | - Irina Krasilnikova
- National Medical Research Center of Children’s Health, 119296 Moscow, Russia; (I.K.); (E.S.)
| | - Elena Sorokina
- National Medical Research Center of Children’s Health, 119296 Moscow, Russia; (I.K.); (E.S.)
| | - Arina Zgodova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (F.F.); (E.S.)
| | - Elena Smolyarchuk
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (F.F.); (E.S.)
| | - Sergey Zavadskiy
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (F.F.); (E.S.)
| | - Liudmila Andreeva
- National Research Centre «Kurchatov Institute» (NRC «Kurchatov Institute»), 123182 Moscow, Russia; (L.A.); (N.M.)
| | - Nikolai Myasoedov
- National Research Centre «Kurchatov Institute» (NRC «Kurchatov Institute»), 123182 Moscow, Russia; (L.A.); (N.M.)
| | - Andrey Fisenko
- National Medical Research Center of Children’s Health, 119296 Moscow, Russia; (I.K.); (E.S.)
| | - Kirill Savostyanov
- National Medical Research Center of Children’s Health, 119296 Moscow, Russia; (I.K.); (E.S.)
| |
Collapse
|
|
6
|
Hasanpour-Segherlou Z, Masheghati F, Shakeri-Darzehkanani M, Hosseini-Siyanaki MR, Lucke-Wold B. Neurodegenerative Disorders in the Context of Vascular Changes after Traumatic Brain Injury. JOURNAL OF VASCULAR DISEASES 2024; 3:319-332. [DOI: 10.3390/jvd3030025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2025]
Abstract
Traumatic brain injury (TBI) results from external biomechanical forces that cause structural and physiological disturbances in the brain, leading to neuronal, axonal, and vascular damage. TBIs are predominantly mild (65%), with moderate (10%) and severe (25%) cases also prevalent. TBI significantly impacts health, increasing the risk of neurodegenerative diseases such as dementia, post injury. The initial phase of TBI involves acute disruption of the blood–brain barrier (BBB) due to vascular shear stress, leading to ischemic damage and amyloid-beta accumulation. Among the acute cerebrovascular changes after trauma are early progressive hemorrhage, micro bleeding, coagulopathy, neurovascular unit (NVU) uncoupling, changes in the BBB, changes in cerebral blood flow (CBF), and cerebral edema. The secondary phase is characterized by metabolic dysregulation and inflammation, mediated by oxidative stress and reactive oxygen species (ROS), which contribute to further neurodegeneration. The cerebrovascular changes and neuroinflammation include excitotoxicity from elevated extracellular glutamate levels, coagulopathy, NVU, immune responses, and chronic vascular changes after TBI result in neurodegeneration. Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury. There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes. Also, the patterns of cerebrovascular dysfunction and stroke vulnerability after TBI are different in males and females based on animal studies.
Collapse
Affiliation(s)
| | | | | | | | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA
| |
Collapse
|
|
7
|
Wang Q, Yang C, Chen S, Li J. Miniaturized Electrochemical Sensing Platforms for Quantitative Monitoring of Glutamate Dynamics in the Central Nervous System. Angew Chem Int Ed Engl 2024; 63:e202406867. [PMID: 38829963 DOI: 10.1002/anie.202406867] [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: 04/10/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/05/2024]
Abstract
Glutamate is one of the most important excitatory neurotransmitters within the mammalian central nervous system. The role of glutamate in regulating neural network signaling transmission through both synaptic and extra-synaptic paths highlights the importance of the real-time and continuous monitoring of its concentration and dynamics in living organisms. Progresses in multidisciplinary research have promoted the development of electrochemical glutamate sensors through the co-design of materials, interfaces, electronic devices, and integrated systems. This review summarizes recent works reporting various electrochemical sensor designs and their applicability as miniaturized neural probes to in vivo sensing within biological environments. We start with an overview of the role and physiological significance of glutamate, the metabolic routes, and its presence in various bodily fluids. Next, we discuss the design principles, commonly employed validation models/protocols, and successful demonstrations of multifunctional, compact, and bio-integrated devices in animal models. The final section provides an outlook on the development of the next generation glutamate sensors for neuroscience and neuroengineering, with the aim of offering practical guidance for future research.
Collapse
Affiliation(s)
- Qi Wang
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Chunyu Yang
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Shulin Chen
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Jinghua Li
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
- Chronic Brain Injury Program, The Ohio State University, Columbus, OH 43210, USA
| |
Collapse
|
|
8
|
Dekundy A, Pichler G, El Badry R, Scheschonka A, Danysz W. Amantadine for Traumatic Brain Injury-Supporting Evidence and Mode of Action. Biomedicines 2024; 12:1558. [PMID: 39062131 PMCID: PMC11274811 DOI: 10.3390/biomedicines12071558] [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: 06/27/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions.
Collapse
Affiliation(s)
- Andrzej Dekundy
- Merz Therapeutics GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt am Main, Germany; (A.D.); (A.S.)
| | - Gerald Pichler
- Department of Neurology, Albert-Schweitzer-Hospital Graz, Albert-Schweitzer-Gasse 36, 8020 Graz, Austria;
| | - Reda El Badry
- Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut University, Assiut 71526, Egypt;
| | - Astrid Scheschonka
- Merz Therapeutics GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt am Main, Germany; (A.D.); (A.S.)
| | - Wojciech Danysz
- Danysz Pharmacology Consulting, Vor den Gärten 16, 61130 Nidderau, Germany
| |
Collapse
|
|
9
|
Kim HM, Jo HS, Kim EJ, Na JM, Park HK, Han JY, Kim KH, Choi I, Song MK. The Effect of Repetitive Transcranial Magnetic Stimulation on Cognition in Diffuse Axonal Injury in a Rat Model. Neurol Int 2024; 16:689-700. [PMID: 39051213 PMCID: PMC11270180 DOI: 10.3390/neurolint16040052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/27/2024] Open
Abstract
Diffuse axonal injury (DAI) following sudden acceleration and deceleration can lead to cognitive function decline. Various treatments have been proposed. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive stimulation technique, is a potential treatment for enhancing neuroplasticity in cases of brain injury. The therapeutic efficacy of rTMS on cognitive function remains unconfirmed. This study investigated the effects of rTMS and the underlying molecular biomechanisms using a rat model of DAI. Sprague-Dawley rats (n = 18) were randomly divided into two groups: one receiving rTMS after DAI and the other without brain stimulation. All rats were subjected to sudden acceleration and deceleration using a DAI modeling machine to induce damage. MRI was performed to confirm the DAI lesion. The experimental group received rTMS at a frequency of 1 Hz over the frontal cortex for 10 min daily for five days. To assess spatial memory, we conducted the Morris water maze (MWM) test one day post-brain damage and one day after the five-day intervention. A video tracking system recorded the escape latency. After post-MWM tests, all rats were euthanized, and their brain tissues, particularly from the hippocampus, were collected for immunohistochemistry and western blot analyses. The escape latency showed no difference on the MWM test after DAI, but a significant difference was observed after rTMS between the two groups. Immunohistochemistry and western blot analyses indicated increased expression of BDNF, VEGF, and MAP2 in the hippocampal brain tissue of the DAI-T group. In conclusion, rTMS improved cognitive function in the DAI rat model. The increased expression of BDNF, VEGF, and MAP2 in the DAI-T group supports the potential use of rTMS in treating cognitive impairments associated with DAI.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Insung Choi
- Department of Physical & Rehabilitation Medicine, Chonnam National University Medical School & Hospital, Gwangju 61469, Republic of Korea; (H.-M.K.); (H.-S.J.); (E.-J.K.); (J.-M.N.); (H.-K.P.); white-- (J.-Y.H.); (K.-H.K.)
| | - Min-Keun Song
- Department of Physical & Rehabilitation Medicine, Chonnam National University Medical School & Hospital, Gwangju 61469, Republic of Korea; (H.-M.K.); (H.-S.J.); (E.-J.K.); (J.-M.N.); (H.-K.P.); white-- (J.-Y.H.); (K.-H.K.)
| |
Collapse
|
|
10
|
Dennis EL, Keleher F, Bartnik-Olson B. Neuroimaging Correlates of Functional Outcome Following Pediatric TBI. ADVANCES IN NEUROBIOLOGY 2024; 42:33-84. [PMID: 39432037 DOI: 10.1007/978-3-031-69832-3_3] [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: 10/22/2024]
Abstract
Neuroimaging plays an important role in assessing the consequences of TBI across the postinjury period. While identifying alterations to the brain is important, associating those changes to functional, cognitive, and behavioral outcomes is an essential step to establishing the value of advanced neuroimaging for pediatric TBI. Here we highlight research that has revealed links between advanced neuroimaging and outcome after TBI and point to opportunities where neuroimaging could expand our ability to prognosticate and potentially uncover opportunities to intervene.
Collapse
Affiliation(s)
- Emily L Dennis
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Finian Keleher
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Brenda Bartnik-Olson
- Department of Radiology, School of Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA.
| |
Collapse
|
|
11
|
Fernández Rodriguez E, Villar Taibo R, Bernabeu I. Hypopituitarism after traumatic brain injury in adults: Clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN). ENDOCRINOL DIAB NUTR 2023; 70:584-591. [PMID: 37977921 DOI: 10.1016/j.endien.2023.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/20/2023] [Indexed: 11/19/2023]
Abstract
Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.
