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Meanti R, Bresciani E, Rizzi L, Molteni L, Coco S, Omeljaniuk RJ, Torsello A. Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases. Biomed Pharmacother 2025; 186:118044. [PMID: 40209306 DOI: 10.1016/j.biopha.2025.118044] [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: 12/28/2024] [Revised: 03/25/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025] Open
Abstract
The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.
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Affiliation(s)
- Ramona Meanti
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Elena Bresciani
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Laura Rizzi
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Laura Molteni
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Silvia Coco
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Robert J Omeljaniuk
- Department of Biology, Lakehead University, 955 Oliver Rd, Thunder Bay, Ontario P7B 5E1, Canada.
| | - Antonio Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
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2
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Liu S, Ma Z. The role of cannabinoid-mediated signaling pathways and mechanisms in brain disorders. Cell Signal 2025; 128:111653. [PMID: 39952540 DOI: 10.1016/j.cellsig.2025.111653] [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: 12/12/2024] [Revised: 01/17/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
Cannabinoids play significant roles in the central nervous system (CNS), but cannabinoid-mediated physiopathological functions are not elaborated. Cannabinoid receptors (CBRs) mediate functions that include the regulation of neuroinflammation, oxidative stress, apoptosis, autophagy, and neurogenesis. Microglia are the primary immune cells responsible for mediating neuroinflammation in the CNS. Therefore, this article primarily focuses on microglia to summarize the inflammatory pathways mediated by cannabinoids in the CNS, including nuclear factor-κB (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK), protein kinase B (Akt), and cAMP-dependent protein kinase (PKA) signaling pathways. Additionally, we provide a table summarizing the role of cannabinoids in various brain diseases. Medical use of cannabinoids has protective effects in preventing and treating brain diseases; however, excessive and repeated use can be detrimental to the CNS. We propose that cannabinoids hold significant potential for preventing and treating brain diseases, including ferroptosis, lactate metabolism, and mitophagy, providing new insights for further research on cannabinoids.
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Affiliation(s)
- Shunfeng Liu
- School of Basic Medicine, Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disorders, Qingdao University, Qingdao 266071, China
| | - Zegang Ma
- School of Basic Medicine, Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disorders, Qingdao University, Qingdao 266071, China.
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Alraddadi EA, Aljuhani FF, Alsamiri GY, Hafez SY, Alselami G, Almarghalani DA, Alamri FF. The Effects of Cannabinoids on Ischemic Stroke-Associated Neuroinflammation: A Systematic Review. J Neuroimmune Pharmacol 2025; 20:12. [PMID: 39899062 PMCID: PMC11790784 DOI: 10.1007/s11481-025-10171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
Stroke represents a significant burden on global health and the economy, with high mortality rates, disability, and recurrence. Ischemic stroke is a serious condition that occurs when a blood vessel in the brain is interrupted, reducing the blood supply to the affected area. Inflammation is a significant component in stroke pathophysiology. Neuroinflammation is triggered following the acute ischemic ictus, where the blood-brain barrier (BBB) breaks down, causing damage to the endothelial cells. The damage will eventually generate oxidative stress, activate the pathological phenotypes of astrocytes and microglia, and lead to neuronal death in the neurovascular unit. As a result, the brain unleashes a robust neuroinflammatory response, which can further worsen the neurological outcomes. Neuroinflammation is a complex pathological process involved in ischemic damage and repair. Finding new neuroinflammation molecular targets is essential to develop effective and safe novel treatment approaches against ischemic stroke. Accumulating studies have investigated the pharmacological properties of cannabinoids (CBs) for many years, and recent research has shown their potential therapeutic use in treating ischemic stroke in rodent models. These findings revealed promising impacts of CBs in reducing neuroinflammation and cellular death and ameliorating neurological deficits. In this review, we explore the possibility of the therapeutic administration of CBs in mitigating neuroinflammation caused by a stroke. We summarize the results from several preclinical studies evaluating the efficacy of CBs anti-inflammatory interventions in ischemic stroke. Although convincing preclinical evidence implies that CBs targeting neuroinflammation are promising for ischemic stroke, translating these findings into the clinical setting has proven to be challenging. The translation hurdle is due to the essence of the CBs ability to cause anxiety, cognitive deficit, and psychosis. Future studies are warranted to address the dose-beneficial effect of CBs in clinical trials of ischemic stroke-related neuroinflammation treatment.
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Affiliation(s)
- Eman A Alraddadi
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Faisal F Aljuhani
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Ghadah Y Alsamiri
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Salwa Y Hafez
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- College of Nursing, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Ghaida Alselami
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Daniyah A Almarghalani
- Stroke Research Unit, Taif University, Taif, Saudi Arabia
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Faisal F Alamri
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
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Yang X, Wang J, Jia X, Yang Y, Fang Y, Ying X, Li H, Zhang M, Wei J, Pan Y. Microglial polarization in Alzheimer's disease: Mechanisms, implications, and therapeutic opportunities. J Alzheimers Dis 2025:13872877241313223. [PMID: 39894910 DOI: 10.1177/13872877241313223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Microglial cells, the resident immune cells in the central nervous system, play a crucial role in the pathogenesis of AD. Microglia can undergo polarization, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in response to different stimuli. Dysregulation of microglial polarization towards the pro-inflammatory phenotype leads to the release of inflammatory cytokines, oxidative stress, and synaptic dysfunction. These processes contribute to neuronal damage and cognitive decline in AD. However, several challenges remain in this field. The complex molecular mechanisms governing microglial polarization in AD need to be further elucidated. In this review, we discuss the mechanisms underlying microglial polarization in AD and its implications in disease progression.
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Affiliation(s)
- Xinmao Yang
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jie Wang
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xiaotao Jia
- Department of Neurology, The Affifiliated Xi'an Central Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, PR China
| | - Yaqian Yang
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yan Fang
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xiaoping Ying
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Hong Li
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Meiqian Zhang
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jing Wei
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yanfang Pan
- Department of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
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Cai Y, Tong F, Li K, Wang Q, Ding J, Wang X. Cannabinoid receptor 2 agonist AM1241 alleviates epileptic seizures and epilepsy-associated depression via inhibiting neuroinflammation in a pilocarpine-induced chronic epilepsy mouse model. Mol Cell Neurosci 2024; 130:103958. [PMID: 39151841 DOI: 10.1016/j.mcn.2024.103958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/09/2024] [Accepted: 08/11/2024] [Indexed: 08/19/2024] Open
Abstract
Increasing evidence suggests that cannabinoid receptor 2 (CB2R) serves as a promising anti-inflammatory target. While inflammation is known to play crucial roles in the pathogenesis of epilepsy, the involvement of CB2R in epilepsy remains unclear. This study aimed to investigate the effects of a CB2R agonist, AM1241, on epileptic seizures and depressive-like behaviors in a mouse model of chronic epilepsy induced by pilocarpine. A chronic epilepsy mouse model was established by intraperitoneal administration of pilocarpine. The endogenous cannabinoid system (eCBs) in the hippocampus was examined after status epilepticus (SE). Animals were then treated with AM1241 and compared with a vehicle-treated control group. Additionally, the role of the AMPK/NLRP3 signaling pathway was explored using the selective AMPK inhibitor dorsomorphin. Following SE, CB2R expression increased significantly in hippocampal microglia. Administration of AM1241 significantly reduced seizure frequency, immobility time in the tail suspension test, and neuronal loss in the hippocampus. In addition, AM1241 treatment attenuated microglial activation, inhibited pro-inflammatory polarization of microglia, and suppressed NLRP3 inflammasome activation in the hippocampus after SE. Further, the therapeutic effects of AM1241 were abolished by the AMPK inhibitor dorsomorphin. Our findings suggest that CB2R agonist AM1241 may alleviate epileptic seizures and its associated depression by inhibiting neuroinflammation through the AMPK/NLRP3 signaling pathway. These results provide insight into a novel therapeutic approach for epilepsy.
