Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke

Abstract

A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson’s disease 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 pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). 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 neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and 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 ischemia/reperfusion injury.

Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor

“…it inhibits mitochondrial permeability transition pores, when given in nanomolar concentrations, by binding to the inner side of the mitochondrial membrane [43]. Mitochondrial mechanisms have been suggested to underlie antioxidant, antiapoptotic, neuroprotective efficiency of pramipexole which is visible already after its low doses [44,45]. It is currently unknown whether such non-dopaminergic mechanism indeed contributes also to the inhibitory influence of pramipexole on harmaline effects described in the present study and earlier [5] and to the tremorolytic effects of this drug in ET [21].…”

Nrf2/HO-1 mediates neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury

“…PPX inhibits the early brain injury after subarachnoid hemorrhage ( Ma et al, 2016 ) and significantly reduces lipid peroxidation in a rat model of Parkinson's disease ( Zou et al, 2000 ). Recently, our laboratory reported that PPX post-treatment provides mitochondrial-mediated neuroprotection via closing mtPTPs in an ischemic stroke model ( Andrabi et al, 2019 ). Furthermore, pre-treatment of PPX protects PC12 cells treated with hydrogen peroxide through the activation of mitogen-activated protein ( Fujita et al, 2006 ).…”

Mitochondrial MPTP: A Novel Target of Ethnomedicine for Stroke Treatment by Apoptosis Inhibition

“…A great deal of evidence has declassified such a fact that anti-apoptotic Bcl-2 and Bcl-x L can inhibit MPTP opening, whereas pro-apoptotic Bax and Bak proteins can stimulate MPTP opening (D'Orsi et al, 2017). Results from in vitro model of ischemic stroke in rats have shown that increased Bax/Bcl-2 ratio in ischemic insult could irritate MPTP opening, which may cause increased neuronal apoptosis (Andrabi et al, 2017;Andrabi et al, 2019). Actually, members in Bcl-2 family could also regulate two potential MPTP opening stimuli: Ca 2+ homeostasis and energy metabolism of neurons (D'Orsi et al, 2017;Peña-Blanco and García-Sáez, 2018).…”