Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke

Abstract

Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment’s various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33–35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment’s neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.

Protective effects of combined treatment with mild hypothermia and edaravone against cerebral ischemia/reperfusion injury via oxidative stress and Nrf2 pathway regulation

“…For example, a recent research revealed that MH with bone mesenchymal stem cell transplantation improved the prognosis of rats with cerebral ischemia (19). Combined therapy with phenothiazines and MH also enhanced neuroprotection in ischemic rats through regulating the PI3K/Akt pathway (20). It has also been reported that the Notch inhibitor DAPT combined with MH exerted a synergistic effect on post-stroke seizures (21).…”

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

“…It is thought that chlorpromazine protects against neuronal injury by mitigating reactive oxygen species (ROS) accumulation as well as oxidative stress, which results from increased brain metabolism [7]. Promethazine has been observed to reduce mitochondrial permeability during ischemia, mitigating cerebral injury [8,9]. 2…”

The effect of levomepromazine on the healthy and injured developing mouse brain – An in vitro and in vivo study

“…A pivotal mechanism in this context seems to be excitotoxicity, characterized by excessive release and impaired re‐uptake of glutamate, ultimately leading to neurodegeneration and cell death ( Vannucci and Hagberg, 2004 ). A pharmacologic class with the potential to counter these noxious effects are phenothiazines which have been shown to be anti-excitotoxic, anti-apoptotic and anti-oxidative ( Geng et al, 2017 ; An et al, 2017 ; Varga et al, 2017 ; Gonzalez-Munoz et al, 2010 ). The long-standing phenothiazine LMP is currently experiencing a revival due to its favourable risk profile, flexible routes of administration, convenient dosing interval, as well as its potent sedative, analgesic and anaesthetic mechanisms of action ( van der Zwaan et al, 2012 ; Hohl et al, 2013 ).…”

“…It is also used off-label as an add-on sedative in Pediatric Intensive Care Units, as it appears to have no major side effects ( van der Zwaan et al, 2012 ; Hohl et al, 2013 ; Snoek et al, 2014 ). With regard to brain injury, various phenothiazines proved to be neuroprotective due to their anti-excitotoxic, anti-apoptotic and anti-oxidative properties ( Geng et al, 2017 ; An et al, 2017 ; Varga et al, 2017 ; Gonzalez-Munoz et al, 2010 ). The neuroprotective effect of LMP is a widely under-researched topic, with only two studies showing beneficial effects via inhibition of lipid peroxidase and scavenging reactive oxygen species in vitro ( Hadjimitova et al, 2002 ; Jeding et al, 1995 ).…”