Mitochondrial Fusion Promoter Given During Ischemia Has Greater Neuroprotective Efficacy Than When Given at Onset of Reperfusion in Rats with Cardiac Ischemia/Reperfusion Injury

Article type: Research Article

Authors: Chunchai, Titikorn^{a; b} | Apaijai, Nattayaporn^{a; b; c} | Janjek, Sornram^{a; b} | Arunsak, Busarin^{a; b} | Nipon, Chattipakorn^{a; b; c} | Chattipakorn, Siriporn C.^{a; b; d; *}

Affiliations: [a] Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [b] Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand | [c] Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [d] Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand

Correspondence: [*] Correspondence to: Siriporn C. Chattipakorn, DDS, PhD, Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Tel.: +66 53 935 329; E-mails: [email protected]; [email protected].

Abstract: Background:Cardiac ischemia/reperfusion (I/R) injury has been shown to impose deleterious effects not only on the heart but also on the brain. Our previous study demonstrated that pretreatment with a mitochondrial fusion promoter (M1) provided central neuroprotective effects following cardiac I/R injury. Objective:To investigate the effects of M1 given during the ischemic phase and M1 given at the beginning of reperfusion on brain pathologies following cardiac I/R. Methods:Male Wistar rats were randomly divided into either a sham operation (n = 6) or cardiac I/R injury (n = 18) group. Rats with cardiac I/R injury were then randomly divided into 3 subgroups: 1) Control, 2) M1 treatment during cardiac ischemia (2 mg/kg, intravenous (i.v.)), and 3) M1 treatment at the beginning of reperfusion (2 mg/kg, i.v.). After euthanasia, the brain of each rat was removed for further analysis. Results:Cardiac I/R injury caused brain mitochondrial dynamic imbalance, brain mitochondrial dysfunction, brain apoptosis, microglial dysmorphology, brain inflammation, tau hyperphosphorylation, and synaptic dysplasticity. M1 treatment at both time points effectively improved these parameters. M1 given during the ischemic phase had greater efficacy with regard to preventing brain mitochondrial dysfunction and suppressing brain inflammation, when compared to M1 given at the beginning of reperfusion. Conclusions:Our findings suggest that treatment with this mitochondrial fusion promoter prevents mitochondrial dynamic imbalance in the brain of rats with cardiac I/R injury, thereby attenuating brain pathologies. Interestingly, giving the mitochondrial fusion promoter during the ischemic phase exerted greater neuroprotection than if given at the beginning of reperfusion.

Keywords: Alzheimer’s disease, brain, ischemic/reperfusion injury, microglia, mitochondrial function, mitochondrial fusion promoter

DOI: 10.3233/JAD-230859

Journal: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 205-217, 2024