Abstract

Background: Mitochondrial improvement is the central player of neuroprotection following cerebral ischemia/ reperfusion injury (I/RI). The present study evaluated the neuroprotective and anti-inflammatory effects of a new mitochondrial-acting drug, sonlicraomanol (SONL), in rats with cerebral I/RI, by focusing on the role of mitochondrial ATP-sensitive potassium (mK-ATP) channels and mitochondrial biogenesis.

Methods: Cerebral I/RI was modeled in Sprague Dawley rats (n=36) through induction of two hours of local ischemia via middle cerebral artery occlusion, followed by 24 hours of reperfusion. SONL at the concentrations of 10 and 50μM was intraperitoneally administered to rats for one week before the onset of occlusion. Cerebral infarcted areas, brain activity, mitochondrial function and biogenesis, and the levels of pro-inflammatory cytokines were quantified by triphenyl-tetrazolium chloride, behavioral tests, fluorometry, immunoblotting, and ELISA, respectively.

Results: Administration of SONL significantly reduced cerebral infarct volume and neurological activity in a dosedependent manner, as compared with the untreated control group (p<0.01). SONL (50μM) significantly reversed the I/RI-induced changes in mitochondrial membrane depolarization, mitochondrial reactive oxygen species (mitoROS), superoxide dismutase (mnSOD), and pro-inflammatory cytokines TNF-α, IL-1β, IL-6 (p<0.01). As well, the expression of mitochondrial biogenesis proteins PGC-1α, NRF1, and TFAM was upregulated following SONL 50 μM treatment. Importantly, the inhibition of mK-ATP channels through 5-hydoxydecanoate significantly eliminated the neuroprotective, anti-inflammatory, and mitochondrial impacts of SONL.

Conclusion: SONL post-conditioning had a significant neuroprotective effect which was mediated through increasing mK-ATP channels activity and subsequent improvement of mitochondrial biogenesis and function, and reduction of inflammatory responses.