Mitochondrial Fusion Promoter Alleviates Brain Damage in Rats with Cardiac Ischemia/Reperfusion Injury

Article type: Research Article

Authors: Surinkaew, Poomarin^{a; b; c; 1} | Apaijai, Nattayaporn^{b; c; 1} | Sawaddiruk, Passakorn^{b; c; d} | Jaiwongkam, Thidarat^{b; c} | Kerdphoo, Sasiwan^{b; c} | Chattipakorn, Nipon^{b; c; e} | Chattipakorn, Siriporn C.^{b; c; f; *}

Affiliations: [a] Department of Anesthesiology, Lamphun Hospital, Lamphun, Thailand | [b] Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, 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 Anesthesiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [e] Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [f] 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; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Tel.: +011 66 53 935 329; Fax: +011 66 53 935 368; E-mails: scchattipakorn@gmail.com; siriporn.c@cmu.ac.th.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Cardiac ischemia/reperfusion (I/R) injury induces brain damage through increased blood-brain barrier (BBB) breakdown, microglial hyperactivity, pro-inflammatory cytokines, amyloid-β deposition, loss of dendritic spines, brain mitochondrial dysfunction, and imbalanced mitochondrial dynamics. Previous studies demonstrated that mitochondrial fusion promoter reduced cardiac damage from cardiac I/R injury; however, following cardiac I/R injury, the roles of mitochondrial dynamics on the brain have not been investigated. Objective:To investigate the effects of pharmacological modulation using mitochondrial fusion promoter (M1) in the brain of rats following cardiac I/R injury. Methods:Twenty-four male Wistar rats were separated into two groups; 1) sham-operation (n = 8) and 2) cardiac I/R injury (n = 16). Rats in the cardiac I/R injury group were randomly received either normal saline solution as a vehicle or a mitochondrial fusion promoter (M1, 2 mg/kg) intravenously. Both treatments were given to the rats 15 minutes before cardiac I/R injury. At the end of the reperfusion protocol, the brain was rapidly removed to investigate brain mitochondrial function, mitochondrial dynamics proteins, microglial activity, and Alzheimer’s disease (AD) related proteins. Results:Cardiac I/R injury induced brain mitochondrial dynamics imbalance as indicated by reduced mitochondrial fusion proteins expression without alteration in mitochondrial fission, brain mitochondrial dysfunction, BBB breakdown, increased macrophage infiltration, apoptosis, and AD-related proteins. Pretreatment with M1 effectively increased the expression of mitofusin 2, a mitochondrial outer membrane fusion protein, reduced brain mitochondrial dysfunction, BBB breakdown, macrophage infiltration, apoptosis, and AD-related proteins in rats following cardiac I/R injury. Conclusion:This mitochondrial fusion promoter significantly protected rats with cardiac I/R injury against brain damage.

Keywords: Amyloid plaque, brain, heart, ischemia-reperfusion injury, microglia, mitochondrial fusion

DOI: 10.3233/JAD-200495

Journal: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 993-1003, 2020