Collapse
Affiliation(s)
- Eva Fernández Rodriguez
- Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Rocío Villar Taibo
- Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
| | - Ignacio Bernabeu
- Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
| |
Collapse
|
|
12
|
Zhao Y, Ning YL, Zhou YG. A 2AR and traumatic brain injury. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 170:225-265. [PMID: 37741693 DOI: 10.1016/bs.irn.2023.07.006] [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: 09/25/2023]
Abstract
Accumulating evidence has revealed the adenosine 2A receptor is a key tuner for neuropathological and neurobehavioral changes following traumatic brain injury by experimental animal models and a few clinical trials. Here, we highlight recent data involving acute/sub-acute and chronic alterations of adenosine and adenosine 2A receptor-associated signaling in pathological conditions after trauma, with an emphasis of traumatic brain injury, including neuroinflammation, cognitive and psychiatric disorders, and other severe consequences. We expect this would lead to the development of therapeutic strategies for trauma-related disorders with novel mechanisms of action.
Collapse
Affiliation(s)
- Yan Zhao
- Department of Army Occupational Disease, State Key Laboratory of Trauma and Chemical Poisoning, Research Institute of Surgery and Daping Hospital, Army Medical University, P.R. China; Institute of Brain and Intelligence, Army Medical University, Chongqing, P.R. China
| | - Ya-Lei Ning
- Department of Army Occupational Disease, State Key Laboratory of Trauma and Chemical Poisoning, Research Institute of Surgery and Daping Hospital, Army Medical University, P.R. China; Institute of Brain and Intelligence, Army Medical University, Chongqing, P.R. China
| | - Yuan-Guo Zhou
- Department of Army Occupational Disease, State Key Laboratory of Trauma and Chemical Poisoning, Research Institute of Surgery and Daping Hospital, Army Medical University, P.R. China; Institute of Brain and Intelligence, Army Medical University, Chongqing, P.R. China.
| |
Collapse
|
|
13
|
Takahashi K, Ishibashi Y, Chujo K, Suzuki I, Sato K. Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity. Int J Mol Sci 2023; 24:12605. [PMID: 37628787 PMCID: PMC10454411 DOI: 10.3390/ijms241612605] [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: 05/18/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
Human induced pluripotent stem cell (hiPSC)-derived neural cells have started to be used in safety/toxicity tests at the preclinical stage of drug development. As previously reported, hiPSC-derived neurons exhibit greater tolerance to excitotoxicity than those of primary cultures of rodent neurons; however, the underlying mechanisms remain unknown. We here investigated the functions of L-glutamate (L-Glu) transporters, the most important machinery to maintain low extracellular L-Glu concentrations, in hiPSC-derived neural cells. We also clarified the contribution of respective L-Glu transporter subtypes. At 63 days in vitro (DIV), we detected neuronal circuit functions in hiPSC-derived neural cells by a microelectrode array system (MEA). At 63 DIV, exposure to 100 μM L-Glu for 24 h did not affect the viability of neural cells. 100 µM L-Glu in the medium decreased to almost 0 μM in 60 min. Pharmacological inhibition of excitatory amino acid transporter 1 (EAAT1) and EAAT2 suppressed almost 100% of L-Glu decrease. In the presence of this inhibitor, 100 μM L-Glu dramatically decreased cell viability. These results suggest that in hiPSC-derived neural cells, EAAT1 and EAAT2 are the predominant L-Glu transporters, and their uptake potentials are the reasons for the tolerance of hiPSC-derived neurons to excitotoxicity.
Collapse
Affiliation(s)
- Kanako Takahashi
- Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-city, Kanagawa 210-9501, Japan; (K.T.); (K.C.)
| | - Yuto Ishibashi
- Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Miyagi 982-8577, Japan; (Y.I.); (I.S.)
| | - Kaori Chujo
- Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-city, Kanagawa 210-9501, Japan; (K.T.); (K.C.)
| | - Ikuro Suzuki
- Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Miyagi 982-8577, Japan; (Y.I.); (I.S.)
| | - Kaoru Sato
- Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-city, Kanagawa 210-9501, Japan; (K.T.); (K.C.)
| |
Collapse
|
|
14
|
Kochanek PM, Herrmann JR, Bleck TP. The Evolution of Ketamine in Severe Pediatric Traumatic Brain Injury, From Contraband to Promising Neuroprotectant? Crit Care Med 2023; 51:677-680. [PMID: 37052437 DOI: 10.1097/ccm.0000000000005826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Affiliation(s)
- Patrick M Kochanek
- Department of Critical Care Medicine, Safar Center for Resuscitation Research, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Jeremy R Herrmann
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Thomas P Bleck
- Ken and Ruth Davee Department of Neurology, Northwestern University, Northwestern University Feinberg School of Medicine, Chicago, IL
| |
Collapse
|
|
15
|
Mira RG, Quintanilla RA, Cerpa W. Mild Traumatic Brain Injury Induces Mitochondrial Calcium Overload and Triggers the Upregulation of NCLX in the Hippocampus. Antioxidants (Basel) 2023; 12:antiox12020403. [PMID: 36829963 PMCID: PMC9952386 DOI: 10.3390/antiox12020403] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Traumatic brain injury (TBI) is brain damage due to external forces. Mild TBI (mTBI) is the most common form of TBI, and repeated mTBI is a risk factor for developing neurodegenerative diseases. Several mechanisms of neuronal damage have been described in the cortex and hippocampus, including mitochondrial dysfunction. However, up until now, there have been no studies evaluating mitochondrial calcium dynamics. Here, we evaluated mitochondrial calcium dynamics in an mTBI model in mice using isolated hippocampal mitochondria for biochemical studies. We observed that 24 h after mTBI, there is a decrease in mitochondrial membrane potential and an increase in basal matrix calcium levels. These findings are accompanied by increased mitochondrial calcium efflux and no changes in mitochondrial calcium uptake. We also observed an increase in NCLX protein levels and calcium retention capacity. Our results suggest that under mTBI, the hippocampal cells respond by incrementing NCLX levels to restore mitochondrial function.
Collapse
Affiliation(s)
- Rodrigo G. Mira
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontifica Universidad Católica de Chile, Santiago 8331150, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6213515, Chile
| | - Rodrigo A. Quintanilla
- Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago 8910060, Chile
| | - Waldo Cerpa
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontifica Universidad Católica de Chile, Santiago 8331150, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6213515, Chile
- Correspondence:
| |
Collapse
|
|
16
|
Aychman MM, Goldman DL, Kaplan JS. Cannabidiol's neuroprotective properties and potential treatment of traumatic brain injuries. Front Neurol 2023; 14:1087011. [PMID: 36816569 PMCID: PMC9932048 DOI: 10.3389/fneur.2023.1087011] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
Cannabidiol (CBD) has numerous pharmacological targets that initiate anti-inflammatory, antioxidative, and antiepileptic properties. These neuroprotective benefits have generated interest in CBD's therapeutic potential against the secondary injury cascade from traumatic brain injury (TBI). There are currently no effective broad treatment strategies for combating the damaging mechanisms that follow the primary injury and lead to lasting neurological consequences or death. However, CBD's effects on different neurotransmitter systems, the blood brain barrier, oxidative stress mechanisms, and the inflammatory response provides mechanistic support for CBD's clinical utility in TBI. This review describes the cascades of damage caused by TBI and CBD's neuroprotective mechanisms to counter them. We also present challenges in the clinical treatment of TBI and discuss important future clinical research directions for integrating CBD in treatment protocols. The mechanistic evidence provided by pre-clinical research shows great potential for CBD as a much-needed improvement in the clinical treatment of TBI. Upcoming clinical trials sponsored by major professional sport leagues are the first attempts to test the efficacy of CBD in head injury treatment protocols and highlight the need for further clinical research.
Collapse
|
|
17
|
Venturini S, Bhatti F, Timofeev I, Carpenter KLH, Hutchinson PJ, Guilfoyle MR, Helmy A. Microdialysis-Based Classifications of Abnormal Metabolic States after Traumatic Brain Injury: A Systematic Review of the Literature. J Neurotrauma 2023; 40:195-209. [PMID: 36112699 DOI: 10.1089/neu.2021.0502] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
After traumatic brain injury (TBI), cerebral metabolism can become deranged, contributing to secondary injury. Cerebral microdialysis (CMD) allows cerebral metabolism assessment and is often used with other neuro-monitoring modalities. CMD-derived parameters such as the lactate/pyruvate ratio (LPR) show a failure of oxidative energy generation. CMD-based abnormal metabolic states can be described following TBI, informing the etiology of physiological derangements. This systematic review summarizes the published literature on microdialysis-based abnormal metabolic classifications following TBI. Original research studies in which the populations were patients with TBI were included. Studies that described CMD-based classifications of metabolic abnormalities were included in the synthesis of the narrative results. A total of 825 studies underwent two-step screening after duplicates were removed. Fifty-three articles that used CMD in TBI patients were included. Of these, 14 described abnormal metabolic states based on CMD parameters. Classifications were heterogeneous between studies. LPR was the most frequently used parameter in the classifications; high LPR values were described as metabolic crisis. Ischemia was consistently defined as high LPR with low CMD substrate levels (glucose or pyruvate). Mitochondrial dysfunction, describing inability to use energy substrate despite availability, was identified based on raised LPR with near-normal levels of pyruvate. This is the first systematic review summarizing the published literature on microdialysis-based abnormal metabolic states following TBI. Although variability exists among individual classifications, there is broad agreement about broad definitions of metabolic crisis, ischemia, and mitochondrial dysfunction. Identifying the etiology of deranged cerebral metabolism after TBI is important for targeting therapeutic interventions.
