Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease:: Importance of antioxidant and cannabinoid receptor-independent properties
Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease:: Importance of antioxidant and cannabinoid receptor-independent properties
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DOI：
10.1016/j.brainres.2006.11.063
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发表时间：
2007-02-23
期刊：
影响因子：
2.9
通讯作者：
Fernandez-Ruiz, Javier
中科院分区：
文献类型：
--
作者：
Garcia-Arencibia, Moises;Gonzalez, Sara;Fernandez-Ruiz, Javier
我们最近证明了两种植物衍生的大麻素，δ(9)-四氢大麻酚和大麻二酚（CBD），在帕金森病（PD）动物模型中具有神经保护作用，可能是因为它们的抗氧化特性。为了进一步探讨这一问题，我们研究了一系列基于大麻素的化合物的神经保护作用，这些化合物对大麻素信号系统的不同元素具有更高的选择性，用于局部应用6-羟多巴胺引起的单侧黑质纹状体多巴胺能神经元病变的大鼠。我们使用了CB1受体激动剂arachidonyl-2-chloroethylamide （ACEA）、CB2受体激动剂HU-308、非选择性激动剂WIN55,212-2和内源性大麻素失活抑制剂AM404和UCM707，所有这些药物都是口服的。每天给药ACEA或WIN55,212-2并不能逆转6-羟多巴胺诱导的损伤侧多巴胺（DA）消耗，而HU-308产生了一个小的恢复，这支持了CB2而不是CB1受体可能参与的可能性。AM404显著恢复了损伤侧6-羟多巴胺诱导的DA消耗和酪氨酸羟化酶缺陷。这可能是由AM404的抗氧化特性引起的，而AM404的抗氧化特性来源于其结构中酚基的存在，而不是AM404阻断内源性大麻素转运体的能力，因为另一种缺乏抗氧化特性的转运体抑制剂UCM707没有产生同样的效果。在未受损的对侧结构中没有观察到这些影响。我们还检查了CBD在PD大鼠模型中提供神经保护作用的时间。我们发现，正如预期的那样，在病变后立即给予CBD能够恢复6-羟多巴胺诱导的DA耗竭，但在1周后开始治疗时却没有这样做。此外，CBD的作用暗示了Cu， zn -超氧化物歧化酶mRNA水平的上调，Cu， zn -超氧化物歧化酶是内源性防御氧化应激的关键酶。综上所述，我们的研究结果表明，那些具有抗氧化大麻素受体独立特性的大麻素对PD患者黑质纹状体多巴胺能神经元的进行性变性提供了神经保护。此外，CB2（但不是CB1）受体的激活，或其他其他机制，也可能在一定程度上促进大麻素在这种疾病中的潜力。(c) 2006 Elsevier B.V.版权所有
We have recently demonstrated that two plant-derived cannabinoids, Delta(9)-tetrahydrocannabinol and cannabidiol (CBD), are neuroprotective in an animal model of Parkinson's disease (PD), presumably because of their antioxidant properties. To further explore this issue, we examined the neuroprotective effects of a series of cannabinoid-based compounds, with more selectivity for different elements of the cannabinoid signalling system, in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine. We used the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 receptor agonist HU-308, the non-selective agonist WIN55,212-2, and the inhibitors of the endocannabinoid inactivation AM404 and UCM707, all of them administered i.p. Daily administration of ACEA or WIN55,212-2 did not reverse 6-hydroxydopamine-induced dopamine (DA) depletion in the lesioned side, whereas HU-308 produced a small recovery that supports a possible involvement of CB2 but not CB1 receptors. AM404 produced a marked recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side. Possibly, this is caused by the antioxidant properties of AM404, which are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter, because UCM707, another transporter inhibitor devoid of antioxidant properties, did not produce the same effect. None of these effects were observed in non-lesioned contralateral structures. We also examined the timing for the effect of CBD to provide neuroprotection in this rat model of PD. We found that CBD, as expected, was able to recover 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion, but it failed to do that when the treatment started 1 week later. In addition, the effect of CBD implied an upregulation of mRNA levels for Cu,Zn-superoxide dismutase, a key enzyme in endogenous defenses against oxidative stress. In summary, our results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. In addition, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease. (c) 2006 Elsevier B.V. All rights reserved.