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Affiliation(s)
- Yiying Cai
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fangchao Tong
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kexian Li
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiang Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of the State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
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Mao J, Guo Y, Li H, Ge H, Zhang C, Feng H, Zhong J, Hu R, Wang X. Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice. Heliyon 2024; 10:e26909. [PMID: 38439827 PMCID: PMC10909704 DOI: 10.1016/j.heliyon.2024.e26909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/06/2024] Open
Abstract
Background Early brain injury (EBI) caused by inflammatory responses in acute phase of Intracerebral hemorrhage (ICH) plays a vital role in the pathological progression of ICH. Increasing evidences demonstrate A1 reactive astrocytes are associated with the severity of EBI. G-protein coupled estrogen receptor 1 (GPER1) has been proved mediating the neuroprotective effects of estrogen in central nervous system (CNS) disease. However, whether GPER1 plays a protective effect on ICH and A1 reactive astrocytes activation is not well studied. Methods ICH model was established by infused the autologous whole blood into the right basal ganglia in wild type and GPER1 knockout mice. GPER1 specific agonist G1 and antagonist G15 were administered by intraperitoneal injection at 1 h or 0.5 h after ICH. Neurological function was detected on day 1 and day 3 by open field test and corner turn test following ICH. Besides, A1 reactive astrocytes were determined by immunofluorescence staining after ICH on day 3. To further identify the possible mechanism of GPER1 mediated neuroprotective effect, Western blot assays was performed after ICH on day 3. Results After ICH, G1 treatment alleviated mice neurobehavior deficits on day 1 and day 3. Meanwhile, G1 treatment also significantly reduced the GFAP positive astrocytes and the C3 positive cells after ICH. Interestingly, G15 reversed the protective effect of G1 on the neurobehavior of ICH mice. Meanwhile, the expression of GFAP+C3+ A1 reactive astrocytes were also reduced by activation of GPER1. Mechanistic studies indicated TLR4 and NF-κB mediated the neuroprotective effect of GPER1. Conclusion Generally, activation of GPER1 alleviated the EBI through inhibiting A1 reactive astrocytes activation via TLR4/NF-κB pathway after ICH in mice. Additionally, GPER1may be a promising target for ICH treatment.
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Affiliation(s)
- Jianchao Mao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yongkun Guo
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
| | - Huanhuan Li
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Hongfei Ge
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Chao Zhang
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Hua Feng
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Jun Zhong
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Rong Hu
- Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Xinjun Wang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
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Zhang G, Lu J, Zheng J, Mei S, Li H, Zhang X, Ping A, Gao S, Fang Y, Yu J. Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage. Neural Regen Res 2024; 19:161-170. [PMID: 37488863 PMCID: PMC10479839 DOI: 10.4103/1673-5374.375343] [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: 12/27/2022] [Revised: 03/27/2023] [Accepted: 04/02/2023] [Indexed: 07/26/2023] Open
Abstract
Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage. The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation. However, the effect of Spi1 on intracerebral hemorrhage remains unclear. In this study, we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome. We showed that high Spi1 expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis, glycolysis, and autophagy, as well as debris clearance and sustained remyelination. Notably, microglia with higher levels of Spi1 expression were characterized by activation of pathways associated with a variety of hemorrhage-related cellular processes, such as complement activation, angiogenesis, and coagulation. In conclusion, our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage. This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.
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Affiliation(s)
- Guoqiang Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jianan Lu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jingwei Zheng
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Shuhao Mei
- Department of Neurosurgery, Huashan Hospital of Fudan University School of Medicine, Shanghai, China
| | - Huaming Li
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xiaotao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - An Ping
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Shiqi Gao
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jun Yu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, Zhejiang Province, China
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Tang L, Wang L, Jin F, Hao Y, Zhao T, Zheng W, He Z. Inflammatory regulation by restraining M2 microglial polarization: Neurodestructive effects of Kallikrein-related peptidase 8 activation in intracerebral hemorrhage. Int Immunopharmacol 2023; 124:110855. [PMID: 37678029 DOI: 10.1016/j.intimp.2023.110855] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/09/2023]
Abstract
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
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Affiliation(s)
- Ling Tang
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Liyuan Wang
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Feng Jin
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Yuehan Hao
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Tianming Zhao
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Wenxu Zheng
- Geriatric Department of Dalian Friendship Hospital, Dalian, Liaoning, PR China.
| | - Zhiyi He
- Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, PR China.
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Chen N, Wang YL, Sun HF, Wang ZY, Zhang Q, Fan FY, Ma YC, Liu FX, Zhang YK. Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment. World J Stem Cells 2023; 15:561-575. [PMID: 37424949 PMCID: PMC10324506 DOI: 10.4252/wjsc.v15.i6.561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 04/22/2023] [Accepted: 05/16/2023] [Indexed: 06/26/2023] Open
Abstract
The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.
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Affiliation(s)
- Na Chen
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yan-Lin Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hui-Fang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Ya Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Fei-Yan Fan
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yu-Cheng Ma
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Fei-Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yun-Ke Zhang
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou 450008, Henan Province, China
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Grabon W, Rheims S, Smith J, Bodennec J, Belmeguenai A, Bezin L. CB2 receptor in the CNS: from immune and neuronal modulation to behavior. Neurosci Biobehav Rev 2023; 150:105226. [PMID: 37164044 DOI: 10.1016/j.neubiorev.2023.105226] [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: 12/30/2022] [Revised: 03/20/2023] [Accepted: 05/06/2023] [Indexed: 05/12/2023]
Abstract
Despite low levels of cannabinoid receptor type 2 (CB2R) expression in the central nervous system in human and rodents, a growing body of evidence shows CB2R involvement in many processes at the behavioral level, through both immune and neuronal modulations. Recent in vitro and in vivo evidence have highlighted the complex role of CB2R under physiological and inflammatory conditions. Under neuroinflammatory states, its activation seems to protect the brain and its functions, making it a promising target in a wide range of neurological disorders. Here, we provide a complete and updated overview of CB2R function in the central nervous system of rodents, spanning from modulation of immune function in microglia but also in other cell types, to behavior and neuronal activity, in both physiological and neuroinflammatory contexts.
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Affiliation(s)
- Wanda Grabon
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France; Epilepsy Institute IDEE, 59 boulevard Pinel - F-69500 Bron, France.
| | - Sylvain Rheims
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France; Epilepsy Institute IDEE, 59 boulevard Pinel - F-69500 Bron, France; Department of Functional Neurology and Epileptology, Hospices Civils de Lyon - France
| | - Jonathon Smith
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France; Epilepsy Institute IDEE, 59 boulevard Pinel - F-69500 Bron, France
| | - Jacques Bodennec
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France; Epilepsy Institute IDEE, 59 boulevard Pinel - F-69500 Bron, France
| | - Amor Belmeguenai
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France; Epilepsy Institute IDEE, 59 boulevard Pinel - F-69500 Bron, France
| | - Laurent Bezin
- Université Claude Bernard Lyon 1, CNRS, Inserm, Centre de Recherche en Neurosciences de Lyon, U10208 UMR5292, TIGER Team - F-69500 Bron, France.
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11
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Schouten M, Dalle S, Koppo K. Molecular Mechanisms Through Which Cannabidiol May Affect Skeletal Muscle Metabolism, Inflammation, Tissue Regeneration, and Anabolism: A Narrative Review. Cannabis Cannabinoid Res 2022; 7:745-757. [PMID: 36454174 DOI: 10.1089/can.2022.0220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: Cannabidiol (CBD), a nonintoxicating constituent of the cannabis plant, recently gained a lot of interest among athletes, since it is no longer considered as a prohibited substance by the World Anti-Doping Agency. The increasing prevalence of CBD use among athletes is driven by a perceived improvement in muscle recovery and a reduction in pain. However, compelling evidence from intervention studies is lacking and the precise mechanisms through which CBD may improve muscle recovery remain unknown. This highlights the need for more scientific studies and an evidence-based background. In the current review, the state-of-the-art knowledge on the effects of CBD on skeletal muscle tissue is summarized with special emphasis on the underlying mechanisms and molecular targets. More specifically, the large variety of receptor families that are believed to be involved in CBD's physiological effects are discussed. Furthermore, in vivo and in vitro studies that investigated the actual effects of CBD on skeletal muscle metabolism, inflammation, tissue regeneration, and anabolism are summarized, together with the functional effects of CBD supplementation on muscle recovery in human intervention trials. Overall, CBD was effective to increase the expression of metabolic regulators in muscle of obese mice (e.g., Akt, glycogen synthase kinase-3). CBD treatment in rodents reduced muscle inflammation following eccentric exercise (i.e., nuclear factor kappa B [NF-κB]), in a model of muscle dystrophy (e.g., interleukin-6, tumor necrosis factor alpha) and of obesity (e.g., COX-2, NF-κB). In addition, CBD did not affect in vitro or in vivo muscle anabolism, but improved satellite cell differentiation in dystrophic muscle. In humans, there are some indications that CBD supplementation improved muscle recovery (e.g., creatine kinase) and performance (e.g., squat performance). However, CBD doses were highly variable (between 16.7 and 150 mg) and there are some methodological concerns that should be considered. Conclusion: CBD has the prospective to become an adequate supplement that may improve muscle recovery. However, this research domain is still in its infancy and future studies addressing the molecular and functional effects of CBD in response to exercise are required to further elucidate the ergogenic potential of CBD.
