Liu Qingkun, Hazan Ariela, Grinman Eddie, Angulo Jesus A
Department of Biological Sciences, Hunter College, United States; Department of Biochemistry, The Graduate Center of The City University of New York, United States.
Department of Biological Sciences, Hunter College, United States.
Brain Res. 2017 Mar 15;1659:148-155. doi: 10.1016/j.brainres.2017.01.029. Epub 2017 Jan 25.
Methamphetamine (METH) is a widely abused psychostimulant displaying potent addictive and neurotoxic properties. METH induces neurotoxicity of dopaminergic terminals and striatal neurons in the striatum. Despite much information on neurotransmitters, the role of neuropeptides is poorly understood. In this study, we investigated the role of the neuropeptide neurotensin on the METH-induced apoptosis of some striatal neurons in mice. We observed that a single injection of METH (30mg/kg, ip) induced the loss of approximately 15% of striatal neurons. An agonist of the neurotensin receptor 1 (PD149163, ip at various doses) attenuated the METH-induced striatal neuron apoptosis. Utilizing quantitative real time PCR, we showed that METH also up-regulated neurotensin gene expression with 96% increase in preproneurotensin mRNA levels in the striatum as compared to the control. Additionally, NTR1 agonist (ip injection) attenuated hyperthermia at 2h post-METH injection; hyperthermia is a putative and significant component of METH-induced neurotoxicity. To investigate the role of neurotensin without affecting core body temperature, we performed stereotactic injection of PD149163 into the striatum and observed that this compound maintained attenuated the METH-induced apoptosis in the striatum, while leaving core body temperature unaffected. There was no effect of NTR1 agonist on METH-induced dopamine terminal degeneration, as evidenced by tyrosine hydroxylase levels determined by Western blot. These data indicate that the neuropeptide neurotensin modulates the striatal neuronal apoptosis induced by METH through diverse mechanisms that need to be investigated. Furthermore, due to its neuroprotective properties, neurotensin receptor agonists show potential as drug candidates for the treatment of METH abuse and some neurological disorders.
甲基苯丙胺（METH）是一种被广泛滥用的精神兴奋剂，具有强大的成瘾性和神经毒性。METH会诱导纹状体中多巴胺能终末和纹状体神经元的神经毒性。尽管关于神经递质已有很多信息，但神经肽的作用却知之甚少。在本研究中，我们调查了神经肽神经降压素对METH诱导的小鼠部分纹状体神经元凋亡的作用。我们观察到单次注射METH（30mg/kg，腹腔注射）会导致约15%的纹状体神经元丧失。神经降压素受体1的激动剂（PD149163，不同剂量腹腔注射）可减轻METH诱导的纹状体神经元凋亡。利用定量实时PCR，我们发现METH还上调了神经降压素基因表达，与对照组相比，纹状体中前神经降压素mRNA水平增加了96%。此外，NTR1激动剂（腹腔注射）可减轻METH注射后2小时的体温过高；体温过高是METH诱导的神经毒性的一个假定且重要的组成部分。为了在不影响核心体温的情况下研究神经降压素的作用，我们将PD149163立体定向注射到纹状体中，观察到该化合物可维持减轻METH诱导的纹状体凋亡，同时不影响核心体温。如通过蛋白质免疫印迹法测定的酪氨酸羟化酶水平所示，NTR1激动剂对METH诱导的多巴胺终末变性没有影响。这些数据表明，神经肽神经降压素通过多种需要研究的机制调节METH诱导的纹状体神经元凋亡。此外，由于其神经保护特性，神经降压素受体激动剂显示出作为治疗METH滥用和某些神经疾病的候选药物的潜力。
