García-Arencibia Moisés, González Sara, de Lago Eva, Ramos José A, Mechoulam Raphael, Fernández-Ruiz Javier
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Brain Res. 2007 Feb 23;1134(1):162-70. doi: 10.1016/j.brainres.2006.11.063. Epub 2006 Dec 28.
We have recently demonstrated that two plant-derived cannabinoids, Delta9-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.
我们最近证明，两种植物源大麻素，Δ9-四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，可能是由于它们的抗氧化特性。为了进一步探讨这个问题，我们研究了一系列基于大麻素的化合物对由局部应用6-羟基多巴胺引起黑质纹状体多巴胺能神经元单侧损伤的大鼠的神经保护作用，这些化合物对大麻素信号系统的不同成分具有更高的选择性。我们使用了CB1受体激动剂花生四烯酰-2-氯乙酰胺（ACEA）、CB2受体激动剂HU-308、非选择性激动剂WIN55,212-2，以及内源性大麻素失活抑制剂AM404和UCM707，所有这些均通过腹腔注射给药。每日给予ACEA或WIN55,212-2并不能逆转6-羟基多巴胺诱导的损伤侧多巴胺（DA）耗竭，而HU-308产生了轻微的恢复，这支持了CB2而非CB1受体可能参与其中。AM404使损伤侧6-羟基多巴胺诱导的DA耗竭和酪氨酸羟化酶缺乏得到显著恢复。这可能是由AM404的抗氧化特性引起的，其抗氧化特性源于其结构中酚基团的存在，而不是因为AM404能够阻断内源性大麻素转运体，因为另一种没有抗氧化特性的转运体抑制剂UCM707没有产生相同的效果。在未损伤的对侧结构中未观察到这些效应。我们还研究了CBD在该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，CBD在损伤后立即给药时能够恢复6-羟基多巴胺诱导的DA耗竭，但在损伤1周后开始治疗时则不能。此外，CBD 的作用意味着铜锌超氧化物歧化酶（一种内源性抗氧化应激关键酶）的mRNA水平上调。总之，我们的结果表明，那些具有与大麻素受体无关的抗氧化特性的大麻素可对PD中发生的黑质纹状体多巴胺能神经元的进行性退化提供神经保护。此外，CB2（而非CB1）受体的激活或其他额外机制在一定程度上也可能有助于大麻素在该疾病中的潜在作用。
