Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal.
Eur J Neurosci. 2012 Nov;36(9):3173-83. doi: 10.1111/j.1460-9568.2012.08232.x. Epub 2012 Jul 17.
It has been reported that the hippocampus is very susceptible to methamphetamine (METH) and that neuropeptide Y (NPY) is an important neuroprotective agent against hippocampal excitotoxicity. However, there is very little information regarding the role of the NPYergic system in this brain region under conditions of METH toxicity. To clarify this issue, we investigated the role of NPY and its receptors against METH-induced neuronal cell death in hippocampal organotypic slice cultures. Our data show that NPY (1 μm) is neuroprotective in DG, CA3 and CA1 subregions via Y(2) receptors. Moreover, the selective activation of Y(1) receptors (1 μm [Leu(31) ,Pro(34) ]NPY) partially prevented the toxicity induced by METH in DG and CA3 subfields, but completely blocked its toxicity in the CA1 pyramidal cell layer. Regarding Y(2) receptors, its activation (300 nm NPY13-36) completely prevented METH-induced toxicity in all subregions analysed, which involved changes in levels of pro- and anti-apoptotic proteins Bcl-2 and Bax, respectively. Besides neuronal cell death, we also showed that METH triggers a microglial response in the mouse hippocampus which was attenuated by Y(2) receptor activation. To better clarify the effect of METH and the NPY system on microglial cells, we further used the N9 microglial cell line. We found that both NPY and the Y(2) receptor agonist were able to protect microglia against METH-induced cell death. Overall, our data demonstrate that METH is toxic to both neurons and microglial cells, and that NPY, mainly via Y(2) receptors, has an important protective role against METH-induced cell death and microgliosis.
据报道，海马体对甲基苯丙胺（METH）非常敏感，神经肽 Y（NPY）是对抗海马体兴奋毒性的重要神经保护剂。然而，关于 NPY 能系统在 METH 毒性作用下在该脑区的作用，信息非常有限。为了阐明这个问题，我们在海马体器官型切片培养物中研究了 NPY 及其受体在 METH 诱导的神经元细胞死亡中的作用。我们的数据表明，NPY（1μm）通过 Y（2）受体对 DG、CA3 和 CA1 亚区具有神经保护作用。此外，Y（1）受体的选择性激活（1μm[Leu（31），Pro（34）]NPY）部分预防了 DG 和 CA3 亚区中 METH 诱导的毒性，但完全阻断了 CA1 锥体神经元层中的毒性。关于 Y（2）受体，其激活（300nmNPY13-36）完全阻止了所有分析的亚区中 METH 诱导的毒性，这涉及到促凋亡和抗凋亡蛋白 Bcl-2 和 Bax 的水平变化。除了神经元细胞死亡外，我们还表明 METH 在小鼠海马体中引发小胶质细胞反应，该反应被 Y（2）受体激活所减弱。为了更好地阐明 METH 和 NPY 系统对小胶质细胞的影响，我们进一步使用了 N9 小胶质细胞系。我们发现 NPY 和 Y（2）受体激动剂都能够保护小胶质细胞免受 METH 诱导的细胞死亡。总的来说，我们的数据表明 METH 对神经元和小胶质细胞都有毒性，而 NPY 主要通过 Y（2）受体，在对抗 METH 诱导的细胞死亡和小胶质细胞增生方面具有重要的保护作用。
