The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation
The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation
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DOI：
10.1007/s12035-018-1129-2
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发表时间：
2019-02-01
影响因子：
5.1
通讯作者：
Santamaria, Abel
中科院分区：
文献类型：
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作者：
Aguilera-Portillo, Gabriela;Rangel-Lopez, Edgar;Santamaria, Abel
内源性大麻素系统（ECS）积极参与中枢神经系统内的几个生理过程。其中，已经确定它通过大麻素受体（CBr）的调节输入参与N-甲基-D-天冬氨酸受体（NMDAr）的下调。喹啉酸（QUIN）通过犬尿氨酸途径（KP）产生后，可通过选择性过度激活NMDAr作为兴奋性毒素，从而参与神经系统疾病的发生和发展。在这项工作中，我们评估了URB 597对脂肪酸酰胺水解酶（FAAH）的药理学抑制以及随之而来的内源性花生四烯酸酰胺水平的增加是否可以防止QUIN诱导的兴奋性毒性损伤。URB 597（0.3mg/kg/天x7天，在纹状体损伤之前、期间和之后给药）对大鼠中QUIN诱导的运动（不对称行为）和生化（脂质过氧化和蛋白质羰基化）改变具有保护作用。URB 597还保留了纹状体的结构完整性，并阻止了QUIN（1 L纹状体内，240 nmol/L）诱导的神经元损失（评估为微管相关蛋白-2和谷氨酸脱羧酶定位），同时改变了CBr 1（CB 1）和NMDAR亚基1（NR 1）的早期定位模式。总之，这些研究结果支持的概念，内源性大麻素系统的药理学操作起着神经保护作用，对中枢神经系统的兴奋性毒性损伤。
The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system. Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders. In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3mg/kg/dayx7days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1L intrastriatal, 240nmol/L), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.