Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke

Abstract

Dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson disease (PD) and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received the pramipexole (0.25 mg and 1 mg/kg b.w.) at 1 h, 6, 12 and 18 h post occlusion. A panel of neurological tests and 2, 3, 5 -Triphenyl tetrazolium chloride staining were performed after 24 h of the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, ROS and Ca2+ respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph. Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c. Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioural tests and 2, 3, 5- Triphenyl tetrazolium chloride staining. Post stroke treatment with pramipexole reduced the mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting has shown that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemic/reperfusion injury.