Neuroprotective Effects of Phenothiazines on Acute Ischemic Stroke

Abstract

ABSTRACT Background Standard therapeutic strategies for acute ischemic stroke (AIS) include endovascular mechanical thrombectomy, intravenous thrombolysis, bridging therapy, and conventional conservative treatment. Despite the implementation of standardized treatments, nearly half of patients still experience significant motor or speech dysfunction, severely impacting their quality of life. Consequently, there is a pressing need for effective neuroprotective adjunctive therapies to further improve functional outcomes and prognosis. Phenothiazines, primarily chlorpromazine and promethazine (C + P), have been proposed as potential neuroprotective agents. Preclinical evidence suggests that phenothiazines may induce mild hypothermic responses, exert anti‐inflammatory effects, and promote a hypometabolic state, thereby potentially contributing to improved neurological outcomes. cns70960-sec-0001 Methods We reviewed and synthesized the mechanisms underlying the neuroprotective effects of phenothiazines, with a particular focus on C + P. cns70960-sec-0002 Results This review highlights the neuroprotective mechanisms of phenothiazines related to mild hypothermia, anti‐inflammation, and metabolic reduction, along with relevant preclinical and clinical evidence. We also compare the distinct mechanisms of action between C + P and conventional anesthetic sedatives and draw partial comparisons with natural hibernation. Our findings reveal that C + P possesses unique features and advantages in neuroprotection, particularly regarding metabolic suppression and hypothermia. cns70960-sec-0003 Conclusions This review explores the adjunctive role of phenothiazines following AIS and elucidates their modulatory mechanisms, which may exert neuroprotective effects through multiple pathways and potentially improve AIS outcomes. This approach may facilitate the identification of novel specific targets for conventional drugs, thereby offering a new perspective on addressing the challenges associated with AIS. cns70960-sec-0004 For acute ischemic stroke due to large vessel occlusion, adjunctive neuroprotective therapy with mechanical thrombectomy is important; however, current treatment options are relatively limited. Phenothiazines such as chlorpromazine and promethazine (C + P) have shown potential neuroprotective effects in preclinical studies. This review describes several reported mechanisms that may underlie the neuroprotective actions of C + P, thus offering a new perspective on pharmacological neuroprotection as an adjunctive therapy. graphical