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Affiliation(s)
- Moniek Schouten
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Sebastiaan Dalle
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Katrien Koppo
- Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
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12
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Gündel D, Deuther-Conrad W, Ueberham L, Kaur S, Otikova E, Teodoro R, Toussaint M, Lai TH, Clauß O, Scheunemann M, Bormans G, Bachmann M, Kopka K, Brust P, Moldovan RP. Structure-Based Design, Optimization, and Development of [ 18F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET. J Med Chem 2022; 65:9034-9049. [PMID: 35771668 DOI: 10.1021/acs.jmedchem.2c00256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RKi = 0.6 nM; CB1RKi/CB2RKi > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [18F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [18F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [18F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.
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Affiliation(s)
- Daniel Gündel
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Winnie Deuther-Conrad
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Lea Ueberham
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Sarandeep Kaur
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Elina Otikova
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Rodrigo Teodoro
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Magali Toussaint
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Thu Hang Lai
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany.,Department of Research and Development, ROTOP Pharmaka GmbH, 01069 Dresden, Germany
| | - Oliver Clauß
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Matthias Scheunemann
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Guy Bormans
- Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, BE-3000 Leuven, Belgium
| | - Michael Bachmann
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
| | - Klaus Kopka
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany.,Faculty of Chemistry and Food Chemistry, School of Science, TU Dresden, 01069 Dresden, Germany
| | - Peter Brust
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany.,The Lübeck Institute of Experimental Dermatology, University Medical Center Schleswig-Holstein, 23562 Lübeck, Germany
| | - Rareş-Petru Moldovan
- Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, 04318 Leipzig, Germany
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13
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Wendimu MY, Hooks SB. Microglia Phenotypes in Aging and Neurodegenerative Diseases. Cells 2022; 11:2091. [PMID: 35805174 PMCID: PMC9266143 DOI: 10.3390/cells11132091] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/24/2022] [Accepted: 06/29/2022] [Indexed: 02/08/2023] Open
Abstract
Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.
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Affiliation(s)
| | - Shelley B. Hooks
- Hooks Lab, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA;
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14
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Raut SB, Marathe PA, van Eijk L, Eri R, Ravindran M, Benedek DM, Ursano RJ, Canales JJ, Johnson LR. Diverse therapeutic developments for post-traumatic stress disorder (PTSD) indicate common mechanisms of memory modulation. Pharmacol Ther 2022; 239:108195. [PMID: 35489438 DOI: 10.1016/j.pharmthera.2022.108195] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 12/20/2022]
Abstract
Post-traumatic stress disorder (PTSD), characterized by abnormally persistent and distressing memories, is a chronic debilitating condition in need of new treatment options. Current treatment guidelines recommend psychotherapy as first line management with only two drugs, sertraline and paroxetine, approved by U.S. Food and Drug Administration (FDA) for treatment of PTSD. These drugs have limited efficacy as they only reduce symptoms related to depression and anxiety without producing permanent remission. PTSD remains a significant public health problem with high morbidity and mortality requiring major advances in therapeutics. Early evidence has emerged for the beneficial effects of psychedelics particularly in combination with psychotherapy for management of PTSD, including psilocybin, MDMA, LSD, cannabinoids, ayahuasca and ketamine. MDMA and psilocybin reduce barrier to therapy by increasing trust between therapist and patient, thus allowing for modification of trauma related memories. Furthermore, research into the memory reconsolidation mechanisms has allowed for identification of various pharmacological targets to disrupt abnormally persistent memories. A number of pre-clinical and clinical studies have investigated novel and re-purposed pharmacological agents to disrupt fear memory in PTSD. Novel therapeutic approaches like neuropeptide Y, oxytocin, cannabinoids and neuroactive steroids have also shown potential for PTSD treatment. Here, we focus on the role of fear memory in the pathophysiology of PTSD and propose that many of these new therapeutic strategies produce benefits through the effect on fear memory. Evaluation of recent research findings suggests that while a number of drugs have shown promising results in preclinical studies and pilot clinical trials, the evidence from large scale clinical trials would be needed for these drugs to be incorporated in clinical practice.
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Affiliation(s)
- Sanket B Raut
- Schools of Psychological Sciences, College of Health and Medicine, University of Tasmania, TAS 7250, Australia
| | - Padmaja A Marathe
- Department of Pharmacology and Therapeutics, Seth GS Medical College & KEM Hospital, Parel, Mumbai 400 012, India
| | - Liza van Eijk
- Department of Psychology, College of Healthcare Sciences, James Cook University, QLD 4811, Australia
| | - Rajaraman Eri
- Health Sciences, College of Health and Medicine, University of Tasmania, TAS 7250, Australia
| | - Manoj Ravindran
- Medicine, College of Health and Medicine, University of Tasmania, TAS 7250, Australia; Department of Psychiatry, North-West Private Hospital, Burnie TAS 7320, Australia
| | - David M Benedek
- Centre for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA
| | - Robert J Ursano
- Centre for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA
| | - Juan J Canales
- Schools of Psychological Sciences, College of Health and Medicine, University of Tasmania, TAS 7250, Australia
| | - Luke R Johnson
- Schools of Psychological Sciences, College of Health and Medicine, University of Tasmania, TAS 7250, Australia; Centre for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA.
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15
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Alaqel SI, Dlamini S, Almarghalani DA, Shettigar A, Alhadidi Q, Kodithuwakku SH, Stary C, Tillekeratne LMV, Shah ZA. Synthesis and Development of a Novel First-in-Class Cofilin Inhibitor for Neuroinflammation in Hemorrhagic Brain Injury. ACS Chem Neurosci 2022; 13:1014-1029. [PMID: 35302736 PMCID: PMC9996837 DOI: 10.1021/acschemneuro.2c00010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is devastating among stroke types with high mortality. To date, not a single therapeutic intervention has been successful. Cofilin plays a critical role in inflammation and cell death. In the current study, we embarked on designing and synthesizing a first-in-class small-molecule inhibitor of cofilin to target secondary complications of ICH, mainly neuroinflammation. A series of compounds were synthesized, and two lead compounds SZ-3 and SK-1-32 were selected for further studies. Neuronal and microglial viabilities were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay using neuroblastoma (SHSY-5Y) and human microglial (HMC-3) cell lines, respectively. Lipopolysaccharide (LPS)-induced inflammation in HMC-3 cells was used for neurotoxicity assay. Other assays include nitric oxide (NO) by Griess reagent, cofilin inhibition by F-actin depolymerization, migration by scratch wound assay, tumor necrosis factor (TNF-α) by enzyme-linked immunosorbent assay (ELISA), protease-activated receptor-1 (PAR-1) by immunocytochemistry and Western blotting (WB), and protein expression levels of several proteins by WB. SK-1-32 increased neuronal/microglial survival, reduced NO, and prevented neurotoxicity. However, SZ-3 showed no effect on neuronal/microglial survival but prevented microglia from LPS-induced inflammation by decreasing NO and preventing neurotoxicity. Therefore, we selected SZ-3 for further molecular studies, as it showed potent anti-inflammatory activities. SZ-3 decreased cofilin severing activity, and its treatment of LPS-activated HMC-3 cells attenuated microglial activation and suppressed migration and proliferation. HMC-3 cells subjected to thrombin, as an in vitro model for hemorrhagic stroke, and treated with SZ-3 after 3 h showed significantly decreased NO and TNF-α, significantly increased protein expression of phosphocofilin, and decreased PAR-1. In addition, SZ-3-treated SHSY-5Y showed a significant increase in cell viability by significantly reducing nuclear factor-κ B (NF-κB), caspase-3, and high-temperature requirement (HtrA2). Together, our results support the novel idea of targeting cofilin to counter neuroinflammation during secondary injury following ICH.
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Affiliation(s)
- Saleh I. Alaqel
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
| | - Samkeliso Dlamini
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
| | - Daniyah A. Almarghalani
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH, USA 43614
| | - Arjun Shettigar
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
| | - Qasim Alhadidi
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
| | - Sinali H. Kodithuwakku
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
| | - Creed Stary
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA 94305
| | | | - Zahoor A. Shah
- Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA 43614
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16
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Zhang R, Yong VW, Xue M. Revisiting Minocycline in Intracerebral Hemorrhage: Mechanisms and Clinical Translation. Front Immunol 2022; 13:844163. [PMID: 35401553 PMCID: PMC8993500 DOI: 10.3389/fimmu.2022.844163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/24/2022] [Indexed: 01/31/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is an important subtype of stroke with an unsatisfactory prognosis of high mortality and disability. Although many pre-clinical studies and clinical trials have been performed in the past decades, effective therapy that meaningfully improve prognosis and outcomes of ICH patients is still lacking. An active area of research is towards alleviating secondary brain injury after ICH through neuroprotective pharmaceuticals and in which minocycline is a promising candidate. Here, we will first discuss new insights into the protective mechanisms of minocycline for ICH including reducing iron-related toxicity, maintenance of blood-brain barrier, and alleviating different types of cell death from preclinical data, then consider its shortcomings. Finally, we will review clinical trial perspectives for minocycline in ICH. We hope that this summary and discussion about updated information on minocycline as a viable treatment for ICH can facilitate further investigations.
