Alleviating CB2-Dependent ER Stress and Mitochondrial Dysfunction Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment.
J Neuroimmune Pharmacol
; 19(1): 1, 2024 01 12.
Article
in En
| MEDLINE
| ID: mdl-38214766
ABSTRACT
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 ß-Arrestin1. Inhibiting ER stress by URB597 improved these changes by activating CB2/ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzamides
/
Carbamates
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Brain Ischemia
/
Mitochondrial Diseases
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Cognitive Dysfunction
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Neuroimmune Pharmacol
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
/
NEUROLOGIA
Year:
2024
Document type:
Article
Affiliation country: