Li Fengwu, Gao Jie, Kohls Wesley, Geng Xiaokun, Ding Yuchuan
Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China.
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
Brain Circ. 2022 Jun 30;8(2):69-75. doi: 10.4103/bc.bc_27_22. eCollection 2022 Apr-Jun.
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.
每年全球约有1500万人因中风死亡或致残。中风是脑损伤的主要原因，会导致持续性神经功能缺损和严重身体残疾。尽管进行了100多项临床试验，但中风治疗方法的适用性和疗效有限，因此，需要识别新的治疗方法来应对这一日益严重的问题。中风后氧化损伤和乳酸性酸中毒是广泛认可的脑缺血/再灌注损伤形式。然而，针对这些损伤机制的治疗并不有效。在本综述中，我们提出了一种新颖的方法，将这些已确立的损伤机制与对脑葡萄糖代谢的新见解相结合。具体而言，脑糖异生的新证据为理解缺血后的氧化损伤和乳酸毒性提供了缺失的环节。因此，糖异生功能障碍可能在很大程度上导致氧化和乳酸损伤。我们进一步回顾，在缺血早期和再灌注前开始的低温可能改善糖异生功能障碍，随后提供低温保护的重要机制。我们将重点关注药物辅助低温的疗效，并提出一种将副作用降至最低的联合方案。总之，本研究将推进我们对缺血性损伤基本机制的认识，并应用这一知识来开发中风临床治疗迫切需要的新治疗策略。
