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

• Main Authors: Chia-Yu Chang, 張嘉祐
• Other Authors: 胡淼琳
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/aj93gy

博士 === 國立中興大學 === 食品暨應用生物科技學系所 === 105 === 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.