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Affiliation(s)
- Ruiyi Zhang
- The Departments of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - V. Wee Yong
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - Mengzhou Xue
- The Departments of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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17
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Liu Y, Fu H, Wang T. Neuroinflammation in perioperative neurocognitive disorders: From bench to the bedside. CNS Neurosci Ther 2022; 28:484-496. [PMID: 34990087 PMCID: PMC8928922 DOI: 10.1111/cns.13794] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 12/17/2022] Open
Abstract
The perioperative neurocognitive disorders (PNDs) are one of the most common complications in elderly patients characterized by various forms of cognitive decline after anesthesia and surgery. Although the etiology for PNDs remained unclear, neuroinflammation has been characterized as one of the major causes, especially in the elderly patients. The activation of glial cells including microglia and astrocytes plays a significant role in the inflammatory responses in central nerve system (CNS). Although carefully designed, clinical studies on PNDs showed controversial results. Meanwhile, preclinical studies provided evidence from various levels, including behavior performance, protein levels, and gene expression. In this review, we summarize high‐quality studies and recent advances from both clinical and preclinical studies and provide a broad view from the onset of PNDs to its potential therapeutic targets. Future studies are needed to investigate the signaling pathways in PNDs for prevention and treatment, as well as the relationship of PNDs and future neurocognitive dysfunction.
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Affiliation(s)
- Yang Liu
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Huiqun Fu
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Tianlong Wang
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
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18
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Li L, Luo Q, Shang B, Yang X, Zhang Y, Pan Q, Wu N, Tang W, Du D, Sun X, Jiang L. Selective activation of cannabinoid receptor-2 reduces white matter injury via PERK signaling in a rat model of traumatic brain injury. Exp Neurol 2022; 347:113899. [PMID: 34678230 DOI: 10.1016/j.expneurol.2021.113899] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/30/2021] [Accepted: 10/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND PURPOSE Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. METHODS The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies. RESULTS JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist. CONCLUSIONS This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.
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Affiliation(s)
- Lin Li
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Neurosurgery, Nanchong Central Hospital, Nanchong, China
| | - Qing Luo
- Department of Ultrasound, Nanchong Central Hospital, Nanchong, China
| | - Bin Shang
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong, China
| | - Xiaomin Yang
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Zhang
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiuling Pan
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Wu
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Tang
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Donglin Du
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaochuan Sun
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Li Jiang
- Department of Neurosurgery, Neural injury and protection laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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19
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Liu J, He J, Huang Y, Ge L, Xiao H, Zeng L, Jiang Z, Lu M, Hu Z. Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1362. [PMID: 34733914 PMCID: PMC8506532 DOI: 10.21037/atm-21-2590] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/14/2021] [Indexed: 01/01/2023]
Abstract
Background Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown. This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms. Methods ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×105 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and pro-inflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM). Results The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH. Conclusions Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model.
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Affiliation(s)
- Jianyang Liu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jialin He
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan Huang
- National Health Commission Key Laboratory of Birth Defects Research, Prevention, and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China
| | - Lite Ge
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Han Xiao
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Liuwang Zeng
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Zheng Jiang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming Lu
- Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, China.,Hunan Provincial Key Laboratory of Neurorestoratology, Second Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhiping Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
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20
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Central Nervous System Tissue Regeneration after Intracerebral Hemorrhage: The Next Frontier. Cells 2021; 10:cells10102513. [PMID: 34685493 PMCID: PMC8534252 DOI: 10.3390/cells10102513] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/13/2021] [Accepted: 09/17/2021] [Indexed: 12/11/2022] Open
Abstract
Despite marked advances in surgical techniques and understanding of secondary brain injury mechanisms, the prognosis of intracerebral hemorrhage (ICH) remains devastating. Harnessing and promoting the regenerative potential of the central nervous system may improve the outcomes of patients with hemorrhagic stroke, but approaches are still in their infancy. In this review, we discuss the regenerative phenomena occurring in animal models and human ICH, provide results related to cellular and molecular mechanisms of the repair process including by microglia, and review potential methods to promote tissue regeneration in ICH. We aim to stimulate research involving tissue restoration after ICH.
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21
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Prowse N, Hayley S. Microglia and BDNF at the crossroads of stressor related disorders: Towards a unique trophic phenotype. Neurosci Biobehav Rev 2021; 131:135-163. [PMID: 34537262 DOI: 10.1016/j.neubiorev.2021.09.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022]
Abstract
Stressors ranging from psychogenic/social to neurogenic/injury to systemic/microbial can impact microglial inflammatory processes, but less is known regarding their effects on trophic properties of microglia. Recent studies do suggest that microglia can modulate neuronal plasticity, possibly through brain derived neurotrophic factor (BDNF). This is particularly important given the link between BDNF and neuropsychiatric and neurodegenerative pathology. We posit that certain activated states of microglia play a role in maintaining the delicate balance of BDNF release onto neuronal synapses. This focused review will address how different "activators" influence the expression and release of microglial BDNF and address the question of tropomyosin receptor kinase B (TrkB) expression on microglia. We will then assess sex-based differences in microglial function and BDNF expression, and how microglia are involved in the stress response and related disorders such as depression. Drawing on research from a variety of other disorders, we will highlight challenges and opportunities for modulators that can shift microglia to a "trophic" phenotype with a view to potential therapeutics relevant for stressor-related disorders.
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Affiliation(s)
- Natalie Prowse
- Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
| | - Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
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22
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Zhai X, Chen K, Yang H, Li B, Zhou T, Wang H, Zhou H, Chen S, Zhou X, Wei X, Bai Y, Li M. Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury. J Nanobiotechnology 2021; 19:274. [PMID: 34496892 PMCID: PMC8425042 DOI: 10.1186/s12951-021-01022-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. METHODS CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. RESULTS CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. CONCLUSIONS CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy.
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Affiliation(s)
- Xiao Zhai
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Kai Chen
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Huan Yang
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Bo Li
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Tianjunke Zhou
- Basic Medicine College, Naval Medical University, Shanghai, 200433, China
| | - Haojue Wang
- Basic Medicine College, Naval Medical University, Shanghai, 200433, China
| | - Huipeng Zhou
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Shaofeng Chen
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xiaoyi Zhou
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xiaozhao Wei
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| | - Yushu Bai
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
| | - Ming Li
- Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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23
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Hashiesh HM, Sharma C, Goyal SN, Jha NK, Ojha S. Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist. Front Pharmacol 2021; 12:702675. [PMID: 34393784 PMCID: PMC8363263 DOI: 10.3389/fphar.2021.702675] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022] Open
Abstract
The endocannabinoid system has attracted attention as a pharmacological target for several pathological conditions. Cannabinoid (CB2)-selective agonists have been the focus of pharmacological studies because modulation of the CB2 receptor (CB2R) can be useful in the treatment of pain, inflammation, arthritis, addiction, and cancer among other possible therapeutic applications while circumventing CNS-related adverse effects. Increasing number of evidences from different independent preclinical studies have suggested new perspectives on the involvement of CB2R signaling in inflammation, infection and immunity, thus play important role in cancer, cardiovascular, renal, hepatic and metabolic diseases. JWH133 is a synthetic agonist with high CB2R selectivity and showed to exert CB2R mediated antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory activities. Cumulative evidences suggest that JWH133 protects against hepatic injury, renal injury, cardiotoxicity, fibrosis, rheumatoid arthritis, and cancer as well as against oxidative damage and inflammation, inhibits fibrosis and apoptosis, and acts as an immunosuppressant. This review provides a comprehensive overview of the polypharmacological properties and therapeutic potential of JWH133. This review also presents molecular mechanism and signaling pathways of JWH133 under various pathological conditions except neurological diseases. Based on the available data, this review proposes the possibilities of developing JWH133 as a promising therapeutic agent; however, further safety and toxicity studies in preclinical studies and clinical trials in humans are warranted.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sameer N Goyal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.,Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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24
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Hashiesh HM, Jha NK, Sharma C, Gupta PK, Jha SK, Patil CR, Goyal SN, Ojha SK. Pharmacological potential of JWH133, a cannabinoid type 2 receptor agonist in neurodegenerative, neurodevelopmental and neuropsychiatric diseases. Eur J Pharmacol 2021; 909:174398. [PMID: 34332924 DOI: 10.1016/j.ejphar.2021.174398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/15/2021] [Accepted: 07/28/2021] [Indexed: 12/09/2022]
Abstract
The pharmacological activation of cannabinoid type 2 receptors (CB2R) gained attention due to its ability to mitigate neuroinflammatory events without eliciting psychotropic actions, a limiting factor for the drugs targeting cannabinoid type 1 receptors (CB1R). Therefore, ligands activating CB2R are receiving enormous importance for therapeutic targeting in numerous neurological diseases including neurodegenerative, neuropsychiatric and neurodevelopmental disorders as well as traumatic injuries and neuropathic pain where neuroinflammation is a common accompaniment. Since the characterization of CB2R, many CB2R selective synthetic ligands have been developed with high selectivity and functional activity. Among numerous ligands, JWH133 has been found one of the compounds with high selectivity for CB2R. JWH133 has been reported to exhibit numerous pharmacological activities including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory. Recent studies have shown that JWH133 possesses potent neuroprotective properties in several neurological disorders, including neuropathic pain, anxiety, epilepsy, depression, alcoholism, psychosis, stroke, and neurodegeneration. Additionally, JWH133 showed to protect neurons from oxidative damage and inflammation, promote neuronal survival and neurogenesis, and serve as an immunomodulatory agent. The present review comprehensively examined neuropharmacological activities of JWH133 in neurological disorders including neurodegenerative, neurodevelopmental and neuropsychiatric using synoptic tables and elucidated pharmacological mechanisms based on reported observations. Considering the cumulative data, JWH133 appears to be a promising CB2R agonist molecule for further evaluation and it can be a prototype agent in drug discovery and development for a unique class of agents in neurotherapeutics. Further, regulatory toxicology and pharmacokinetic studies are required to determine safety and proceed for clinical evaluation.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Piyush Kumar Gupta
- Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida, 201310, Uttar Pradesh, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Chandragouda R Patil
- Department of Pharmacology, Delhi Pharmaceutical Sciences & Research University, Pushp Vihar, New Delhi, 110017, India
| | - Sameer N Goyal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Shreesh K Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates.
