Abstract
Previous studies have shown neuroprotective effects of hypothermia. However, its effects on subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) remain unclear. In this study, a SAH rat model was employed to study the effects and mechanisms of pramipexole-induced hypothermia on EBI after SAH. Dose-response experiments were performed to select the appropriate pramipexole concentration and frequency of administration for induction of mild hypothermia (33–36 °C). Western blot, neurobehavioral evaluation, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Fluoro-Jade B (FJB) staining were used to detect the effects of pramipexole-induced hypothermia on SAH-induced EBI, as well as to study whether controlled rewarming could attenuate these effects. Inhibitors targeting the PI3K/AKT/GSK3β pathway were administered to determine whether the neuroprotective effect of pramipexole-induced hypothermia was mediated by PI3K/AKT/GSK3β signaling pathway. The results showed that intraperitoneal injection of pramipexole at 0.25 mg/kg body weight once per 8 hours was found to successfully and safely maintain rats at mild hypothermia. Pramipexole-induced hypothermia ameliorated SAH-induced brain cell death, blood-brain barrier damage and neurobehavioral deficits in a PI3K/AKT/GSK3β signaling-dependent manner. Therefore, we may conclude that pramipexole-induced hypothermia could effectively inhibit EBI after SAH in rats via PI3K/AKT/GSK3β signaling pathway.
Highlights
Hypothermia has been considered to be a valuable clinical treatment[8]
The present study demonstrated that the dopamine receptor agonist pramipexole, when administered after subarachnoid hemorrhage (SAH), induced mild hypothermia effectively and safely
PI3K was phosphorylated to some extent under SAH, suggesting PI3K activation maybe a self-help measure in brain cells after SAH, which is enhanced by pramipexole-induced hypothermia
Summary
Hypothermia has been considered to be a valuable clinical treatment[8]. Current hypothermia research focuses on cerebral ischemia and traumatic brain injury, but whether hypothermia, under SAH conditions, plays a neuroprotective effect is still unclear[15,16]. Previous studies have shown that talipexole could inhibit brain damage due to ischemia through inducing hypothermia[20]. Hydroxysafflor yellow A and tetramethylpyazine analogues regulate Bcl-2/Bax levels by activating PI3K/AKT/ GSK3β signaling pathway to inhibit caspase-dependent apoptosis pathway in brain cells, and thereby inhibit apoptosis induced by ischemia and reperfusion[25,26]. Pramipexole pretreatment could increase Bcl-2 and inhibit caspase-3-dependent apoptosis in human neuroblastoma SH-SY5Y cells treated with 1-methyl– 4-phenylpyridinium[19]. Whether pramipexole induced-hypothermia could inhibit caspase3-dependent apoptosis via PI3K/AKT/GSK3β signaling pathway, and exert a neuroprotective effect has not been reported. We sought to test whether pramipexole could induce hypothermia and the effects of pramipexole on EBI in a rat SAH model in this study
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