Collapse
Affiliation(s)
- Sara Venturini
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Faheem Bhatti
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Ivan Timofeev
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Keri L H Carpenter
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Peter J Hutchinson
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Mathew R Guilfoyle
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Adel Helmy
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
18
|
Rauchman SH, Zubair A, Jacob B, Rauchman D, Pinkhasov A, Placantonakis DG, Reiss AB. Traumatic brain injury: Mechanisms, manifestations, and visual sequelae. Front Neurosci 2023; 17:1090672. [PMID: 36908792 PMCID: PMC9995859 DOI: 10.3389/fnins.2023.1090672] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Traumatic brain injury (TBI) results when external physical forces impact the head with sufficient intensity to cause damage to the brain. TBI can be mild, moderate, or severe and may have long-term consequences including visual difficulties, cognitive deficits, headache, pain, sleep disturbances, and post-traumatic epilepsy. Disruption of the normal functioning of the brain leads to a cascade of effects with molecular and anatomical changes, persistent neuronal hyperexcitation, neuroinflammation, and neuronal loss. Destructive processes that occur at the cellular and molecular level lead to inflammation, oxidative stress, calcium dysregulation, and apoptosis. Vascular damage, ischemia and loss of blood brain barrier integrity contribute to destruction of brain tissue. This review focuses on the cellular damage incited during TBI and the frequently life-altering lasting effects of this destruction on vision, cognition, balance, and sleep. The wide range of visual complaints associated with TBI are addressed and repair processes where there is potential for intervention and neuronal preservation are highlighted.
Collapse
Affiliation(s)
| | - Aarij Zubair
- NYU Long Island School of Medicine, Mineola, NY, United States
| | - Benna Jacob
- NYU Long Island School of Medicine, Mineola, NY, United States
| | - Danielle Rauchman
- Department of Neuroscience, University of California, Santa Barbara, Santa Barbara, CA, United States
| | - Aaron Pinkhasov
- NYU Long Island School of Medicine, Mineola, NY, United States
| | | | - Allison B Reiss
- NYU Long Island School of Medicine, Mineola, NY, United States
| |
Collapse
|
|
19
|
Fesharaki-Zadeh A. Oxidative Stress in Traumatic Brain Injury. Int J Mol Sci 2022; 23:ijms232113000. [PMID: 36361792 PMCID: PMC9657447 DOI: 10.3390/ijms232113000] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/17/2022] Open
Abstract
Traumatic Brain Injury (TBI) remains a major cause of disability worldwide. It involves a complex neurometabolic cascade, including oxidative stress. The products of this manuscript is examining the underlying pathophysiological mechanism, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). This process in turn leads to secondary injury cascade, which includes lipid peroxidation products. These reactions ultimately play a key role in chronic inflammation and synaptic dysfunction in a synergistic fashion. Although there are no FDA approved antioxidant therapy for TBI, there is a number of antioxidant therapies that have been tested and include free radical scavengers, activators of antioxidant systems, inhibitors of free radical generating enzymes, and antioxidant enzymes. Antioxidant therapies have led to cognitive and functional recovery post TBI, and they offer a promising treatment option for patients recovering from TBI. Current major challenges in treatment of TBI symptoms include heterogenous nature of injury, as well as access to timely treatment post injury. The inherent benefits of antioxidant therapies include minimally reported side effects, and relative ease of use in the clinical setting. The current review also provides a highlight of the more studied anti-oxidant regimen with applicability for TBI treatment with potential use in the real clinical setting.
Collapse
Affiliation(s)
- Arman Fesharaki-Zadeh
- Yale School of Medicine, Department of Neurology, Yale University, New Haven, CT 06510, USA
| |
Collapse
|
|
20
|
Beri A, Pisulkar SG, Bansod AV, Dahihandekar C. Paradigm Shift in Materials for Skull Reconstruction Facilitated by Science and Technological Integration. Cureus 2022; 14:e28731. [PMID: 36204019 PMCID: PMC9528855 DOI: 10.7759/cureus.28731] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/03/2022] [Indexed: 12/04/2022] Open
Abstract
The surgical repair of a bone deficiency in the skull caused by a prior procedure or accident is known as cranioplasty. There are various types of cranioplasties, but the majority entail raising the scalp and reshaping the skull using either the original piece of bone from the skull or a specially molded graft created from Titanium (plate or mesh), artificial bone in place of, a stable biomaterial (prefabricated customized implant to match the exact contour and shape of the skull). Cranioplasty, one of the oldest surgical treatments for cranial abnormalities, has undergone several changes throughout the years to discover the best material to improve patient outcomes. Various materials have been utilized in cranioplasty throughout history. As biomedical technology progresses, surgeons will have access to new materials. There is still no agreement on the optimum material, and research into biologic and nonbiologic alternatives is ongoing in the hopes of finding the finest reconstruction material. The materials and techniques used in cranioplasty are covered in this article.
Collapse
|
|
21
|
Gruenbaum BF, Zlotnik A, Fleidervish I, Frenkel A, Boyko M. Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies. Int J Mol Sci 2022; 23:ijms23179628. [PMID: 36077024 PMCID: PMC9456007 DOI: 10.3390/ijms23179628] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood–brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae.
Collapse
Affiliation(s)
- Benjamin F. Gruenbaum
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Alexander Zlotnik
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
| | - Ilya Fleidervish
- Department of Physiology and Cell Biology, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Amit Frenkel
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
| | - Matthew Boyko
- Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
- Correspondence:
| |
Collapse
|
|
22
|
Yilmaz İ, Karaarslan N, Somay H, Ozbek H, Ates O. Curcumin-Impregnated Drug Delivery Systems May Show Promise in the Treatment of Diseases Secondary to Traumatic Brain Injury: Systematic Review. J Pharmacol Pharmacother 2022. [DOI: 10.1177/0976500x221112479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Traumatic brain injury (TBI) is a major social health problem, especially in young adults, and progresses with advanced functional losses. In this study, curcumin was directed to the damaged brain tissue by crossing the blood–brain barrier through drug delivery systems. Thus, the study asked whether it can be effective in the treatment of TBI, which has not had a radical treatment method in clinics yet. Methods A comprehensive and systematic literature search in the PubMed electronic database was performed. Descriptive statistics were used to evaluate the data obtained. The results were presented as frequency and percentage (%) or amount. Results Two clinical trials investigated curcumin for the treatment of TBI. One study tested curcumin in living mammalian subjects using an amyloLipid nanovesicle. In three studies, curcumin was investigated together with the drug delivery system for the treatment of TBI. Conclusion Drug delivery systems prepared with nanomaterials may have a potential therapeutic effect in treating TBI by increasing neuroprotection because they can penetrate the central nervous system more rapidly.
Collapse
Affiliation(s)
- İbrahim Yilmaz
- Ministry of Health, Dr Ismail Fehmi Cumalioglu City Hospital, Unit of Pharmacovigilance and Rational Use of Drugs, Tekirdag, Turkey
- Department of Medical Services and Techniques, Vocational School of Health Services, Istanbul Rumeli University, Istanbul, Istanbul, Turkey
| | - Numan Karaarslan
- Department of Neurosurgery, Halic University School of Medicine, Istanbul, Istanbul, Turkey
| | - Hakan Somay
- Department of Neurosurgery, Kadikoy Medicana Hospital, Istanbul, Istanbul, Turkey
| | - Hanefi Ozbek
- Department of Medical Pharmacology, İzmir Bakırçay University School of Medicine, Izmir, Izmir, Turkey
| | - Ozkan Ates
- Department of Neurosurgery, Istanbul Koc University School of Medicine, Istanbul, Istanbul, Turkey
| |
Collapse
|
|
23
|
A 5-HT6R Agonist Alleviates Cognitive Dysfunction after Traumatic Brain Injury in Rats by Increasing BDNF Expression. Behav Brain Res 2022; 433:113997. [DOI: 10.1016/j.bbr.2022.113997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/26/2022] [Accepted: 07/03/2022] [Indexed: 11/22/2022]
|
|
24
|
Xu P, Huang X, Niu W, Yu D, Zhou M, Wang H. Metabotropic glutamate receptor 5 upregulation of γ-aminobutyric acid transporter 3 expression ameliorates cognitive impairment after traumatic brain injury in mice. Brain Res Bull 2022; 183:104-115. [DOI: 10.1016/j.brainresbull.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 03/07/2022] [Indexed: 11/16/2022]
|
|
25
|
Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System. Metabolites 2022; 12:metabo12050459. [PMID: 35629963 PMCID: PMC9143347 DOI: 10.3390/metabo12050459] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 02/04/2023] Open
Abstract
Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their long-term capabilities. Recent studies have identified a new set of glutamate-based approaches, such as blood glutamate scavengers, which have the potential to provide alternatives to traditional antidepressants. In this review, we hypothesize as to the involvement of the glutamate system in the development of depression. We identify the mechanisms underlying glutamate dysregulation, offering new perspectives on the therapeutic modalities of depression with a focus on its relationship to blood–brain barrier (BBB) permeability. Ultimately, we conclude that in diseases with impaired BBB permeability, such as depression following stroke or traumatic brain injury, or in neurogenerative diseases, the glutamate system should be considered as a pathway to treatment. We propose that drugs such as blood glutamate scavengers should be further studied for treatment of these conditions.