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25
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Teodoro R, Gündel D, Deuther-Conrad W, Ueberham L, Toussaint M, Bormans G, Brust P, Moldovan RP. Development of [ 18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain. Int J Mol Sci 2021; 22:ijms22158051. [PMID: 34360817 PMCID: PMC8347709 DOI: 10.3390/ijms22158051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/16/2022] Open
Abstract
Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.
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Affiliation(s)
- Rodrigo Teodoro
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
| | - Daniel Gündel
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
| | - Winnie Deuther-Conrad
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
| | - Lea Ueberham
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
| | - Magali Toussaint
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
| | - Guy Bormans
- Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, BE-3000 Leuven, Belgium;
| | - Peter Brust
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
- The Lübeck Institute of Experimental Dermatology, University Medical Center Schleswig-Holstein, 23562 Lübeck, Germany
| | - Rareş-Petru Moldovan
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany; (R.T.); (D.G.); (W.D.-C.); (L.U.); (M.T.); (P.B.)
- Correspondence: ; Tel.: +49-3412-3417-94634
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26
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Hashiesh HM, Sharma C, Goyal SN, Sadek B, Jha NK, Kaabi JA, Ojha S. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid. Biomed Pharmacother 2021; 140:111639. [PMID: 34091179 DOI: 10.1016/j.biopha.2021.111639] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/12/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R. The ligands activate CB2R are of endogenous, synthetic and plant origin. In recent years, β-caryophyllene (BCP), a natural bicyclic sesquiterpene in cannabis as well as non-cannabis plants, has received attention due to its selective agonist property on CB2R. BCP has been well studied in a variety of pathological conditions mediating CB2R selective agonist property. The focus of the present manuscript is to represent the CB2R selective agonist mediated pharmacological mechanisms and therapeutic potential of BCP. The present narrative review summarizes insights into the CB2R-selective pharmacological properties and therapeutic potential of BCP such as cardioprotective, hepatoprotective, neuroprotective, nephroprotective, gastroprotective, chemopreventive, antioxidant, anti-inflammatory, and immunomodulator. The available evidences suggest that BCP, can be an important candidate of plant origin endowed with CB2R selective properties that may provide a pharmacological rationale for its pharmacotherapeutic application and pharmaceutical development like a drug. Additionally, given the wide availability in edible plants and dietary use, with safety, and no toxicity, BCP can be promoted as a nutraceutical and functional food for general health and well-being. Further, studies are needed to explore pharmacological and pharmaceutical opportunities for therapeutic and preventive applications of use of BCP in human diseases.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Sameer N Goyal
- Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule 424001, Maharashtra, India
| | - Bassem Sadek
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh 201310, India
| | - Juma Al Kaabi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates; Zayed Bin Sultan Al Nahyan Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
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27
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Saxena S, Kruys V, Vamecq J, Maze M. The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders. Front Aging Neurosci 2021; 13:671499. [PMID: 34122048 PMCID: PMC8193130 DOI: 10.3389/fnagi.2021.671499] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/04/2021] [Indexed: 12/14/2022] Open
Abstract
The aseptic trauma of peripheral surgery activates a systemic inflammatory response that results in neuro-inflammation; the microglia, the resident immunocompetent cells in the brain, are a key element of the neuroinflammatory response. In most settings microglia perform a surveillance role in the brain detecting and responding to “invaders” to maintain homeostasis. However, microglia have also been implicated in producing harm possibly by changing its phenotype from its beneficial, anti-inflammatory state (termed M2) into an injurious pro-inflammatory state (termed M1); it is likely that there are intermediates states between these polar phenotypes and some consider that a gradient exists with a number of intermediates, rather than a strict dichotomy between M1 and M2. In the pro-inflammatory phenotypes, microglia can disrupt synaptic plasticity such as long- term potentiation that can result in disorders of learning and memory of the type observed in Peri-operative Neurocognitive Disorders. Therefore, investigators have sought strategies to prevent microglia from provoking this adverse event in the perioperative period. In preclinical studies microglia can be depleted by removing trophic factors required for its maintenance; subsequent repopulation with a more beneficial microglial phenotype may result in memory enhancement, improved sensory motor function, as well as suppression of neuroinflammatory and oxidative stress pathways. Another approach consists of preventing microglial activation using the non-specific P38 MAP kinase blockers such as minocycline. Perhaps a more physiologic approach is the use of inhibitors of potassium (K+) channels that are required to convert the microglia into an active state. In this context the specific K+ channels that are implicated are termed Kv1.3 and KCa3.1 and high selective inhibitors for each have been developed. Data are accumulating demonstrating the utility of these K+ channel blockers in preventing Perioperative Neurocognitive Disorders.
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Affiliation(s)
- Sarah Saxena
- Department of Anesthesia, University Hospital Center (CHU de Charleroi), Charleroi, Belgium.,Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, United States
| | - Veronique Kruys
- Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, ULB Immunology Research Center (UIRC), Free University of Brussels (ULB), Gosselies, Belgium
| | - Joseph Vamecq
- Inserm, CHU Lille, Univ Lille, Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition and Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU Lille, University of North France, Lille, France
| | - Mervyn Maze
- Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, United States
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28
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Prospects of Therapeutic Target and Directions for Ischemic Stroke. Pharmaceuticals (Basel) 2021; 14:ph14040321. [PMID: 33916253 PMCID: PMC8065883 DOI: 10.3390/ph14040321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/26/2021] [Accepted: 03/28/2021] [Indexed: 12/12/2022] Open
Abstract
Stroke is a serious, adverse neurological event and the third leading cause of death and disability worldwide. Most strokes are caused by a block in cerebral blood flow, resulting in neurological deficits through the death of brain tissue. Recombinant tissue plasminogen activator (rt-PA) is currently the only immediate treatment medication for stroke. The goal of rt-PA administration is to reduce the thrombus and/or embolism via thrombolysis; however, the administration of rt-PA must occur within a very short therapeutic timeframe (3 h to 6 h) after symptom onset. Components of the pathological mechanisms involved in ischemic stroke can be used as potential biomarkers in current treatment. However, none are currently under investigation in clinical trials; thus, further studies investigating biomarkers are needed. After ischemic stroke, microglial cells can be activated and release inflammatory cytokines. These cytokines lead to severe neurotoxicity via the overactivation of microglia in prolonged and lasting insults such as stroke. Thus, the balanced regulation of microglial activation may be necessary for therapy. Stem cell therapy is a promising clinical treatment strategy for ischemic stroke. Stem cells can increase the functional recovery of damaged tissue after post-ischemic stroke through various mechanisms including the secretion of neurotrophic factors, immunomodulation, the stimulation of endogenous neurogenesis, and neovascularization. To investigate the use of stem cell therapy for neurological diseases in preclinical studies, however, it is important to develop imaging technologies that are able to evaluate disease progression and to “chase” (i.e., track or monitor) transplanted stem cells in recipients. Imaging technology development is rapidly advancing, and more sensitive techniques, such as the invasive and non-invasive multimodal techniques, are under development. Here, we summarize the potential risk factors and biomarker treatment strategies, stem cell-based therapy and emerging multimodal imaging techniques in the context of stroke. This current review provides a conceptual framework for considering the therapeutic targets and directions for the treatment of brain dysfunctions, with a particular focus on ischemic stroke.
