Donepezil provides neuroprotective effects against brain injury and Alzheimer's pathology under conditions of cardiac ischemia/reperfusion injury

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Ongnok, Benjamin^1,2,3  Khuanjing, Thawatchai^2,3  Chunchai, Titikorn^1,2,3  Kerdphoo, Sasiwan^1,3  Jaiwongkam, Thidarat^1,3  Chattipakorn, Nipon^1,2,3  Chattipakorn, Siriporn C.^1,2,4 

[1] Chiang Mai Univ, Fac Med, Cardiac Electrophysiol Res & Training Ctr, Neuroelectrophysiol Unit, Chiang Mai 50200, Thailand

[2] Chiang Mai Univ, Ctr Excellence Cardiac Electrophysiol Res, Chiang Mai 50200, Thailand

[3] Chiang Mai Univ, Dept Physiol, Cardiac Electrophysiol Unit, Chiang Mai 50200, Thailand

[4] Chiang Mai Univ, Fac Dent, Dept Oral Biol & Diagnost Sci, Chiang Mai 50200, Thailand

关键词: Acetylcholinesterase inhibitor;    Donepezil;    Brain;    Cardiac ischemia/reperfusion injury;    Neuroinflammation;    Mitochondria;    Alzheimer's disease;   

DOI  :  10.1016/j.bbadis.2020.165975

来源: Elsevier

【 摘 要 】

Cardiac ischemia/reperfusion (I/R) injury induces brain pathology. Donepezil, a well-known acetylcholine esterase (AChE) inhibitor, has been proven to exert neuroprotective effects against several neurodegenerative diseases. However, the comprehensive mechanism regarding the therapeutic potential of donepezil on the brain under cardiac I/R injury remains obscure. Here, we hypothesized that treatment with donepezil ameliorates brain pathology following cardiac I/R injury by decreasing blood brain barrier (BBB) breakdown, oxidative stress, neuroinflammation, mitochondrial dysfunction, mitochondrial dynamics imbalance, microglial activation, amyloid-beta (A beta) accumulation, neuronal apoptosis, and dendritic spine loss. Forty-eight adult male Wistar rats were subjected to surgery for cardiac I/R injury. Then, rats were randomly divided into four groups to receive either (1) saline (vehicle group), donepezil 3 mg/kg via intravenously administered (2) before ischemia (pretreatment group), (3) during ischemia (ischemia group), or (4) at the onset of reperfusion (reperfusion group). At the end of cardiac I/R paradigm, the brains were evaluated for BBB breakdown, brain inflammation, oxidative stress, mitochondrial function, mitochondrial dynamics, microglial morphology, A beta production, neuronal apoptosis, and dendritic spine density. Administration of donepezil at all time points equally showed an attenuation of brain damage in response to cardiac I/R injury, as indicated by increased expression of BBB junction protein, reduced brain inflammation and oxidative stress, improved mitochondrial function and mitochondrial dynamics, and alleviated A beta accumulation and microglial activation, resulting in protection of neuronal apoptosis and preservation of dendritic spine number. These findings suggest that donepezil potentially protects brain pathology caused by cardiac I/R injury regardless the timing of treatment.

【 授权许可】

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