Collapse
|
|
26
|
Axonal injury is detected by βAPP immunohistochemistry in rapid death from head injury following road traffic collision. Int J Legal Med 2022; 136:1321-1339. [PMID: 35488928 PMCID: PMC9375765 DOI: 10.1007/s00414-022-02807-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/21/2022] [Indexed: 11/23/2022]
Abstract
The accumulation of βAPP caused by axonal injury is an active energy-dependent process thought to require blood circulation; therefore, it is closely related to the post-injury survival time. Currently, the earliest reported time at which axonal injury can be detected in post-mortem traumatic brain injury (TBI) tissue by βAPP (Beta Amyloid Precursor Protein) immunohistochemistry is 35 min. The aim of this study is to investigate whether βAPP staining for axonal injury can be detected in patients who died rapidly after TBI in road traffic collision (RTC), in a period of less than 30 min. We retrospectively studied thirty-seven patients (group 1) died very rapidly at the scene; evidenced by forensic assessment of injuries short survival, four patients died after a survival period of between 31 min and 12 h (group 2) and eight patients between 2 and 31 days (group 3). The brains were comprehensively examined and sampled at the time of the autopsy, and βAPP immunohistochemistry carried out on sections from a number of brain areas. βAPP immunoreactivity was demonstrated in 35/37 brains in group 1, albeit with a low frequency and in a variable pattern, and with more intensity and frequency in all brains of group 2 and 7/8 brains from group 3, compared with no similar βAPP immunoreactivity in the control group. The results suggest axonal injury can be detected in those who died rapidly after RTC in a period of less than 30 min, which can help in the diagnosis of severe TBI with short survival time.
Collapse
|
|
27
|
Acute and Delayed Effects of Mechanical Injury on Calcium Homeostasis and Mitochondrial Potential of Primary Neuroglial Cell Culture: Potential Causal Contributions to Post-Traumatic Syndrome. Int J Mol Sci 2022; 23:ijms23073858. [PMID: 35409216 PMCID: PMC8998891 DOI: 10.3390/ijms23073858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023] Open
Abstract
In vitro models of traumatic brain injury (TBI) help to elucidate the pathological mechanisms responsible for cell dysfunction and death. To simulate in vitro the mechanical brain trauma, primary neuroglial cultures were scratched during different periods of network formation. Fluorescence microscopy was used to measure changes in intracellular free Ca2+ concentration ([Ca2+]i) and mitochondrial potential (ΔΨm) a few minutes later and on days 3 and 7 after scratching. An increase in [Ca2+]i and a decrease in ΔΨm were observed ~10 s after the injury in cells located no further than 150–200 µm from the scratch border. Ca2+ entry into cells during mechanical damage of the primary neuroglial culture occurred predominantly through the NMDA-type glutamate ionotropic channels. MK801, an inhibitor of this type of glutamate receptor, prevented an acute increase in [Ca2+]i in 99% of neurons. Pathological changes in calcium homeostasis persisted in the primary neuroglial culture for one week after injury. Active cell migration in the scratch area occurred on day 11 after neurotrauma and was accompanied by a decrease in the ratio of live to dead cells in the areas adjacent to the injury. Immunohistochemical staining of glial fibrillary acidic protein and β-III tubulin showed that neuronal cells migrated to the injured area earlier than glial cells, but their repair potential was insufficient for survival. Mitochondrial Ca2+ overload and a drop in ΔΨm may cause delayed neuronal death and thus play a key role in the development of the post-traumatic syndrome. Preventing prolonged ΔΨm depolarization may be a promising therapeutic approach to improve neuronal survival after traumatic brain injury.
Collapse
|
|
28
|
Dong Y, Chen S, Liu TL, Li J. Materials and Interface Designs of Waterproof Field-Effect Transistor Arrays for Detection of Neurological Biomarkers. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2106866. [PMID: 35023615 PMCID: PMC8930526 DOI: 10.1002/smll.202106866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/05/2021] [Indexed: 06/14/2023]
Abstract
The continuous, real-time, and concurrent detection of multiple biomarkers in bodily fluids is of high significance for advanced healthcare. While active, semiconductor-based biochemical sensing platforms provide levels of functionality exceeding those of their conventional passive counterparts, the stability of the active biosensors in the liquid environment for continuous operation remains a challenging topic. This work reports the development of a class of flexible and waterproof field-effect transistor arrays for multiplexed biochemical sensing. In this design, monolithic, ultrathin, dense, and low defect nanomembranes consisting of monocrystalline Si and thermally grown SiO2 simultaneously serve as high-performance backplane electronics for signal transduction and stable biofluid barriers with high structural integrity due to the high formation temperature. Coupling the waterproof transistors with various ion-selective membranes through the gate electrode allows for sensitive and selective detection of multiple ions as biomarkers for traumatic brain injury. The study also demonstrates a similar encapsulation structure which enables the design of waterproof amperometric sensors based on this materials strategy and integration scheme. Overall, key advantages in flexibility, stability, and multifunctionality highlight the potential of using such electronic sensing platforms for concurrent, continuous detection of various neurological biomarkers, proving a promising approach for early diagnosis and intervention of chronic diseases.
Collapse
Affiliation(s)
- Yan Dong
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Shulin Chen
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Tzu-Li Liu
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Jinghua Li
- Department of Materials Science and Engineering, Chronic Brain Injury Program, The Ohio State University, Columbus, OH, 43210, USA
| |
Collapse
|
|
29
|
Fan J, Du J, Zhang Z, Shi W, Hu B, Hu J, Xue Y, Li H, Ji W, Zhuang J, Lv P, Cheng K, Chen K. The Protective Effects of Hydrogen Sulfide New Donor Methyl S-(4-Fluorobenzyl)- N-(3,4,5-Trimethoxybenzoyl)-l-Cysteinate on the Ischemic Stroke. Molecules 2022; 27:1554. [PMID: 35268655 PMCID: PMC8911759 DOI: 10.3390/molecules27051554] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 01/29/2023] Open
Abstract
In this paper, we report the design, synthesis and biological evaluation of a novel S-allyl-l-cysteine (SAC) and gallic acid conjugate S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-l-cysteinate (MTC). We evaluate the effects on ischemia-reperfusion-induced PC12 cells, primary neurons in neonatal rats, and cerebral ischemic neuronal damage in rats, and the results showed that MTC increased SOD, CAT, GPx activity and decreased LDH release. PI3K and p-AKT protein levels were significantly increased by activating PI3K/AKT pathway. Mitochondrial pro-apoptotic proteins Bax and Bim levels were reduced while anti-apoptotic protein Bcl-2 levels were increased. The levels of cleaved caspase-9 and cleaved caspase-3 were also reduced in the plasma. The endoplasmic reticulum stress (ERS) was decreased, which in turns the survival rate of nerve cells was increased, so that the ischemic injury of neurons was protected accordingly. MTC activated the MEK-ERK signaling pathway and promoted axonal regeneration in primary neurons of the neonatal rat. The pretreatment of MEK-ERK pathway inhibitor PD98059 and PI3K/AKT pathway inhibitor LY294002 partially attenuated the protective effect of MTC. Using a MCAO rat model indicated that MTC could reduce cerebral ischemia-reperfusion injury and decrease the expression of proinflammatory factors. The neuroprotective effect of MTC may be due to inhibition of the over-activation of the TREK-1 channel and reduction of the current density of the TREK1 channel. These results suggested that MTC has a protective effect on neuronal injury induced by ischemia reperfusion, so it may have the potential to become a new type of neuro-ischemic drug candidate.
