Disrupted mitochondrial genes and inflammation following stroke

LIFE SCIENCES

卷:166

Article

Gibbs, Whitney S.¹  Weber, Rachel A.²  Schnellmann, Rick G.^5,6  Adkins, DeAnna L.^2,3,4 

[1] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC USA

[2] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA

[3] Med Univ South Carolina, Ctr Biomed Imaging, Charleston, SC USA

[4] Med Univ South Carolina, Hlth Sci & Res, Coll Hlth Profess, Charleston, SC USA

[5] Ralph H Johnson VA Med Ctr, Charleston, SC USA

[6] Univ Arizona, Coll Pharm, Dept Pharm & Toxicol, Tucson, AZ 85721 USA

关键词: Cerebral ischemia;    Respiratory complexes;    Oxidative stress;    Sensorimotor cortex;    Et-1;   

DOI  :  10.1016/j.lfs.2016.09.021

来源: Elsevier

【 摘 要 】

Aims: Determine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. Main methods: Rats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24 h, 72 h and 144 h and mRNA expression of key mitochondria proteins and indicators of inflammation, apoptosis and potential regenerative processes in ipsilesion cortex and striatum, using RT-qPCR. Mitochondrial proteins were examined at 144 h using immunoblot analysis. Key findings: Rats with stroke induced-behavioral deficits had sustained, 144 h post-lesion, decreases in mitochondrial-encoded electron transport chain proteins NADH dehydrogenase subunit-1 and cytochrome c oxidase subunit-1 (mRNA and protein) and mitochondrial DNA content in perilesion motor and sensory cortex. Uncoupling-protein-2 gene expression, but not superoxide dismutase-2, remained elevated in ipsilateral cortex and striatumat this time. Cortical inflammatory cytokine, interleukin-6, was increased early and was followed by increased macrophage marker F4/80 after stroke. Cleaved caspase-3 activation was elevated in cortex and growth associated protein-43 was elevated in the cortex and striatum six days post-lesion. Significance: We identified a relationship between three disrupted pathways, (1) sustained loss of mitochondrial proteins and mitochondrial DNA copy number in the cortex linked to decreased mitochondrial gene transcription; (2) early inflammatory response mediated by interleukin-6 followed by macrophages; (3) apoptosis in conjunction with the activation of regenerative pathways. The stroke-induced spatial and temporal profiles lay the foundation to target pharmacological therapeutics to these three pathways. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

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