Department of Neurosurgery, AnNing Branch Hospital, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, Gansu Province, 730070, China.
Department of Neurosurgery, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, Gansu Province, 730050, China.
Neurosci Lett. 2019 Aug 10;707:134305. doi: 10.1016/j.neulet.2019.134305. Epub 2019 May 29.
Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptative responses that provide a defense against additional stress from the same (tolerance) or other (cross-tolerance) stimuli. Such endogenous modulators mediate the tolerance induced by numerous sublethal physical and chemical stress factors, of which epileptic preconditioning (EPC) and mild global ischemia are two most important mutually protective actions. However, the evidence for the complicated underlying mechanisms involved in this neuroprotective effects are lacking. During hypoxia/ischemia (H/I) and intense neural activity, lactate released from astrocytes is taken up by neurons and is stored for energy, a process mediated by monocarboxylate transporters (MCTs) in central nervous system (CNS). The present study investigated whether ischemic preconditioning (IPC) or EPC can provide protection to CNS against epilepsy or cerebral infarction respectively through regulation of MCTs expression in vivo. Rats were subjected to transitory middle cerebral artery occlusion (MCAO) or kainic acid (KA) preconditioning protocol respectively, followed by KA induced epilepsy or lethal MCAO as well as lactate transportation inhibitor injection, with a subsequent evaluation of behavior and infarct volume as well as MCTs expression in rats brain. IPC reduced the severity of status epilepticus induced by KA injection and EPC reduce infarct volume resulted from lethal MCAO. However, lactate transport blocking attenuated this neuroprotective effect and MCTs expression followed the same variation trends. These findings demonstrate that MCTs dependent mechanism is involved in the cross-tolerance between epilepsy and cerebral infarction, provide a potential basis for the clinical treatment of patients with brain diseases characterized by epilepsy and H/I.
有害刺激施加在接近但低于细胞损伤阈值的剂量下，会诱导适应性反应，为来自相同（耐受）或其他（交叉耐受）刺激的额外应激提供防御。这种内源性调节剂介导了许多亚致死物理和化学应激因素诱导的耐受，其中癫痫预处理（EPC）和轻度全脑缺血是两种最重要的相互保护作用。然而，缺乏涉及这种神经保护作用的复杂潜在机制的证据。在缺氧/缺血（H/I）和强烈的神经活动期间，星形胶质细胞释放的乳酸被神经元摄取并储存为能量，这一过程由中枢神经系统（CNS）中的单羧酸转运蛋白（MCTs）介导。本研究通过在体内调节 MCTs 的表达，研究了缺血预处理（IPC）或 EPC 是否可以分别为中枢神经系统提供对癫痫或脑梗死的保护。大鼠分别接受短暂性大脑中动脉闭塞（MCAO）或海人酸（KA）预处理方案，随后接受 KA 诱导的癫痫发作或致死性 MCAO 以及乳酸转运抑制剂注射，随后评估大鼠的行为和梗死体积以及大脑中的 MCTs 表达。IPC 减轻了 KA 注射诱导的癫痫持续状态的严重程度，EPC 减轻了致死性 MCAO 引起的梗死体积。然而，乳酸转运阻断削弱了这种神经保护作用，MCTs 的表达也随之呈现出相同的变化趋势。这些发现表明，MCTs 依赖性机制参与了癫痫和脑梗死之间的交叉耐受，为以癫痫和 H/I 为特征的脑疾病患者的临床治疗提供了潜在的依据。