Collapse
Affiliation(s)
- Jing Fan
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Junxi Du
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Zhongwei Zhang
- Intensive Care Unit, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Wenjing Shi
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Binyan Hu
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Jiaqin Hu
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Yan Xue
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou 510080, China; (Y.X.); (W.J.); (J.Z.)
| | - Haipeng Li
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Wenjin Ji
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou 510080, China; (Y.X.); (W.J.); (J.Z.)
| | - Jian Zhuang
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 96 DongChun Road, Guangzhou 510080, China; (Y.X.); (W.J.); (J.Z.)
| | - Pengcheng Lv
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| | - Kui Cheng
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kun Chen
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China; (J.F.); (J.D.); (W.S.); (B.H.); (J.H.); (H.L.)
| |
Collapse
|
|
30
|
Alkhachroum A, Kromm J, De Georgia MA. Big data and predictive analytics in neurocritical care. Curr Neurol Neurosci Rep 2022; 22:19-32. [PMID: 35080751 DOI: 10.1007/s11910-022-01167-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To describe predictive data and workflow in the intensive care unit when managing neurologically ill patients. RECENT FINDINGS In the era of Big Data in medicine, intensive critical care units are data-rich environments. Neurocritical care adds another layer of data with advanced multimodal monitoring to prevent secondary brain injury from ischemia, tissue hypoxia, and a cascade of ongoing metabolic events. A step closer toward personalized medicine is the application of multimodal monitoring of cerebral hemodynamics, bran oxygenation, brain metabolism, and electrophysiologic indices, all of which have complex and dynamic interactions. These data are acquired and visualized using different tools and monitors facing multiple challenges toward the goal of the optimal decision support system. In this review, we highlight some of the predictive data used to diagnose, treat, and prognosticate the neurologically ill patients. We describe information management in neurocritical care units including data acquisition, wrangling, analysis, and visualization.
Collapse
Affiliation(s)
- Ayham Alkhachroum
- Miller School of Medicine, Neurocritical Care Division, Department of Neurology, University of Miami, Miami, FL, 33146, USA
| | - Julie Kromm
- Cumming School of Medicine, Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada
- Cumming School of Medicine, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Michael A De Georgia
- Center for Neurocritical Care, Neurological Institute, University Hospital Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106-5040, USA.
| |
Collapse
|
|
31
|
Lin PH, Kuo LT, Luh HT. The Roles of Neurotrophins in Traumatic Brain Injury. LIFE (BASEL, SWITZERLAND) 2021; 12:life12010026. [PMID: 35054419 PMCID: PMC8780368 DOI: 10.3390/life12010026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 02/08/2023]
Abstract
Neurotrophins are a collection of structurally and functionally related proteins. They play important roles in many aspects of neural development, survival, and plasticity. Traumatic brain injury (TBI) leads to different levels of central nervous tissue destruction and cellular repair through various compensatory mechanisms promoted by the injured brain. Many studies have shown that neurotrophins are key modulators of neuroinflammation, apoptosis, blood–brain barrier permeability, memory capacity, and neurite regeneration. The expression of neurotrophins following TBI is affected by the severity of injury, genetic polymorphism, and different post-traumatic time points. Emerging research is focused on the potential therapeutic applications of neurotrophins in managing TBI. We conducted a comprehensive review by organizing the studies that demonstrate the role of neurotrophins in the management of TBI.
Collapse
Affiliation(s)
- Ping-Hung Lin
- Department of Medical Education, School of Medicine, National Taiwan University, Taipei 100, Taiwan;
| | - Lu-Ting Kuo
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan;
| | - Hui-Tzung Luh
- Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, New Taipei City 235, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan
- Correspondence: ; Tel.: +886-956279587
| |
Collapse
|
|
32
|
Mira RG, Lira M, Cerpa W. Traumatic Brain Injury: Mechanisms of Glial Response. Front Physiol 2021; 12:740939. [PMID: 34744783 PMCID: PMC8569708 DOI: 10.3389/fphys.2021.740939] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/20/2021] [Indexed: 11/17/2022] Open
Abstract
Traumatic brain injury (TBI) is a heterogeneous disorder that involves brain damage due to external forces. TBI is the main factor of death and morbidity in young males with a high incidence worldwide. TBI causes central nervous system (CNS) damage under a variety of mechanisms, including synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Glial cells comprise most cells in CNS, which are mediators in the brain’s response to TBI. In the CNS are present astrocytes, microglia, oligodendrocytes, and polydendrocytes (NG2 cells). Astrocytes play critical roles in brain’s ion and water homeostasis, energy metabolism, blood-brain barrier, and immune response. In response to TBI, astrocytes change their morphology and protein expression. Microglia are the primary immune cells in the CNS with phagocytic activity. After TBI, microglia also change their morphology and release both pro and anti-inflammatory mediators. Oligodendrocytes are the myelin producers of the CNS, promoting axonal support. TBI causes oligodendrocyte apoptosis, demyelination, and axonal transport disruption. There are also various interactions between these glial cells and neurons in response to TBI that contribute to the pathophysiology of TBI. In this review, we summarize several glial hallmarks relevant for understanding the brain injury and neuronal damage under TBI conditions.
Collapse
Affiliation(s)
- Rodrigo G Mira
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Matías Lira
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Waldo Cerpa
- Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
| |
Collapse
|
|
33
|
Saulino PA, Greenwald BD, Gordon DJ. The changing landscape of the use of medical marijuana after traumatic brain injury: a narrative review. Brain Inj 2021; 35:1510-1520. [PMID: 34632896 DOI: 10.1080/02699052.2021.1978548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To summarize the potential therapeutic benefits of medical marijuana for patients with traumatic brain injury (TBI). METHODS A systematic search was conducted using PubMed and Cochran's library for information regard the safety and efficacy of medical marijuana as a therapeutic agent. We investigated, in depth, articles specifically evaluating medical marijuana's use in TBI, as well as articles that summarized the effects of marijuana in general. Articles from the year 2000-2020 were included. RESULTS A total of 37 articles met our inclusion criteria. An additional 3 articles were obtained from reference lists. CONCLUSION Studies have shown that medical marijuana can potentially aid the recovery from TBI by modulating the endocannabinoid system, reducing inflammation and secondary injury. Adverse cognitive and physiological effects have been observed in the acute setting as well as chronically, though more research is necessitated. There is also the concern of significant drug-drug interactions that have not been thoroughly studied. Thus, while there is evidence that medical marijuana can be beneficial in the treatment of TBI, more research is necessitated to fully explore the long-term efficacy and adverse effects.
Collapse
Affiliation(s)
- Patrick A Saulino
- Rutgers Robert Wood Johnson Medical School, Ringgold Standard Institution, Piscataway, New Jersey, USA
| | - Brian D Greenwald
- Center for Brain Injuries, JFK Johnson Rehabilitation Institute, Ringgold Standard Institution - Physical Medicine and Rehabilitation, Edison, New Jersey, USA.,Rutgers Robert Wood Johnson Medical School New Brunswick, - Physical Medicine and Rehabilitation, Edison, New Jersey, USA
| | - Dustin J Gordon
- Rehabilitation Specialists, Ringgold Standard Institution, Fairleigh Dickinson University, Fair Lawn, New Jersey, USA.,Fairleigh Dickinson University in Teaneck, New Jersey, USA
| |
Collapse
|
|
34
|
Abstract
Traumatic brain injury (TBI) involves structural damage to the brain regions causing death or disability in patients with lifelong sufferings. Accidental injuries to the brain, besides structural damage, if any, cause activation of various deleterious pathways leading to subsequent neuronal death and permanent dysfunction. However, immediate medical management/treatments could reduce the chances of disability and suffering to the patients. The objective of the current review is to review triggered molecular pathways following TBI and discuss possible targets that could restore brain functions. Understanding the pathologic process is always useful to device novel treatment strategies and may rescue the patient with TBI from death or associated co-morbidities. The current review significantly contributes to improve our understanding about the molecular pathways and neuronal death following TBI and helps us to provide possible targets that could be useful in the management/treatment of TBI.
Collapse
Affiliation(s)
- Kajal Bagri
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Rahul Deshmukh
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
| |
Collapse
|
|
35
|
Ladol S, Sharma D. The effects of Hippophae rhamnoides in neuroprotection and behavioral alterations against iron-induced epilepsy. Epilepsy Res 2021; 175:106695. [PMID: 34186382 DOI: 10.1016/j.eplepsyres.2021.106695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 06/18/2021] [Indexed: 10/21/2022]
Abstract
Epilepsy is a neurological disorder in which malfunctioning of the electrical activity of the brain causes recurrent, unprovoked seizures. Epilepsy causes wide symptoms that include cognitive dysfunction, anxiety, behavioral alterations, and histological impairments. In this study, the effect of Hippophae rhamnoides (Sea buckthorn/Sbt) on electrophysiology, behavior, and histology in iron-induced epilepsy was analyzed. Rats were randomly divided into four groups (n = 8); Control group, Epileptic group, Sbt treated epileptic group, and Sbt treated group. To induce epilepsy, the intracortical iron injection was administered at a dose of 5 μl of 100 mM FeCl3. A significant increase in epileptiform activity, behavioral abnormalities, and histological impairments was observed in the iron-induced epileptic rats. Hippophae rhamnoides berry extract was administered orally at a dose of 1 ml/kg body wt. for one month. Sbt administration significantly reduced the epileptiform activity, improved behavioral abnormalities, and improved histological impairments in epileptic rats. In conclusion, this study demonstrates the antiepileptic effect of Sbt that probably has exerted by its neuroprotective and behavioral alteration potential against iron-induced epilepsy.
