Humanin Exerts Neuroprotection During Cardiac Ischemia-Reperfusion Injury

Article type: Research Article

Authors: Kumfu, Sirinart^{a; b; c} | Charununtakorn, Savitree T.^{a; b; c} | Jaiwongkam, Thidarat^{a; b; c} | Chattipakorn, Nipon^{a; b; c} | Chattipakorn, Siriporn C.^{a; c; d; *}

Affiliations: [a] Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [b] Department of Physiology, Cardiac Electrophysiology Unit, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [c] Center of Excellence in Cardiac Electrophysiology Research, 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, 50200, Thailand. Tel.: +66 53 935329; Fax: +66 53 935368; E-mails: [email protected]; [email protected].

Abstract:  Cardiac ischemia-reperfusion (I/R) injury has been shown to impair brain function. Humanin analogue (HNG) given prior to cardiac ischemia has been shown to attenuate both heart and brain mitochondrial dysfunction caused by cardiac I/R injury. In a clinical setting, patients received medical treatment for acute myocardial infarction either during or after the onset of myocardial ischemia; thus, in this study, we tested the hypothesis that the administration of HNG during cardiac I/R injury has therapeutic potential for brain protection. Thirty-six male Wistar rats were divided into two groups: a cardiac I/R group (n = 30), and a sham group (n = 6). The I/R rats were then divided into five subgroups to receive: 1) vehicle; 2) HNG (84 μg/kg); 3) HNG (168 μg/kg); 4) HNG (252 μg/kg) intravenously administered during the cardiac-ischemia; and 5) HNG at 252 μg/kg given at the onset of reperfusion. At the end of treatment, brains were removed for determination of blood-brain barrier (BBB) breakdown, oxidative stress, brain mitochondrial function, brain mitochondrial dynamics, p-tau, amyloid-β (Aβ) and apoptosis. HNG at a dose of 168 and 252 μg/kg administered during ischemia, and 252 μg/kg given at the onset of reperfusion effectively attenuated the brain mitochondrial dysfunction, tau hyperphosphorylation and Aβ accumulation, and apoptosis, without reducing BBB breakdown, brain oxidative stress, or mitochondrial dynamics, caused by cardiac I/R injury. In conclusion, humanin exerted neuroprotection during induced cardiac I/R injury via improvement in brain mitochondrial function, and the reduction of Alzheimer’s disease pathology and apoptosis.

Keywords: Alzheimer’s disease, brain, ischemia reperfusion injury, mitochondria, oxidative stress, pathology

DOI: 10.3233/JAD-170708

Journal: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1343-1353, 2018