URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors
URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors
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DOI：
10.1007/s12640-016-9698-1
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发表时间：
2017-05-01
影响因子：
3.7
通讯作者：
Santamaria, Abel
中科院分区：
文献类型：
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作者：
Escamilla-Ramirez, Angel;Garcia, Esperanza;Santamaria, Abel
内源性大麻素系统（ECS）调节大脑中的几种生理事件。虽然合成大麻素受体（CBr）激动剂如WIN 55，212-2直接作用于CBr，但如URB 597（脂肪酸酰胺水解酶（FAAH）抑制剂）的试剂通过增加内源性大麻素大麻素（AEA）的内源性水平来诱导CBr的更“生理”活化。在此，我们比较了URB 597和WIN 55，212-2在小鼠中由线粒体毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）产生的毒性模型中评估的不同终点上的治疗前和治疗后功效。MPTP（40 mg/kg，s.c.，单次注射）降低自发活动，耗尽纹状体和黑质多巴胺（DA）水平，增加两个区域的脂质过氧化和蛋白质羰基化水平，降低纹状体酪氨酸羟化酶蛋白水平，并增加N-甲基-d-天冬氨酸受体（NMDAr）亚基1（NR 1）的纹状体蛋白含量。URB597（0.3mg/kg，i.p.，每天一次）和WIN 55，212-2（10 μ g/kg，i. p.，每天两次），在MPTP注射之前或之后连续给药5天，阻止了MPTP引起的改变并下调了NMDAr。我们的研究结果支持ECS对MPTP在小鼠中通过刺激抗氧化活性和诱导NMDAr下调和功能减退而产生的毒性特征的调节作用，并有利于刺激CBr作为有效的实验治疗策略。
Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP (40 mg/kg, s.c., single injection) decreased locomotor activity, depleted the striatal and nigral levels of dopamine (DA), augmented the levels of lipid peroxidation and protein carbonylation in both regions, decreased the striatal protein levels of tyrosine hydroxylase, and increased the striatal protein content of the subunit 1 (NR1) of the N-methyl-d-aspartate receptor (NMDAr). Both URB597 (0.3 mg/kg, i.p., once a day) and WIN55,212-2 (10 mu g/kg, i.p., twice a day), administered for five consecutive days, either before or after the MPTP injection, prevented the alterations elicited by MPTP and downregulated NMDAr. Our results support a modulatory role of the ECS on the toxic profile exerted by MPTP in mice via the stimulation of antioxidant activity and the induction of NMDAr downregulation and hypofunction, and favor the stimulation of CBr as an effective experimental therapeutic strategy.