Collapse
Affiliation(s)
- Stanzin Ladol
- Department of Zoology, Central University of Jammu, Bagla (Rahya Suchani) Distt. Samba, Jammu and Kashmir, 181143, India.
| | - Deepak Sharma
- Neurobiology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
| |
Collapse
|
|
36
|
Perszyk RE, Zheng Z, Banke TG, Zhang J, Xie L, McDaniel MJ, Katzman BM, Pelly SC, Yuan H, Liotta DC, Traynelis SF. The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and Ca 2+ Permeability of GluN1/GluN2A N-Methyl-d-Aspartate Receptors. Mol Pharmacol 2021; 99:399-411. [PMID: 33688039 PMCID: PMC8058507 DOI: 10.1124/molpharm.120.000218] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/01/2021] [Indexed: 12/31/2022] Open
Abstract
NMDA receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic currents. These receptors are involved in several important brain functions, including learning and memory, and have also been implicated in neuropathological conditions and acute central nervous system injury, which has driven therapeutic interest in their modulation. The EU1794 series of positive and negative allosteric modulators of NMDA receptors has structural determinants of action near the preM1 helix that is involved in channel gating. Here, we describe the effects of the negative allosteric modulator EU1794-4 on GluN1/GluN2A channels studied in excised outside-out patches. Coapplication of EU1794-4 with a maximally effective concentration of glutamate and glycine increases the fraction of time the channel is open by nearly 1.5-fold, yet reduces single-channel conductance by increasing access of the channel to several subconductance levels, which has the net overall effect of reducing the macroscopic current. The lack of voltage-dependence of negative modulation suggests this is unrelated to a channel block mechanism. As seen with other NMDA receptor modulators that reduce channel conductance, EU1794-4 also reduces the Ca2+ permeability relative to monovalent cations of GluN1/GluN2A receptors. We conclude that EU1794-4 is a prototype for a new class of NMDA receptor negative allosteric modulators that reduce both the overall current that flows after receptor activation and the flux of Ca2+ ion relative to monovalent cations. SIGNIFICANCE STATEMENT: NMDA receptors are implicated in many neurological conditions but are challenging to target given their ubiquitous expression. Several newly identified properties of the negative allosteric modulator EU1794-4, including reducing Ca2+ flux through NMDA receptors and attenuating channel conductance, explain why this modulator reduces but does not eliminate NMDA receptor function. A modulator with these properties could have therapeutic advantages for indications in which attenuation of NMDA receptor function is beneficial, such as neurodegenerative disease and acute injury.
Collapse
Affiliation(s)
- Riley E Perszyk
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Zhaoshi Zheng
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Tue G Banke
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Jing Zhang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Lingling Xie
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Miranda J McDaniel
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Brooke M Katzman
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Stephen C Pelly
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Dennis C Liotta
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| | - Stephen F Traynelis
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia (R.E.P., Z.Z., T.G.B., J.Z., L.X., M.J.M., H.Y., S.F.T.) and Department of Chemistry, Emory University, Atlanta, Georgia (B.M.K., S.C.P., D.C.L.)
| |
Collapse
|
|
37
|
Bartnik-Olson BL, Alger JR, Babikian T, Harris AD, Holshouser B, Kirov II, Maudsley AA, Thompson PM, Dennis EL, Tate DF, Wilde EA, Lin A. The clinical utility of proton magnetic resonance spectroscopy in traumatic brain injury: recommendations from the ENIGMA MRS working group. Brain Imaging Behav 2021; 15:504-525. [PMID: 32797399 PMCID: PMC7882010 DOI: 10.1007/s11682-020-00330-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Proton (1H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo 1H magnetic resonance spectroscopy and review 1H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic 1H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of 1H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.
Collapse
Affiliation(s)
| | - Jeffry R Alger
- Departments of Neurology and Radiology, University of California Los Angeles, Los Angeles, CA, USA
- NeuroSpectroScopics LLC, Sherman Oaks, Los Angeles, CA, USA
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Talin Babikian
- Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA
- UCLA Steve Tisch BrainSPORT Program, Los Angeles, CA, USA
| | - Ashley D Harris
- Department of Radiology, University of Calgary, Calgary, Canada
- Child and Adolescent Imaging Research Program, Alberta Children's Hospital Research Institute and the Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
| | - Barbara Holshouser
- Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA, USA
| | - Ivan I Kirov
- Bernard and Irene Schwartz Center for Biomedical Imaging, Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University School of Medicine, New York, NY, USA
| | - Andrew A Maudsley
- Department of Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Paul M Thompson
- Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, Los Angeles, CA, USA
- Departments of Neurology, Pediatrics, Psychiatry, Radiology, Engineering, and Ophthalmology, USC, Los Angeles, CA, USA
| | - Emily L Dennis
- Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, Los Angeles, CA, USA
- Department of Neurology, University of Utah, Salt Lake City, UT, USA
- Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, MA, USA
| | - David F Tate
- Department of Neurology, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Elisabeth A Wilde
- Department of Neurology, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA
- H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA
| | - Alexander Lin
- Center for Clinical Spectroscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
38
|
Gasco V, Cambria V, Bioletto F, Ghigo E, Grottoli S. Traumatic Brain Injury as Frequent Cause of Hypopituitarism and Growth Hormone Deficiency: Epidemiology, Diagnosis, and Treatment. Front Endocrinol (Lausanne) 2021; 12:634415. [PMID: 33790864 PMCID: PMC8005917 DOI: 10.3389/fendo.2021.634415] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Traumatic brain injury (TBI)-related hypopituitarism has been recognized as a clinical entity for more than a century, with the first case being reported in 1918. However, during the 20th century hypopituitarism was considered only a rare sequela of TBI. Since 2000 several studies strongly suggest that TBI-mediated pituitary hormones deficiency may be more frequent than previously thought. Growth hormone deficiency (GHD) is the most common abnormality, followed by hypogonadism, hypothyroidism, hypocortisolism, and diabetes insipidus. The pathophysiological mechanisms underlying pituitary damage in TBI patients include a primary injury that may lead to the direct trauma of the hypothalamus or pituitary gland; on the other hand, secondary injuries are mainly related to an interplay of a complex and ongoing cascade of specific molecular/biochemical events. The available data describe the importance of GHD after TBI and its influence in promoting neurocognitive and behavioral deficits. The poor outcomes that are seen with long standing GHD in post TBI patients could be improved by GH treatment, but to date literature data on the possible beneficial effects of GH replacement therapy in post-TBI GHD patients are currently scarce and fragmented. More studies are needed to further characterize this clinical syndrome with the purpose of establishing appropriate standards of care. The purpose of this review is to summarize the current state of knowledge about post-traumatic GH deficiency.
Collapse
|
|
39
|
Kövesdi E, Szabó-Meleg E, Abrahám IM. The Role of Estradiol in Traumatic Brain Injury: Mechanism and Treatment Potential. Int J Mol Sci 2020; 22:E11. [PMID: 33374952 PMCID: PMC7792596 DOI: 10.3390/ijms22010011] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 01/02/2023] Open
Abstract
Patients surviving traumatic brain injury (TBI) face numerous neurological and neuropsychological problems significantly affecting their quality of life. Extensive studies over the past decades have investigated pharmacological treatment options in different animal models, targeting various pathological consequences of TBI. Sex and gender are known to influence the outcome of TBI in animal models and in patients, respectively. Apart from its well-known effects on reproduction, 17β-estradiol (E2) has a neuroprotective role in brain injury. Hence, in this review, we focus on the effect of E2 in TBI in humans and animals. First, we discuss the clinical classification and pathomechanism of TBI, the research in animal models, and the neuroprotective role of E2. Based on the results of animal studies and clinical trials, we discuss possible E2 targets from early to late events in the pathomechanism of TBI, including neuroinflammation and possible disturbances of the endocrine system. Finally, the potential relevance of selective estrogenic compounds in the treatment of TBI will be discussed.
Collapse
Affiliation(s)
- Erzsébet Kövesdi
- Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Center for Neuroscience, Szentágothai Research Center, University of Pécs, H-7624 Pecs, Hungary;
| | - Edina Szabó-Meleg
- Department of Biophysics, Medical School, University of Pécs, H-7624 Pecs, Hungary;
| | - István M. Abrahám
- Molecular Neuroendocrinology Research Group, Institute of Physiology, Medical School, Center for Neuroscience, Szentágothai Research Center, University of Pécs, H-7624 Pecs, Hungary;
| |
Collapse
|
|
40
|
Song S, Gao Y, Sheng Y, Rui T, Luo C. Targeting NRF2 to suppress ferroptosis in brain injury. Histol Histopathol 2020; 36:383-397. [PMID: 33242213 DOI: 10.14670/hh-18-286] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Brain injury is accompanied by serious iron metabolism disorder and oxidative stress. As a novel form of regulated cell death (RCD) depending on lipid peroxidation caused by iron overload, ferroptosis (FPT) further aggravates brain injury, which is different from apoptosis, autophagy and other traditional cell death in terms of biochemistry, morphology and genetics. Noteworthy, transcriptional regulator NRF2 plays a key role in the cell antioxidant system, and many genes related to FPT are under the control of NRF2, including genes for iron regulation, thiol-dependent antioxidant system, enzymatic detoxification of RCS and carbonyls, NADPH regeneration and ROS sources from mitochondria or extra-mitochondria, which place NRF2 in the key position of regulating the ferroptotic death. Importantly, NRF2 can reduce iron load and resist FPT. In the future, it is expected to open up a new way to treat brain injury by targeting NRF2 to alleviate FPT in brain.
