BACKGROUND: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection. METHODS: A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined. RESULTS: C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α. CONCLUSION: Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.
BACKGROUND: Acute ischemic stroke remains a major contributor to mortality and disability worldwide. The use of hypothermia has emerged as a promising neuroprotective strategy, with proven effectiveness in cardiac arrest and neonatal hypoxic-ischemic injury. SUMMARY: This review explores the therapeutic potential of hypothermia in ischemic stroke by examining its impact on post-stroke inflammatory responses. We synthesized evidence from basic and clinical studies to illustrate the inhibitory effects of hypothermia on post-stroke brain inflammation. The underlying mechanisms include modulation of microglial activation and polarization, downregulation of key inflammatory pathways such as MAPKs, NF-KB, and JAK/STAT, protection of the blood-brain barrier integrity, and reduction of immune cell infiltration into the brain. We also discuss the current limitations of hypothermia treatment in clinical practice and highlight future research directions for optimizing protocols and evaluating its clinical efficacy in stroke patients. KEY MESSAGES: Therapeutic hypothermia (TH) has evolved significantly with advancements in medical technologies, especially with the introduction of automated cooling devices, both intravascular and surface based. However, a refined, highly individualized and effective hypothermia protocol may stand robust against the devastating consequences of ischemic stroke, and we think it should become the future development goal.
It is well known that stress can increase the risk of heart attack and stroke although the exact way it does this is unknown. This information is particularly more relevant in a post COVID-19 era where healthcare workers are increasingly facing more stressful working conditions. Thus, it is important to look into alternative methods to deal with stress including meditation and yoga which have shown potential.