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29
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Wilson NL, Peterson SN, Ellis RJ. Cannabis and the Gut-Brain Axis Communication in HIV Infection. Cannabis Cannabinoid Res 2021; 6:92-104. [PMID: 33912676 PMCID: PMC8064951 DOI: 10.1089/can.2020.0037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
People living with HIV infection (PWH) disclose that cannabis is an effective strategy for alleviating symptoms associated with HIV disease. However, some medical providers feel ill-informed to engage in evidence-based conversations. HIV leads to alterations in the gut microbiome, gut-brain axis signaling, and chronic inflammation. The endocannabinoid system regulates homeostasis of multiple organ systems. When deficient, dysregulation of the gut-brain axis can result in chronic inflammation and neuroinflammation. Cannabis along with the naturally occurring endocannabinoids has antioxidant and anti-inflammatory properties that can support healing and restoration as an adjunctive therapy. The purpose of this literature review is to report the physiologic mechanisms that occur in the pathology of HIV and discuss potential benefits of cannabinoids in supporting health and reducing the negative effects of comorbidities in PWH.
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Affiliation(s)
- Natalie L. Wilson
- Department of Community Health Systems, School of Nursing, University of California, San Francisco, San Francisco, California, USA
| | - Scott N. Peterson
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Ronald J. Ellis
- Departments of Neurosciences and Psychiatry, University of California, San Diego, San Diego, California, USA
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30
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Zhang D, Cai G, Liu K, Zhuang Z, Jia K, Pei S, Wang X, Wang H, Xu S, Cui C, Sun M, Guo S, Song W, Cai G. Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1. Aging (Albany NY) 2021; 13:4079-4095. [PMID: 33461167 PMCID: PMC7906161 DOI: 10.18632/aging.202373] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.
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Affiliation(s)
- Dianquan Zhang
- Department of Rehabilitation Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Guoliang Cai
- Postdoctoral Research Workstation of Harbin Sport University, Harbin 150008, China.,Harbin Sport University, Harbin 150008, China
| | - Kai Liu
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Zhe Zhuang
- Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Kunping Jia
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Siying Pei
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Xiuzhen Wang
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Hong Wang
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Shengnan Xu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Cheng Cui
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Manchao Sun
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Sihui Guo
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Wenli Song
- Harbin Sport University, Harbin 150008, China
| | - Guofeng Cai
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China.,Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
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CB2R agonist JWH-133 attenuates chronic inflammation by restraining M1 macrophage polarization via Nrf2/HO-1 pathway in diet-induced obese mice. Life Sci 2020; 260:118424. [PMID: 32949586 DOI: 10.1016/j.lfs.2020.118424] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/31/2020] [Accepted: 09/08/2020] [Indexed: 12/20/2022]
Abstract
AIMS Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages. MATERIALS AND METHODS We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. KEY FINDINGS We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1β, CC motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride. SIGNIFICANCE JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity.
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Zhao J, Wang M, Liu W, Ma Z, Wu J. Activation of cannabinoid receptor 2 protects rat hippocampal neurons against Aβ-induced neuronal toxicity. Neurosci Lett 2020; 735:135207. [DOI: 10.1016/j.neulet.2020.135207] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/29/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
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Neuroinflammation Mediated by NLRP3 Inflammasome After Intracerebral Hemorrhage and Potential Therapeutic Targets. Mol Neurobiol 2020; 57:5130-5149. [PMID: 32856203 DOI: 10.1007/s12035-020-02082-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke; there is still a lack of effective treatment. Microglia are a major component of the innate immune system, and they respond to acute brain injury by activating and forming classic M1-like (pro-inflammatory) or alternative M2-like (anti-inflammatory) phenotype. The existence of the polarization indicates that the role of microglia in disease's progression and recovery after ICH is still unclear, perhaps involving microglial secretion of anti-inflammatory or pro-inflammatory cytokines and chemokines. The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is considered to be the main participant in neuroinflammation. Recent evidence has shown that NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. Furthermore, previous studies have reported that NLRP3 inflammasome is mainly present in microglia, so we speculate that its activation may be strongly associated with microglial polarization. Many scholars have investigated the role of brain injury caused by NLRP3 inflammasome after ICH, but the precise operating mechanisms remain uncertain. This review summarized the activation mechanism of NLRP3 inflammasome after ICH and the possible mechanism of NLRP3 inflammasome promoting neuroinflammation and aggravating nerve injury and discussed the relevant potential therapeutic targets.
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Jiang CT, Wu WF, Deng YH, Ge JW. Modulators of microglia activation and polarization in ischemic stroke (Review). Mol Med Rep 2020; 21:2006-2018. [PMID: 32323760 PMCID: PMC7115206 DOI: 10.3892/mmr.2020.11003] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/06/2020] [Indexed: 12/16/2022] Open
Abstract
Ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. As the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. In response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti‑inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. It has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. In addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified.
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Affiliation(s)
- Cheng-Ting Jiang
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Wan-Feng Wu
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Yi-Hui Deng
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Jin-Wen Ge
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
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Neuroinflammation in CNS diseases: Molecular mechanisms and the therapeutic potential of plant derived bioactive molecules. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100176] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Tanaka M, Sackett S, Zhang Y. Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology. Front Neurol 2020; 11:87. [PMID: 32117037 PMCID: PMC7033501 DOI: 10.3389/fneur.2020.00087] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/24/2020] [Indexed: 12/12/2022] Open
Abstract
Microglia, the resident immune cells of the central nervous system, mediate brain homeostasis by controlling neuronal proliferation/differentiation and synaptic activity. In response to external signals from neuropathological conditions, homeostatic (M0) microglia can adopt one of two activation states: the classical (M1) activation state, which secretes mediators of the proinflammatory response, and the alternative (M2) activation state, which presumably mediates the resolution of neuroinflammation and tissue repair/remodeling. Since chronic inflammatory activation of microglia is correlated with several neurodegenerative diseases, functional modulation of microglial phenotypes has been considered as a potential therapeutic strategy. The endocannabinoid (eCB) system, composed of cannabinoid receptors and ligands and their metabolic/biosynthetic enzymes, has been shown to activate anti-inflammatory signaling pathways that modulate immune cell functions. Growing evidence has demonstrated that endogenous, synthetic, and plant-derived eCB agonists possess therapeutic effects on several neuropathologies; however, the molecular mechanisms that mediate the anti-inflammatory effects have not yet been identified. Over the last decade, it has been revealed that the eCB system modulates microglial activation and population. In this review, we thoroughly examine recent studies on microglial phenotype modulation by eCB in neuroinflammatory and neurodegenerative disease conditions. We hypothesize that cannabinoid 2 receptor (CB2R) signaling shifts the balance of expression between neuroinflammatory (M1-type) genes, neuroprotective (M2-type) genes, and homeostatic (M0-type) genes toward the latter two gene expressions, by which microglia acquire therapeutic functionality.
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Affiliation(s)
- Mikiei Tanaka
- Department of Anatomy, Physiology and Genetics, Uniformed Services University Health Sciences, Bethesda, MD, United States
| | - Scott Sackett
- Department of Anatomy, Physiology and Genetics, Uniformed Services University Health Sciences, Bethesda, MD, United States
| | - Yumin Zhang
- Department of Anatomy, Physiology and Genetics, Uniformed Services University Health Sciences, Bethesda, MD, United States
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Li W, Li L, Li W, Chopp M, Venkat P, Zacharek A, Chen Z, Landschoot-Ward J, Chen J. Spleen associated immune-response mediates brain-heart interaction after intracerebral hemorrhage. Exp Neurol 2020; 327:113209. [PMID: 31987832 DOI: 10.1016/j.expneurol.2020.113209] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/06/2020] [Accepted: 01/24/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND PURPOSE Intracerebral hemorrhage (ICH) patients frequently encounter cardiovascular complications which may contribute to increased mortality and poor long term outcome. ICH induces systemic oxidative stress and activates peripheral immune responses which are involved in the pathological cascade leading to cardiac dysfunction and heart failure after ICH. We have previously reported that ICH induces progressive cardiac dysfunction in mice without primary cardiac diseases. In this study, we have investigated the role of immune response in mediating cardiac dysfunction post ICH in mice. METHODS Adult male C57BL/6 J mice were randomly assigned to the following groups (n = 8/group): 1) sham control; 2) ICH; 3) splenectomy with ICH (ICH + Spx); 4) splenectomy alone (Spx). Echocardiography was performed at 7 and 28 days after ICH. A battery of neurological and cognitive tests were performed. Flow cytometry, western blot and immunostaining were used to test mechanisms of ICH induced cardiac dysfunction. RESULTS Compared to sham control mice, Spx alone does not induce acute (7 day) or chronic (28 day) cardiac dysfunction. ICH induces significant neurological and cognitive deficits, as well as acute and chronic cardiac dysfunction compared to sham control mice. Mice subjected to ICH + Spx exhibit significantly improved neurological and cognitive function compared to ICH mice. Mice with ICH + Spx also exhibit significantly improved acute and chronic cardiac function compared to ICH mice indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased cardiac fibrosis, decreased cardiomyocyte hypertrophy, decreased cardiac infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart. CONCLUSIONS Our study demonstrates that splenectomy attenuates ICH-induced neurological and cognitive impairment as well as ICH-induced cardiac dysfunction in mice. Inflammatory cell infiltration into heart and immune responses mediated by the spleen may contribute to ICH-induce acute and chronic cardiac dysfunction and pathological cardiac remodeling.