Collapse
Affiliation(s)
- Shunchen Song
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yaxuan Gao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yi Sheng
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Tongyu Rui
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chengliang Luo
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China.
| |
Collapse
|
|
41
|
Almalki WH, Alzahrani A, Mahmoud El-Daly MES, Fadel Ahmed ASHF. The emerging potential of SIRT-3 in oxidative stress-inflammatory axis associated increased neuroinflammatory component for metabolically impaired neural cell. Chem Biol Interact 2020; 333:109328. [PMID: 33245927 DOI: 10.1016/j.cbi.2020.109328] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/10/2020] [Accepted: 11/20/2020] [Indexed: 01/20/2023]
Abstract
People suffering from conditions like epilepsy, where there is an excess of neuron excitement, stroke, and cardiac arrest, where there are oxygen and glucose deprivation, Alzheimer, Parkinson, and Huntington's disease that causes metabolic and also oxidative stress-inflammatory axis; are known to be more vulnerable to disturbances in the metabolism, and there is a lot of inadequacy in defining the inflammation's mechanistic connections, as well as neurodegeneration and the bioenergetic deficiencies in the CNS. We retrieved relevant studies from PubMed/ScienceDirect/Medline/Public library of science/Mendeley/Springer link as well as Google Scholar. We used various keywords both individually and in combination with the literature search. 'Epidemiology of neurodegenerative disorders', 'neurodegenerative diseases associated hyper inflammation', 'Mechanism of inflammation in neuronal cell', 'Involvement of SIRTin inflammation', 'Pathogenesis of mitochondrial associated metabolic impairment in neurons', 'Reactive oxygen species-mediated mitochondrial dysfunction' were a few of the keywords used for the search. PINCH, which is a chronic neuro-inflammatory component that cannot be detected in matured neurons which are healthy, though expressed in oxidative stress inflammatory axis related tauopathy and diseases that cause neurodegeneration. We attempted to study the regulatory mechanisms that cause changes in the bioenergetics and its neuronal defects and mitochondrial subcellular localization that are PINCH protein-mediated on the other handSIRT1, the most intensively studied sirtuin, in oxidative stress-mediated inflammatory consequence for many diseases but very few research data explore the role of SIRT-3 for correction of the chronic neuroinflammatory component. Thus, in this review, we investigate the very recently identified molecules involving in the pathogenesis during stimulated oxidative stress-inflammatory axis in the excitatory neuronal cell which changes brain metabolism. Simultaneously, in CNS neurons of diseases with a component of chronic neuroinflammation which exhibit neuroprotective response, the consequences (mechanistic and biological) of SIRT-3, could be emerging future targets for neurodegenerative disorder treatment with impaired metabolisms.
Collapse
Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia.
| | - Abdulaziz Alzahrani
- Department of Pharmacology, College of Clinical Pharmacy, Albaha University, Saudi Arabia
| | | | | |
Collapse
|
|
42
|
Chung D, Shum A, Caraveo G. GAP-43 and BASP1 in Axon Regeneration: Implications for the Treatment of Neurodegenerative Diseases. Front Cell Dev Biol 2020; 8:567537. [PMID: 33015061 PMCID: PMC7494789 DOI: 10.3389/fcell.2020.567537] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/14/2020] [Indexed: 01/06/2023] Open
Abstract
Growth-associated protein-43 (GAP-43) and brain acid-soluble protein 1 (BASP1) regulate actin dynamics and presynaptic vesicle cycling at axon terminals, thereby facilitating axonal growth, regeneration, and plasticity. These functions highly depend on changes in GAP-43 and BASP1 expression levels and post-translational modifications such as phosphorylation. Interestingly, examinations of GAP-43 and BASP1 in neurodegenerative diseases reveal alterations in their expression and phosphorylation profiles. This review provides an overview of the structural properties, regulations, and functions of GAP-43 and BASP1, highlighting their involvement in neural injury response and regeneration. By discussing GAP-43 and BASP1 in the context of neurodegenerative diseases, we also explore the therapeutic potential of modulating their activities to compensate for neuron loss in neurodegenerative diseases.
Collapse
Affiliation(s)
- Daayun Chung
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Andrew Shum
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Gabriela Caraveo
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
43
|
Yuen KCJ, Masel BE, Reifschneider KL, Sheffield-Moore M, Urban RJ, Pyles RB. Alterations of the GH/IGF-I Axis and Gut Microbiome after Traumatic Brain Injury: A New Clinical Syndrome? J Clin Endocrinol Metab 2020; 105:5862647. [PMID: 32585029 DOI: 10.1210/clinem/dgaa398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/18/2020] [Indexed: 12/22/2022]
Abstract
CONTEXT Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking. EVIDENCE ACQUISITION A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms "growth hormone," "traumatic brain injury," and "gut microbiome." EVIDENCE SYNTHESIS Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called "brain injury associated fatigue and altered cognition." Notably, these patients demonstrate distinct characteristics from those with GH deficiency from other non-TBI causes in that their symptom complex improves significantly with recombinant human GH treatment, but does not reverse the underlying mechanistic cause as symptoms typically recur upon treatment cessation. CONCLUSION The reviewed data describe the importance of alterations of the GH/insulin-like growth factor I axis and gut microbiome after brain injury and its influence in promoting neurocognitive and behavioral deficits in a bidirectional relationship, and highlight a new clinical syndrome that may exist in a subset of TBI patients in whom recombinant human GH therapy could significantly improve symptomatology. More studies are needed to further characterize this clinical syndrome.
Collapse
Affiliation(s)
- Kevin C J Yuen
- Barrow Pituitary Center, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, Arizona
| | | | - Kent L Reifschneider
- Division of Endocrinology, Children's Specialty Group, Children's Hospital of The King's Daughters, Norfolk, Virginia
| | - Melinda Sheffield-Moore
- Department of Health and Kinesiology, Texas A & M University, College Station, Texas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555
| | - Randall J Urban
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555
| | - Richard B Pyles
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| |
Collapse
|
|
44
|
Reddy V, Grogan D, Ahluwalia M, Salles ÉL, Ahluwalia P, Khodadadi H, Alverson K, Nguyen A, Raju SP, Gaur P, Braun M, Vale FL, Costigliola V, Dhandapani K, Baban B, Vaibhav K. Targeting the endocannabinoid system: a predictive, preventive, and personalized medicine-directed approach to the management of brain pathologies. EPMA J 2020; 11:217-250. [PMID: 32549916 PMCID: PMC7272537 DOI: 10.1007/s13167-020-00203-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of "personalized medicine" as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
Collapse
Affiliation(s)
- Vamsi Reddy
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Dayton Grogan
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Meenakshi Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Évila Lopes Salles
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA USA
| | - Pankaj Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Hesam Khodadadi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA USA
| | - Katelyn Alverson
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Andy Nguyen
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Srikrishnan P. Raju
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
- Brown University, Providence, RI USA
| | - Pankaj Gaur
- Georgia Cancer Center, Augusta University, Augusta, GA USA
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA
| | - Molly Braun
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
- Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, USA
- VISN 20 Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, USA
| | - Fernando L. Vale
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | | | - Krishnan Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| | - Babak Baban
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA USA
| | - Kumar Vaibhav
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA
| |
Collapse
|
|
45
|
Abrahamson EE, Poloyac SM, Dixon CE, Dekosky ST, Ikonomovic MD. Acute and chronic effects of single dose memantine after controlled cortical impact injury in adult rats. Restor Neurol Neurosci 2020; 37:245-263. [PMID: 31177251 DOI: 10.3233/rnn-190909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. METHODS The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1-5 and 71-75, and spatial memory (Morris water maze test, MWM) was assessed on days 14-21 and 83-90 after CCI injury or sham surgery. RESULTS When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. CONCLUSIONS Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.
Collapse
Affiliation(s)
- Eric E Abrahamson
- Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh PA, USA.,Department of Neurology, University of Pittsburgh, Pittsburgh PA, USA
| | - Samuel M Poloyac
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh PA, USA
| | - C Edward Dixon
- Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh PA, USA.,Department of Neurosurgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Steven T Dekosky
- Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Milos D Ikonomovic
- Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh PA, USA.,Department of Neurology, University of Pittsburgh, Pittsburgh PA, USA.,Department of Psychiatry, University of Pittsburgh, Pittsburgh PA, USA
| |
Collapse
|
|
46
|
Lamade AM, Anthonymuthu TS, Hier ZE, Gao Y, Kagan VE, Bayır H. Mitochondrial damage & lipid signaling in traumatic brain injury. Exp Neurol 2020; 329:113307. [PMID: 32289317 DOI: 10.1016/j.expneurol.2020.113307] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/13/2022]
Abstract
Mitochondria are essential for neuronal function because they serve not only to sustain energy and redox homeostasis but also are harbingers of death. A dysregulated mitochondrial network can cascade until function is irreparably lost, dooming cells. TBI is most prevalent in the young and comes at significant personal and societal costs. Traumatic brain injury (TBI) triggers a biphasic and mechanistically heterogenous response and this mechanistic heterogeneity has made the development of standardized treatments challenging. The secondary phase of TBI injury evolves over hours and days after the initial insult, providing a window of opportunity for intervention. However, no FDA approved treatment for neuroprotection after TBI currently exists. With recent advances in detection techniques, there has been increasing recognition of the significance and roles of mitochondrial redox lipid signaling in both acute and chronic central nervous system (CNS) pathologies. Oxidized lipids and their downstream products result from and contribute to TBI pathogenesis. Therapies targeting the mitochondrial lipid composition and redox state show promise in experimental TBI and warrant further exploration. In this review, we provide 1) an overview for mitochondrial redox homeostasis with emphasis on glutathione metabolism, 2) the key mechanisms of TBI mitochondrial injury, 3) the pathways of mitochondria specific phospholipid cardiolipin oxidation, and 4) review the mechanisms of mitochondria quality control in TBI with consideration of the roles lipids play in this process.
