Perspectives on benefit of early and prereperfusion hypothermia by pharmacological approach in stroke

Abstract

Stroke kills or disables approximately 15 million people worldwide each year. It is the leading cause of brain injury, resulting in persistent neurological deficits and profound physical handicaps. In spite of over 100 clinical trials, stroke treatment modalities are limited in applicability and efficacy, and therefore, identification of new therapeutic modalities is required to combat this growing problem. Poststroke oxidative damage and lactic acidosis are widely-recognized forms of brain ischemia/reperfusion injury. However, treatments directed at these injury mechanisms have not been effective. In this review, we offer a novel approach combining these well-established damage mechanisms with new insights into brain glucose handling. Specifically, emerging evidence of brain gluconeogenesis provides a missing link for understanding oxidative injury and lactate toxicity after ischemia. Therefore, dysfunctional gluconeogenesis may substantially contribute to oxidative and lactate damage. We further review that hypothermia initiated early in ischemia and before reperfusion may ameliorate gluconeogenic dysfunction and subsequently provide an important mechanism of hypothermic protection. We will focus on the efficacy of pharmacologically assisted hypothermia and suggest a combination that minimizes side effects. Together, this study will advance our knowledge of basic mechanisms of ischemic damage and apply this knowledge to develop new therapeutic strategies that are desperately needed in the clinical treatment of stroke.

Keywords: Gluconeogenesis; PCK; ischemic stroke; neuroprotection; pharmacological hypothermia.

Figure 1

Regulation of PH on gluconeogenesis through HIF-1α/XBP-1/FoxO1. Gluconeogenesis is a multistep metabolic process that generates glucose from pyruvate or a related three-carbon compound (lactate, alanine). Conversion of pyruvate to PEP via oxaloacetate, catalyzed by pyruvate carboxylase and PEP carboxy kinase is one of the irreversible steps in the gluconeogenic pathway. HIF-1α regulation and XBP-1-FoxO Signal play the key roles in gluconeogenic activity through PCKs. HIF: Hypoxia-inducible factor, XBP-1: X-box binding protein 1, FoxO: Forkhead box O, PEP: Phosphoenolpyruvate, PH: Pharmacological hypothermia, ROS: Reactive oxygen species, OAA: Oxaloacetate, PCK: Phosphoenolpyruvate carboxykinase, ER: Endoplasmic reticulum