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Affiliation(s)
- Wei Li
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
| | - Linlin Li
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wenkui Li
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA; Department of Physics, Oakland University, Rochester, MI 48309, USA
| | - Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Zhili Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
| | | | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
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Nguyen Ngo Le MA, Wen YT, Ho YC, Kapupara K, Tsai RK. Therapeutic Effects of Puerarin Against Anterior Ischemic Optic Neuropathy Through Antiapoptotic and Anti-Inflammatory Actions. Invest Ophthalmol Vis Sci 2019; 60:3481-3491. [PMID: 31408114 DOI: 10.1167/iovs.19-27129] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1β, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPβ in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.
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Affiliation(s)
- Minh-Anh Nguyen Ngo Le
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yao-Tseng Wen
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yu-Chieh Ho
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,Master Program in Medical Physiology, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Kishan Kapupara
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Rong-Kung Tsai
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
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Du JJ, Liu ZQ, Yan Y, Xiong J, Jia XT, Di ZL, Ren JJ. The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling. J Mol Neurosci 2019; 70:422-432. [PMID: 31732924 DOI: 10.1007/s12031-019-01429-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/03/2019] [Indexed: 12/27/2022]
Abstract
Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation. WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders. The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization. The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning. This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats. Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630. Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.
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Affiliation(s)
- Jing-Jing Du
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Zhi-Qin Liu
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Yue Yan
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Jing Xiong
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Xiao-Tao Jia
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Zheng-Li Di
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Jing-Jing Ren
- Department of Hematology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
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Wang L, Zhang Y, Wang X, Ye Z. Electroacupuncture-induced cannabinoid receptor expression in repair of abducens nerve. Int J Neurosci 2019; 129:923-929. [PMID: 30889365 DOI: 10.1080/00207454.2019.1593980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Objective: Through the development of beagle abducens nerve injury model, taking electroacupuncture as the core and microglia as the starting point, the author investigated whether electroacupuncture can promote the repair of injured abducens nerve by cannabinoid receptor-mediated regulation of microglia activation. Methods: Healthy beagle dogs were randomly divided into five groups: sham operation group (A), injury group (B), electroacupuncture pretreatment group (C), antagonist group (D) and solvent group (E). After stimulation with electroacupuncture, the expression of cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R) in A, B and C microglia cells was detected by Western Bolt analysis, and further the expression of CB2R in five groups was further analyzed by immunofluorescence, thereby statistical differences were analyzed. Results: Among group A, group B and group C, Western Blot analysis showed that there were no significant changes in the expression of CB1R protein after electroacupuncture [F (2, 12)=1.75, p = 0.215]. After electroacupuncture preconditioning for 15 min for 2 weeks, group C was compared with group A and group B, which showed CB2 was affected. The expression of CB2R protein was significantly increased among groups A, B and C [F (2, 12)=5189.57, p < 0.001], but there was no significant difference in the expression of CB2R protein between group A and group B (p > 0.05). The results of immunofluorescence showed that Arginse/CD11b was significantly increased in group C comparing to group A (*p < 0.001), while there was a significant increase in group E comparing to group A about Arginse/CD11b [F (4, 20)=4345.44, p < 0.001]. Conclusions: The CB2R in the cannabinoid receptor is mainly involved in the electro-acupuncture-induced neuroprotection. Electroacupuncture can promote the repair of injured abducens nerve by CB2R-mediated activation of microglia.
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Affiliation(s)
- Lei Wang
- a Department of Emergency Center , Affiliated Hospital 2 of Nantong University , Nantong , Jiangsu , China
| | - Yi Zhang
- b Department of Neurosurgery , Affiliated Hospital 2 of Nantong University , Nantong , Jiangsu , China
| | - Xudong Wang
- c Department of Chinese Traditional Medicine , Affiliated Hospital 2 of Nantong University , Nantong , Jiangsu , China
| | - Zi Ye
- b Department of Neurosurgery , Affiliated Hospital 2 of Nantong University , Nantong , Jiangsu , China
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The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation. Life Sci 2019; 219:40-73. [DOI: 10.1016/j.lfs.2018.12.059] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/06/2018] [Accepted: 12/31/2018] [Indexed: 11/21/2022]
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Tan Q, Li Y, Guo P, Zhou J, Jiang Z, Liu X, Chen Z, Feng H. Tolvaptan attenuated brain edema in experimental intracerebral hemorrhage. Brain Res 2019; 1715:41-46. [PMID: 30703371 DOI: 10.1016/j.brainres.2019.01.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/05/2019] [Accepted: 01/26/2019] [Indexed: 12/25/2022]
Abstract
Arginine-vasopressin (AVP) is believed to be positively correlated with the brain edema formation, but the underlying mechanism is still unclear. In this study, we explored the role of the V2 receptors antagonist tolvaptan on brain edema following intracerebral hemorrhage (ICH) with a rat model. Animals were randomly given tolvaptan or vehicle through oral gavage at 12 h, 36 h, and 60 h after ICH surgery. Brain swelling (%), brain water content(BWC), neurological scores, Evans blue fluorescence and blood-brain barrier (BBB) tight junction proteins were measured to evaluate the effect of tolvaptan in ICH. We found that tolvaptan alleviated the brain swelling (%), decreased the BWC growth, and attenuated the neurological deficits after ICH (p < 0.05, vs vehicle). What's more, tolvaptan increased the expression of ZO-1 and occludin (p < 0.05, vs vehicle), which might be attributed to the down-regulated effects of tolvaptan on MMP-9. These results provided evidence supporting the use of tolvaptan for ICH-induced brain edema. Large animal experiments are required to further explore the efficacy and mechanism of tolvaptan in ICH treatment.
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Affiliation(s)
- Qiang Tan
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Yuhan Li
- State Key Laboratory Of Silkworm Genome Biology, Southwest University, No. 2 Rd Tiansheng, Beibei District of Chongqing, 400715, China
| | - Peiwen Guo
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Jiru Zhou
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Zhouyang Jiang
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Xin Liu
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Zhi Chen
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China
| | - Hua Feng
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, China.
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Promising neuroprotective effects of β-caryophyllene against LPS-induced oligodendrocyte toxicity: A mechanistic study. Biochem Pharmacol 2018; 159:154-171. [PMID: 30529211 DOI: 10.1016/j.bcp.2018.12.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 12/04/2018] [Indexed: 01/09/2023]
Abstract
Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS-induced oligodendrocytes toxicity may be chosen as an efficient model to evaluate the role of oligodendrocytes in neuroprotective activities of compounds. β-Caryophyllene (BCP) is a selective type 2 cannabinoid (CB2) receptor agonist. However, the mechanisms underlying the anti-inflammatory effects of BCP are not completely understood. On this basis, we aimed to investigate the protective effects of a wide range of BCP concentrations against LPS-induced toxicity in a proliferative oligodendrocyte cell line (OLN-93) and evaluate the possible correlation between BCP concentration and selective modulation of CB2, Nrf2, sphingomyelinase (SMase) and peroxisome proliferator-activated receptors (PPAR)-γ signaling pathways. We found that LPS significantly increases the levels of reactive oxygen species (ROS), nitric oxide (NO) metabolite and tumor necrosis factor (TNF)-α production while decreases the level of GSH. BCP could prevent LPS-induced cytotoxicity and excessive production of NO, ROS, and TNF-α. Also, we demonstrated that BCP's protective effects against LPS-induced oligodendrocytes toxicity were mediated via the CB2 receptor through different pathways including Nrf2/HO-1/anti-oxidant axis, and PPAR-γ, at low (0.2 and 1 µM), and high (10-50 µM) concentrations, respectively. Additionally, we observed that the addition of SMase inhibitors imipramine (IMP) and fluoxetine (FLX) synergistically increased the protective effects of BCP. Finally, BCP at low concentrations exerted promising protective effects that could be considered for the treatment of neurodegenerative disorders such as MS. However, more studies using other models of neurodegenerative diseases should be undertaken to assess different parameters such as the activity or expression of SMase.