Collapse
Affiliation(s)
- Andrew M Lamade
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Tamil S Anthonymuthu
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Zachary E Hier
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Yuan Gao
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Valerian E Kagan
- Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Institute for Regenerative Medicine, IM Sechenov First Moscow State Medical University, Russian Federation
| | - Hülya Bayır
- Department of Critical Care Medicine, Safar Center for Resuscitation Research UPMC, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
| |
Collapse
|
|
47
|
Liang KJ, Carlson ES. Resistance, vulnerability and resilience: A review of the cognitive cerebellum in aging and neurodegenerative diseases. Neurobiol Learn Mem 2020; 170:106981. [PMID: 30630042 PMCID: PMC6612482 DOI: 10.1016/j.nlm.2019.01.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/14/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022]
Abstract
In the context of neurodegeneration and aging, the cerebellum is an enigma. Genetic markers of cellular aging in cerebellum accumulate more slowly than in the rest of the brain, and it generates unknown factors that may slow or even reverse neurodegenerative pathology in animal models of Alzheimer's Disease (AD). Cerebellum shows increased activity in early AD and Parkinson's disease (PD), suggesting a compensatory function that may mitigate early symptoms of neurodegenerative pathophysiology. Perhaps most notably, different parts of the brain accumulate neuropathological markers of AD in a recognized progression and generally, cerebellum is the last brain region to do so. Taken together, these data suggest that cerebellum may be resistant to certain neurodegenerative mechanisms. On the other hand, in some contexts of accelerated neurodegeneration, such as that seen in chronic traumatic encephalopathy (CTE) following repeated traumatic brain injury (TBI), the cerebellum appears to be one of the most susceptible brain regions to injury and one of the first to exhibit signs of pathology. Cerebellar pathology in neurodegenerative disorders is strongly associated with cognitive dysfunction. In neurodegenerative or neurological disorders associated with cerebellar pathology, such as spinocerebellar ataxia, cerebellar cortical atrophy, and essential tremor, rates of cognitive dysfunction, dementia and neuropsychiatric symptoms increase. When the cerebellum shows AD pathology, such as in familial AD, it is associated with earlier onset and greater severity of disease. These data suggest that when neurodegenerative processes are active in the cerebellum, it may contribute to pathological behavioral outcomes. The cerebellum is well known for comparing internal representations of information with observed outcomes and providing real-time feedback to cortical regions, a critical function that is disturbed in neuropsychiatric disorders such as intellectual disability, schizophrenia, dementia, and autism, and required for cognitive domains such as working memory. While cerebellum has reciprocal connections with non-motor brain regions and likely plays a role in complex, goal-directed behaviors, it has proven difficult to establish what it does mechanistically to modulate these behaviors. Due to this lack of understanding, it's not surprising to see the cerebellum reflexively dismissed or even ignored in basic and translational neuropsychiatric literature. The overarching goals of this review are to answer the following questions from primary literature: When the cerebellum is affected by pathology, is it associated with decreased cognitive function? When it is intact, does it play a compensatory or protective role in maintaining cognitive function? Are there theoretical frameworks for understanding the role of cerebellum in cognition, and perhaps, illnesses characterized by cognitive dysfunction? Understanding the role of the cognitive cerebellum in neurodegenerative diseases has the potential to offer insight into origins of cognitive deficits in other neuropsychiatric disorders, which are often underappreciated, poorly understood, and not often treated.
Collapse
Affiliation(s)
- Katharine J Liang
- University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences, Seattle, WA, United States
| | - Erik S Carlson
- University of Washington School of Medicine, Seattle, WA, United States.
| |
Collapse
|
|
48
|
Bertogliat MJ, Morris-Blanco KC, Vemuganti R. Epigenetic mechanisms of neurodegenerative diseases and acute brain injury. Neurochem Int 2020; 133:104642. [PMID: 31838024 PMCID: PMC8074401 DOI: 10.1016/j.neuint.2019.104642] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/25/2019] [Accepted: 12/09/2019] [Indexed: 12/22/2022]
Abstract
Epigenetic modifications are emerging as major players in the pathogenesis of neurodegenerative disorders and susceptibility to acute brain injury. DNA and histone modifications act together with non-coding RNAs to form a complex gene expression machinery that adapts the brain to environmental stressors and injury response. These modifications influence cell-level operations like neurogenesis and DNA repair to large, intricate processes such as brain patterning, memory formation, motor function and cognition. Thus, epigenetic imbalance has been shown to influence the progression of many neurological disorders independent of aberrations in the genetic code. This review aims to highlight ways in which epigenetics applies to several commonly researched neurodegenerative diseases and forms of acute brain injury as well as shed light on the benefits of epigenetics-based treatments.
Collapse
Affiliation(s)
- Mario J Bertogliat
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Kahlilia C Morris-Blanco
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; William S. Middleton VA Hospital, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; William S. Middleton VA Hospital, Madison, WI, USA.
| |
Collapse
|
|
49
|
Pinchi E, Luigi C, Paola S, Gianpietro V, Raoul T, Mauro A, Paola F. MicroRNAs: The New Challenge for Traumatic Brain Injury Diagnosis. Curr Neuropharmacol 2020; 18:319-331. [PMID: 31729300 PMCID: PMC7327940 DOI: 10.2174/1570159x17666191113100808] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/30/2019] [Accepted: 11/10/2019] [Indexed: 12/13/2022] Open
Abstract
The acronym TBI refers to traumatic brain injury, an alteration of brain function, or an evidence of brain pathology, that is caused by an external force. TBI is estimated to become the third leading cause of permanent disability and mortality worldwide. TBI-related injuries can be classified in many ways, according to the degree of severity or the pathophysiology of brain injury (primary and secondary damage). Numerous cellular pathways act in secondary brain damage: excitotoxicity (mediated by excitatory neurotransmitters), free radical generation (due to mitochondrial impairment), neuroinflammatory response (due to central nervous system and immunoactivation) and apoptosis. In this scenario, microRNAs are implicated in the regulation of almost all genes at the post-transcriptional level. Several microRNAs have been demonstrated to be specifically expressed in particular cerebral areas; moreover, physiological changes in microRNA expression during normal cerebral development upon the establishment of neural networks have been characterized. More importantly, microRNAs show profound alteration in expression in response to brain pathological states, both traumatic or not. This review summarizes the most important molecular networks involved in TBI and examines the most recent and important findings on TBI-related microRNAs, both in animal and clinical studies. The importance of microRNA research holds promise to find biomarkers able to unearth primary and secondary molecular patterns altered upon TBI, to ultimately identify key points of regulation, as a valuable support in forensic pathology and potential therapeutic targets for clinical treatment.
Collapse
Affiliation(s)
- Enrica Pinchi
- Address correspondence to this author at the Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy; E-mail:
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Dependence on subconcussive impacts of brain metabolism in collision sport athletes: an MR spectroscopic study. Brain Imaging Behav 2019; 13:735-749. [PMID: 29802602 DOI: 10.1007/s11682-018-9861-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Long term neurological impairments due to repetitive head trauma are a growing concern for collision sport athletes. American Football has the highest rate of reported concussions among male high school athletes, a position held by soccer for female high school athletes. Recent research has shown that subconcussive events experienced by collision sport athletes can be a further significant source of accrued damage. Collision sport athletes experience hundreds of subconcussive events in a single season, and these largely go uninvestigated as they produce no overt clinical symptoms. Continued participation by these seemingly uninjured athletes is hypothesized to increase susceptibility to diagnoseable brain injury. This study paired magnetic resonance spectroscopy with head impact monitoring to quantify the relationship between metabolic changes and head acceleration event characteristics in high school-aged male football and female soccer collision sport athletes. During the period of exposure to subconcussive events, asymptomatic male (football) collision sport athletes exhibited statistically significant changes in concentrations of glutamate+glutamine (Glx) and total choline containing compounds (tCho) in dorsolateral prefrontal cortex, and female (soccer) collision sport athletes exhibited changes in glutamate+glutamine (Glx) in primary motor cortex. Neurometabolic alterations observed in football athletes during the second half of the season were found to be significantly associated with the average acceleration per head acceleration events, being best predicted by the accumulation of events exceeding 50 g. These marked deviations in neurometabolism, in the absence of overt symptoms, raise concern about the neural health of adolescent collision-sport athletes and suggest limiting exposure to head acceleration events may help to ameliorate the risk of subsequent cognitive impairment.
Collapse
|