Therapeutic Treatment with Ascorbate Rescues Mice from Heat Stroke-induced Death and Reduces Focal Cerebral Ischemia-induced Brain Infarction in Rats

Abstract

口服維生素C因其有限的生物利用率，因此對氧化壓力相關的疾病的效用並不明顯。然而，卻有證據顯示經由靜脈補充維生素C在危急及嚴重的病人可明顯增加其效用。 熱中風(即俗稱的中暑)被定義為過度高溫所導致的全身性炎症反應及多重器官功能衰竭，其主要症狀表現為中樞神經系統障礙，如譫妄，抽搐和昏迷。熱中風的體溫、免疫及凝血機制的失調和組織器官損傷的反應非常類似於敗血症，因此可能有相似的病理機轉。本研究利用高致死率的熱中風小鼠模型所引發的模擬敗血症全身炎症反應來測試我們的研究假設:超生理劑量的維生素C在重症治療上可以具有療效。我們發現在熱中風的小鼠，維生素C藉由降低熱中風誘發的全身性炎症，凝血異常反應和體溫調節功能障礙及之後的多重器官損傷(尤其是腦下視丘)，因而降低熱中風小鼠死亡。 腦中風是一個重大的公共衛生問題，是成年人排名第三位最常見的死亡原因。局部缺血性的腦中風可導致嚴重的神經系統後遺症，造成終身殘疾。本研究，我們假設於暫時性局部腦缺血的大鼠模型，使用高劑量維生素C可減緩氧化壓力引發的腦缺血再灌注損傷而發揮其療效。的確，我們發現超生理劑量的維生素C，相較於對照組，可藉由減緩神經細胞凋亡及血腦屏障的破壞，進而減少腦梗塞體積和腦水腫及改善神經功能的損傷。 總之，我們的研究結果支持超生理劑量的維生素C可能在重症上有治療功效的假設和概念。靜脈注射高劑量維生素C的給予提供了一種便宜，強效和多重作用的抗氧化劑治療，尤其是對循環的復甦有特別的效果。在重症病人，今後的研究重點應放在使用短期高劑量靜脈注射維生素C作為循環復甦的藥物，或結合其他抗氧化劑，儘早地介入氧化傷害的連鎖反應，優化血管和微循環，以降低細胞的損傷。

The impact of ascorbate (vitamin C, ascorbic acid) on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, parenteral administration can increase the benefit of ascorbate supplementation as is evident in critically ill patients. Heatstroke is defined as a form of excessive hyperthermia associated with a systemic inflammatory response that results in multiple organ dysfunctions in which central nervous system disorders such as delirium, convulsions, and coma are predominant. The thermoregulatory, immune, coagulation and tissue injury responses of heatstroke closely resemble those observed during sepsis and are likely mediated by similar cellular mechanisms. This study was performed by using the characteristic high lethality rate and sepsis-mimic systemic inflammatory response of a murine model of heat stroke to test our hypothesis that supra-physiological doses of ascorbate may have therapeutic use in critical care. We demonstrated that parenteral administration of ascorbate abrogated the lethality and thermoregulatory dysfunction in murine model of heat stroke by attenuating heat stroke-induced accelerated systemic inflammatory, coagulation responses and the resultant multiple organ injury, especially in hypothalamus. Stroke is a major public health problem and ranks third most common cause of death in adults worldwide. Focal ischemic stroke can cause permanent disability and lead to severe neurological sequelae. In this study, we hypothesized that high- dose ascorbate may exert its therapeutic effects through attenuating oxidative stress driven cerebral ischemia-reperfusion injury in a rat model of transient focal cerebral ischemia. Indeed, we did demonstrate that administration of supra-physiological doses of ascorbate significantly improved neurological deficits, the sequelae of brain infarction and edema, in a rat model of transient focal cerebral ischemia by attenuating cerebral neuronal apoptosis and blood brain barrier disruption. Overall, our findings support the hypothesis and notion that supra-physiological doses of ascorbate may have therapeutic use in critical care. Parenteral administration of high-dose ascorbate provides an inexpensive, strong and multifaceted antioxidant therapy, especially robust for resuscitation of the circulation. In critically ill patients, future research should focus on the use of short-term high-dose intravenous ascorbate as a resuscitation drug, or combined with other antioxidants to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and to limit cellular injury.