Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.
Innovative Learning Center, Srinakharinwirot University, Bangkok, Thailand.
J Pineal Res. 2018 Apr;64(3). doi: 10.1111/jpi.12456. Epub 2017 Dec 4.
Chronic amphetamine (AMPH) abuse leads to damage of the hippocampus, the brain area associated with learning and memory process. Previous results have shown that AMPH-induced dopamine neurotransmitter release, reactive oxygen species formation, and degenerative protein aggregation lead to neuronal death. Melatonin, a powerful antioxidant, plays a role as a neuroprotective agent. The objective of this study was to investigate whether the protective effect of melatonin on AMPH-induced hippocampal damage in the postnatal rat acts through the dopaminergic pathway. Four-day-old postnatal rats were subcutaneously injected with 5-10 mg/kg AMPH and pretreated with 10 mg/kg melatonin prior to AMPH exposure for seven days. The results showed that melatonin decreased the AMPH-induced hippocampal neuronal degeneration in the dentate gyrus, CA1, and CA3. Melatonin attenuated the reduction in the expression of hippocampal synaptophysin, PSD-95, α-synuclein, and N-methyl-D-aspartate (NMDA) receptor protein and mRNA caused by AMPH. Melatonin attenuated the AMPH-induced reduction in dopamine transporter (DAT) protein expression in the hippocampus and the reduction in mRNA expression in the ventral tegmental area (VTA). Immunofluorescence demonstrated that melatonin not only prevented the AMPH-induced loss of DAT and NMDA receptor but also prevented AMPH-induced α-synuclein overexpression in the dentate gyrus, CA1, and CA3. Melatonin decreased the AMPH-induced reduction in the protein and mRNA of the NMDA receptor downstream signaling molecule, calcium/calmodulin-dependent protein kinase II (CaMKII), and the melatonin receptors (MT1 and MT2). This study showed that melatonin prevented AMPH-induced toxicity in the hippocampus of postnatal rats possibly via its antioxidative effect and mitochondrial protection.
慢性安非他命（AMPH）滥用会导致海马体受损，海马体与学习和记忆过程有关。先前的研究结果表明，AMPH 诱导的多巴胺神经递质释放、活性氧形成和退行性蛋白聚集导致神经元死亡。褪黑素作为一种强大的抗氧化剂，发挥神经保护作用。本研究旨在探讨褪黑素对 AMPH 诱导的新生大鼠海马损伤的保护作用是否通过多巴胺能途径发挥作用。将 4 日龄新生大鼠皮下注射 5-10mg/kg AMPH，并在 AMPH 暴露前 7 天用 10mg/kg 褪黑素预处理。结果表明，褪黑素减少了 AMPH 诱导的齿状回、CA1 和 CA3 海马神经元变性。褪黑素减弱了 AMPH 引起的海马突触素、PSD-95、α-突触核蛋白和 N-甲基-D-天冬氨酸（NMDA）受体蛋白和 mRNA 表达减少。褪黑素减弱了 AMPH 诱导的海马多巴胺转运体（DAT）蛋白表达减少和腹侧被盖区（VTA）mRNA 表达减少。免疫荧光显示，褪黑素不仅防止了 DAT 和 NMDA 受体的 AMPH 诱导丢失，还防止了 AMPH 诱导的齿状回、CA1 和 CA3 中 α-突触核蛋白过表达。褪黑素降低了 AMPH 诱导的 NMDA 受体下游信号分子钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）和褪黑素受体（MT1 和 MT2）的蛋白和 mRNA 减少。本研究表明，褪黑素通过其抗氧化作用和线粒体保护作用，防止新生大鼠海马中 AMPH 诱导的毒性。