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Du Y, Ren P, Wang Q, Jiang SK, Zhang M, Li JY, Wang LL, Guan DW. Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages. JOURNAL OF INFLAMMATION-LONDON 2018; 15:25. [PMID: 30534003 PMCID: PMC6278147 DOI: 10.1186/s12950-018-0201-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/19/2018] [Indexed: 12/17/2022]
Abstract
Background The anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation. Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation. However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages. Methods We established an incised wound model using mouse skin and used this to evaluate the effect of CB2R agonists (JWH133 or GP1a) and an antagonist (AM630) on wound healing. At various post-injury intervals, we used western blot analysis, immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction assays to determine CB2R protein expression, M1/M2 macrophage infiltration, and the protein and gene expression of M1/M2-associated markers and cytokines in skin lesions. Results Activation of CB2R significantly reduced M1 macrophage infiltration and slightly increased M2 macrophage infiltration. Similarly, gene expression and protein levels of M1-associated markers and cytokines (interleukin [IL]-6, IL-12, CD86 and inducible nitric oxide synthase) were significantly down-regulated after CB2R agonist administration; in contrast, markers and cytokines were increased in the CB2R antagonist–treated group. Conversely, the administration of agonists slightly increased gene expression and protein levels of M2-associated markers and cytokines (IL-4, IL-10, CD206 and arginase-1 [Arg-1]); however, a statistical significance at most time points post-injury was not noted. Conclusion In summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation. These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.
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Affiliation(s)
- Yu Du
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Department of Forensic Medicine, Criminal Investigation Police University of China, Shenyang, 110854 China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Peng Ren
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Department of Forensic Medicine, Criminal Investigation Police University of China, Shenyang, 110854 China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Qi Wang
- 4Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, Guangzhou, 510515 China
| | - Shu-Kun Jiang
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Miao Zhang
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Jiao-Yong Li
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Lin-Lin Wang
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
| | - Da-Wei Guan
- 1Department of Forensic Pathology, China Medical University School of Forensic Medicine, No.77, Puhe Road, Shenyang North New Area, Shenyang, 110122 Liaoning Province People's Republic of China.,Collaborative Laboratory of Intelligentized Forensic Science, Shenyang, 110033 China
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Li W, Li L, Chopp M, Venkat P, Zacharek A, Chen Z, Landschoot-Ward J, Yan T, Chen J. Intracerebral Hemorrhage Induces Cardiac Dysfunction in Mice Without Primary Cardiac Disease. Front Neurol 2018; 9:965. [PMID: 30524357 PMCID: PMC6256175 DOI: 10.3389/fneur.2018.00965] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 10/26/2018] [Indexed: 12/21/2022] Open
Abstract
Background: Intracerebral hemorrhage (ICH) is a life threatening stroke subtype and a worldwide health problem. In this study, we investigate brain-heart interaction after ICH in mice and test whether ICH induces cardiac dysfunction in the absence of primary cardiac disease. We also investigate underlying mechanisms such as oxidative stress and inflammatory responses in mediating cardiac dysfunction post-ICH in mice. Methods: Male, adult (3–4 m) C57BL/6J mice were subjected to sham surgery or ICH using an autologous blood injection model (n = 16/group). Cardiac function was evaluated at 7 and 28 days after ICH using echocardiography (n = 8/group per time point). Western blot and immunostaining analysis were employed to assess oxidative stress and inflammatory responses in the heart. Results: Mice subjected to ICH exhibited significantly decreased cardiac contractile function measured by left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 7 and 28 days after ICH compared to sham-control mice (p < 0.05). ICH induced cardiac dysfunction was significantly worse at 28 days than at 7 days after ICH (p < 0.05). ICH in mice significantly increased cardiomyocyte apoptosis, inflammatory factor expression and inflammatory cell infiltration in heart tissue, and induced cardiac oxidative stress at 7 days post-ICH compared to sham-control mice. Compared to sham-control mice, ICH-mice also exhibited significantly increased (p < 0.05) cardiomyocyte hypertrophy and cardiac fibrosis at 28 days after ICH. Conclusions: ICH induces significant and progressive cardiac dysfunction in mice. ICH increases cardiac oxidative stress and inflammatory factor expression in heart tissue which may play key roles in ICH-induced cardiac dysfunction.
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Affiliation(s)
- Wei Li
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Neurology, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in CNS, Ministry of Education and Tianjin City, Tianjin, China.,Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Linlin Li
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Neurology, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in CNS, Ministry of Education and Tianjin City, Tianjin, China
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.,Department of Physics, Oakland University, Rochester, NY, United States
| | - Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Zhili Chen
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Neurology, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in CNS, Ministry of Education and Tianjin City, Tianjin, China.,Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | | | - Tao Yan
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Neurology, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in CNS, Ministry of Education and Tianjin City, Tianjin, China
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
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Li L, Yun D, Zhang Y, Tao Y, Tan Q, Qiao F, Luo B, Liu Y, Fan R, Xian J, Yu A. A cannabinoid receptor 2 agonist reduces blood-brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats. Brain Res 2018; 1697:113-123. [PMID: 29886251 DOI: 10.1016/j.brainres.2018.06.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND PURPOSE The blood-brain barrier (BBB) disruption and the following development of brain edema, is the most life-threatening secondary injury after intracerebral hemorrhage (ICH). This study is to investigate a potential role and mechanism of JWH133, a selected cannabinoid receptor type2 (CB2R) agonist, on protecting blood-brain barrier integrity after ICH. METHODS 192 adult male Sprague-Dawley (SD) rats were randomly divided into Sham; ICH + Vehicle; ICH + JWH 1.0 mg/kg, ICH + JWH 1.5 mg/kg and ICH + JWH 2.0 mg/kg; ICH + SR + JWH respectively. Animals were euthanized at 24 h following western blots and immunofluorescence staining, we also examined the effect of JWH133 on the brain water contents, neurobehavioral deficits and blood brain barrier (BBB) permeability, meanwhile reassessed the inflammatory cytokines concentrations around the hematoma by enzyme-linked immunosorbent assay (ELISA) in each group. RESULTS JWH133 (1.5 mg/kg) administration ameliorated brain edema, neurological deficits and blood-brain barrier damage, as well as microglia activation. The expression of pro-inflammatory mediators interleukin 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metallopeptidase-2/9 (MMP2/9) were attenuated, but not monocyte chemoattractant protein-1 (MCP-1). Additionally, decreases in zonula occludens-1 (ZO-1) and claudin-5 expression were partially recovered by JWH133. Furthermore, JWH133 upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and P38. However, these effects were reversed by pretreatment with a selective CB2R antagonist, SR144528. CONCLUSIONS CB2R agonist alleviated neuroinflammation and protected blood-brain barrier permeability in a rat ICH model. Further molecular mechanisms revealed which is probably mediated by enhancing the expression of MKP-1, then inhibited MAPKs signal transduction.
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Affiliation(s)
- Lin Li
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Debo Yun
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Yuan Zhang
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Yihao Tao
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Qiang Tan
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Fei Qiao
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Bo Luo
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Yi Liu
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Runjin Fan
- Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China
| | - Jishu Xian
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Anyong Yu
- Department of Emergency, The First Affiliated Hospital of Zunyi Medical College, Guizhou 563003, China.
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Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder. Neuropsychopharmacology 2018; 43:80-102. [PMID: 28745306 PMCID: PMC5719095 DOI: 10.1038/npp.2017.162] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 01/21/2023]
Abstract
Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the USA, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Finally, we propose that a state of endocannabinoid deficiency could represent a stress susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.
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Impact of aging immune system on neurodegeneration and potential immunotherapies. Prog Neurobiol 2017; 157:2-28. [PMID: 28782588 DOI: 10.1016/j.pneurobio.2017.07.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 07/25/2017] [Accepted: 07/28/2017] [Indexed: 12/19/2022]
Abstract
The interaction between the nervous and immune systems during aging is an area of avid interest, but many aspects remain unclear. This is due, not only to the complexity of the aging process, but also to a mutual dependency and reciprocal causation of alterations and diseases between both the nervous and immune systems. Aging of the brain drives whole body systemic aging, including aging-related changes of the immune system. In turn, the immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution that are sources of chronic inflammation in the elderly (termed inflammaging), potentially induces brain aging and memory loss in a reciprocal manner. Therefore, immunotherapeutics including modulation of inflammation, vaccination, cellular immune therapies and "protective autoimmunity" provide promising approaches to rejuvenate neuroinflammatory disorders and repair brain injury. In this review, we summarize recent discoveries linking the aging immune system with the development of neurodegeneration. Additionally, we discuss potential rejuvenation strategies, focusing aimed at targeting the aging immune system in an effort to prevent acute brain injury and chronic neurodegeneration during aging.
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