Disrupted mitochondrial genes and inflammation following stroke.

aimsDetermine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. MAIN

methodsRats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24h, 72h and 144h 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 144h using immunoblot analysis. KEY

findingsRats with stroke induced-behavioral deficits had sustained, 144h 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 striatum at 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.