Singh Sonu, Mishra Akanksha, Mishra Sandeep Kumar, Shukla Shubha
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Academy of Scientific and Innovative Research, New Delhi, India.
Neurochem Int. 2017 Sep;108:388-396. doi: 10.1016/j.neuint.2017.05.017. Epub 2017 May 31.
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway that leading to progressive motor and nonmotor symptoms. The formation of newborn neurons in the adult hippocampus is affected by many factors such as anxiety, depression and impairment in learning and memory that are commonly observed nonmotor symptoms in PD, indicating the role of adult neurogenesis in PD pathophysiology. Acetyl-l-carnitine (ALCAR), regulate mitochondrial metabolism and has been reported to improve cognitive functions in different neurodegenerative disorders through an unknown mechanism. For the first time, we investigated the effect of ALCAR on adult neurogenesis in the 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes and also explored the possible underlying mechanism of action. A single unilateral administration of 6-OHDA into the medial forebrain bundle reduced neural progenitor cell (NPC) proliferation, long-term survival and neuronal differentiation in the hippocampus. Interestingly, chronic treatment with ALCAR (100 mg/kg/day, i.p) potentially enhanced proliferation, long term survival and neuronal differentiation of NPCs in rat model of PD-like phenotypes. ALCAR treatment stimulates cell survival related signals (AKT and BCL-2) by inhibiting cell death related cues (GSK-3β and BAX) which might be responsible for a neuroprotective effect of ALCAR in rat model of PD-like phenotypes. We conclude that ALCAR exerts neuroprotective effects against 6-OHDA-induced impairment in hippocampal neurogenesis by regulating cell survival and cell death-related signals.
帕金森病（PD）的特征是黑质纹状体通路中的多巴胺能神经元变性，导致进行性运动和非运动症状。成年海马体中新生神经元的形成受到许多因素的影响，如焦虑、抑郁以及学习和记忆障碍，这些都是帕金森病中常见的非运动症状，表明成年神经发生在帕金森病病理生理学中的作用。乙酰左旋肉碱（ALCAR）调节线粒体代谢，并且据报道通过未知机制改善不同神经退行性疾病中的认知功能。我们首次研究了ALCAR对6-羟基多巴胺（6-OHDA）诱导的帕金森病样表型大鼠模型中成年神经发生的影响，并探讨了可能的潜在作用机制。向内侧前脑束单侧单次注射6-OHDA可减少海马体中神经祖细胞（NPC）的增殖、长期存活和神经元分化。有趣的是，用ALCAR（100mg/kg/天，腹腔注射）进行慢性治疗可能会增强帕金森病样表型大鼠模型中NPC的增殖、长期存活和神经元分化。ALCAR治疗通过抑制细胞死亡相关信号（GSK-3β和BAX）来刺激细胞存活相关信号（AKT和BCL-2），这可能是ALCAR在帕金森病样表型大鼠模型中发挥神经保护作用的原因。我们得出结论，ALCAR通过调节细胞存活和细胞死亡相关信号，对6-OHDA诱导的海马体神经发生损伤发挥神经保护作用。
