Progesterone induced neuroprotection in reperfusion promoted mitochondrial dysfunction following focal cerebral ischemia in rats

Abstract

Alterations in mitochondrial permeability transition and organelle damage are key players in the development of cerebral ischemic tissue injury due to associated modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetics can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found neuroprotective in various models of neurological diseases through a number of mechanisms. This influenced us to investigate the possible role of P4 via the mitochondria-mediated neuroprotective mechanism in ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in ischemic/stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg) or vehicle at 1h post-occlusion followed by subcutaneous injections at 6, 12, and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination, and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals 2, 3, 5- triphenyltetrazolium chloride staining of isolated brain slices from P4 treated rats showed a reduction in the infarct area in comparison to vehicle group indicating the presence of more viable mitochondria. P4 treatment was also able to attenuate the mitochondrial ROS as well as modulate the mitochondrial permeability transition pore (mPTP) in the tMCAO injury. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals thereby suggesting that P4 has a positive effect on mitochondrial bioenergetics. In conclusion, these results demonstrate that P4 treatment is beneficial in preserving the altered mitochondrial functions in cerebral ischemic injury and thus can help in defining better therapies.