PMID- 38214766 OWN - NLM STAT- MEDLINE DCOM- 20240115 LR - 20240118 IS - 1557-1904 (Electronic) IS - 1557-1890 (Print) IS - 1557-1890 (Linking) VI - 19 IP - 1 DP - 2024 Jan 12 TI - Alleviating CB2-Dependent ER Stress and Mitochondrial Dysfunction Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment. PG - 1 LID - 10.1007/s11481-024-10098-x [doi] LID - 1 AB - Augmentation of endoplasmic reticulum (ER) stress may trigger excessive oxidative stress, which induces mitochondrial dysfunction. The fatty acid amide hydrolase inhibitor, URB597, shows anti-oxidation characteristics in multiple neurological disorders. The present study aimed to determine whether inhibition of ER stress was involved in the protective effects of URB597 against chronic cerebral hypoperfusion (CCH)-induced cognitive impairment. Hippocampal HT-22 cells were exposed to oxygen-glucose deprivation. The cell viability, apoptosis, ER stress, mitochondrial ATP, and oxidative stress levels were assessed following treatment with URB597, benzenebutyric acid (4-PBA), and thapsigargin (TG). Furthermore, the effects of URB597 on ER stress and related pathways were investigated in the CCH animal model, including Morris water maze testing of cognition, western blotting analysis of ER stress signaling, and transmission electron microscopy of mitochondrial and ER ultrastructure changes. The results suggested that cerebral ischemia caused ER stress with upregulation of ER stress signaling-related proteins, mitochondrial dysfunction, neuronal apoptosis, ultrastructural injuries of mitochondria-associated ER membranes, and cognitive decline. Co-immunoprecipitation experiments confirmed the interaction between CB2 and beta-Arrestin1. Inhibiting ER stress by URB597 improved these changes by activating CB2/beta-Arrestin1 signaling, which was reversed by the CB2 antagonist, AM630. Together, the results identified a novel mechanism of URB597, involving CCH-induced cognitive impairment alleviation of CB2-dependent ER stress and mitochondrial dysfunction. Furthermore, this study identified CB2 as a potential target for therapy of ischemic cerebrovascular diseases. CI - (c) 2024. The Author(s). FAU - Wang, Da Peng AU - Wang DP AD - Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Huangpu District, Shanghai, 200025, China. AD - Department of Neurosurgery, Tong Ji Hospital, School of Medicine, Tong Ji University, Shanghai, 200065, China. FAU - Kang, Kai AU - Kang K AD - School of Public Health, Fudan University, Shanghai, 200032, China. AD - Department of Research and Surveillance Evaluation, Shanghai Municipal Center for Health Promotion, Shanghai, 200040, China. FAU - Hai, Jian AU - Hai J AD - Department of Neurosurgery, Tong Ji Hospital, School of Medicine, Tong Ji University, Shanghai, 200065, China. FAU - Lv, Qiao Li AU - Lv QL AD - Jiangxi Key Laboratory of Translational Cancer Research, Jiangxi Cancer Hospital, Jiangxi, 330029, China. lvqiaoli2008@126.com. FAU - Wu, Zhe Bao AU - Wu ZB AD - Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Huangpu District, Shanghai, 200025, China. wzb11748@rjh.com.cn. AD - Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. wzb11748@rjh.com.cn. LA - eng GR - 82001383/National Natural Science Foundation of China/ GR - 82060680/National Natural Science Foundation of China/ GR - 2022YQ004/Shanghai Municipal Health Commission/ GR - 2023M732302/China Postdoctoral Science Foundation/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240112 PL - United States TA - J Neuroimmune Pharmacol JT - Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology JID - 101256586 RN - 0 (cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester) RN - 0 (Benzamides) RN - 0 (Carbamates) SB - IM MH - Rats MH - Animals MH - Rats, Sprague-Dawley MH - *Brain Ischemia/drug therapy MH - *Cognitive Dysfunction/drug therapy/etiology MH - *Mitochondrial Diseases MH - Endoplasmic Reticulum Stress MH - Apoptosis MH - *Benzamides MH - *Carbamates PMC - PMC10786746 OTO - NOTNLM OT - Chronic cerebral hypoperfusion OT - Cognitive impairment OT - Endocannabinoid system OT - Endoplasmic reticulum stress OT - Fatty acid amide hydrolase OT - Mitochondria COIS- The authors declare no conflict of interest. EDAT- 2024/01/12 12:43 MHDA- 2024/01/15 12:42 PMCR- 2024/01/12 CRDT- 2024/01/12 11:07 PHST- 2023/07/05 00:00 [received] PHST- 2023/12/06 00:00 [accepted] PHST- 2024/01/15 12:42 [medline] PHST- 2024/01/12 12:43 [pubmed] PHST- 2024/01/12 11:07 [entrez] PHST- 2024/01/12 00:00 [pmc-release] AID - 10.1007/s11481-024-10098-x [pii] AID - 10098 [pii] AID - 10.1007/s11481-024-10098-x [doi] PST - epublish SO - J Neuroimmune Pharmacol. 2024 Jan 12;19(1):1. doi: 10.1007/s11481-024-10098-x.