Parameshwaran Kodeeswaran, Irwin Michael H, Steliou Kosta, Suppiramaniam Vishnu, Pinkert Carl A
Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
Drug Dev Res. 2015 Mar;76(2):72-81. doi: 10.1002/ddr.21242. Epub 2015 Apr 3.
Mitochondrial dysfunction is a key component of various aging-related pathologies of the brain that result in dementia. As such, it provides an important avenue in development of therapeutic interventions for a host of neurological disorders. A requirement for functional mitochondrial respiratory chain complex I (CI), to accomplish the normal physiological processes regulating memory, seems intuitive. In the present study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day po) was administered to female ICR mice (3-4-month old) that were subsequently treated with the mitochondrial CI inhibitor, rotenone (400 mg/kg/day). After 1 week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a brain region that is involved in regulating memory formation. Electrophysiological recordings in live brain slices showed that long-term potentiation (LTP) was reduced by rotenone exposure (P < 0.05) while pretreatment with PMX-500FI maintained LTP similar to control levels (P > 0.05). Potentiation during theta burst stimulation (TBS) was similar among treatment groups (P > 0.05); however, neurotransmitter release, which increased in control mice after TBS, was lower in rotenone treated mice (P < 0.05), and was accompanied by reduced basal synaptic transmission (P < 0.05), increased proapoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P < 0.05). For each of these determinations, pretreatment with PMX-500FI alleviated the harmful effects of rotenone. These results illustrate that treatment with antioxidant PMX-500FI is protective against rotenone-induced impairment of neuronal bioenergetics in the mouse hippocampus, in regard to both excitatory synaptic physiology and proapoptotic signaling. The protective effect of PMX-500FI against rotenone-induced disruption of cellular bioenergetics may have important therapeutic implications for treating aging-related dementia and other diseases related to mitochondrial dysfunction and/or oxidative damage.
线粒体功能障碍是导致痴呆的各种与衰老相关的脑部病变的关键组成部分。因此，它为开发一系列神经疾病的治疗干预措施提供了一条重要途径。功能性线粒体呼吸链复合体I（CI）对于完成调节记忆的正常生理过程似乎是直观的需求。在本研究中，将合成的硫辛酸肉碱抗氧化剂（PMX - 500FI；100毫克/千克/天，口服）给予雌性ICR小鼠（3 - 4个月大），随后用线粒体CI抑制剂鱼藤酮（400毫克/千克/天）进行处理。1周后，在参与调节记忆形成的脑区海马体中评估鱼藤酮诱导的神经元功能损伤。在活脑切片中的电生理记录显示，鱼藤酮暴露会降低长时程增强（LTP）（P < 0.05），而用PMX - 500FI预处理可使LTP维持在与对照水平相似的水平（P > 0.05）。在theta爆发刺激（TBS）期间的增强在各治疗组之间相似（P > 0.05）；然而，在对照小鼠中TBS后增加的神经递质释放，在鱼藤酮处理的小鼠中较低（P < 0.05），并伴有基础突触传递减少（P < 0.05）、促凋亡信号增加和细胞外信号调节激酶1/2（ERK1/2）磷酸化减少（P < 0.05）。对于这些测定中的每一项，用PMX - 500FI预处理都减轻了鱼藤酮的有害影响。这些结果表明，抗氧化剂PMX - 500FI的治疗在兴奋性突触生理学和促凋亡信号方面，对鱼藤酮诱导的小鼠海马体神经元生物能量学损伤具有保护作用。PMX - 500FI对鱼藤酮诱导的细胞生物能量学破坏的保护作用可能对治疗与衰老相关痴呆以及其他与线粒体功能障碍和/或氧化损伤相关的疾病具有重要的治疗意义。
