Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease.
Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease.
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DOI：
10.3389/fnins.2016.00321
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发表时间：
2016
影响因子：
4.3
通讯作者：
Ojha SK
中科院分区：
文献类型：
--
作者：
Javed H;Azimullah S;Haque ME;Ojha SK
大麻素二型受体（CB2）是内源性大麻素系统的重要组成部分，近年来作为神经调节剂和神经退行性疾病（包括帕金森病（PD））的治疗靶点被发现。据报道，PD患者的大脑中存在CB2受体的下调。因此，CB2受体的激活和上调被认为对PD的神经退行性改变具有保护作用。在本研究中，我们在临床相关的鱼藤酮（ROT）诱导的PD动物模型中，研究了天然存在的CB2受体激动剂β-石竹烯（BCP）介导的CB2受体神经保护作用。每日1次腹腔注射ROT (2.5 mg/kg BW)，连续4周诱导雄性Wistar大鼠PD。在胶质细胞（星形胶质细胞和小胶质细胞）激活后，ROT注射诱导了黑质致密部（SNpc）和DA纹状体纤维中多巴胺能（DA）神经元的显著丧失。ROT还引起氧化损伤，表现为抗氧化酶的丧失和亚硝酸盐水平的升高，以及促炎细胞因子IL-1β、IL-6和TNF-α以及炎症介质NF-κB、COX-2和iNOS的诱导。然而，用BCP治疗可以减弱对rot挑战大鼠的促炎细胞因子和炎症介质的诱导。补充BCP还可以防止谷胱甘肽的消耗，同时减少脂质过氧化和增加抗氧化酶：SOD和过氧化氢酶。酪氨酸羟化酶免疫组化进一步支持了这一结果，表明DA神经元和纤维在神经胶质细胞激活降低后得到了拯救。有趣的是，补充BCP对rot诱导的神经变性具有有效的治疗作用，这是由BCP介导的CB2受体激活和先前给药CB2受体拮抗剂AM630减少BCP的有益作用所证明的。本研究提示，BCP通过激活CB2受体介导的抗炎和抗氧化活性，具有潜在的神经保护作用。
The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial effects of BCP. The present study suggests that BCP has the potential therapeutic efficacy to elicit significant neuroprotection by its anti-inflammatory and antioxidant activities mediated by activation of the CB2 receptors.