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首页> 外文期刊>Brain research >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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Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: Importance of antioxidant and cannabinoid receptor-independent properties.

机译：在帕金森氏病大鼠模型中评估大麻素的神经保护作用：抗氧化剂和大麻素受体非依赖性特性的重要性。

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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 CB(1) receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB(2) 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 CB(2) but not CB(1) 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 CB(2) (but not CB(1)) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease.
机译：我们最近证明，两种植物来源的大麻素Delta（9）-四氢大麻酚和大麻二酚（CBD）在帕金森氏病（PD）的动物模型中具有神经保护作用，大概是因为它们具有抗氧化特性。为了进一步探讨这个问题，我们研究了一系列大麻素类化合物的神经保护作用，对由局部应用6-羟基多巴胺引起的黑质纹状体多巴胺能神经元的单侧病变的大鼠具有更多的大麻素信号传导系统选择性。我们使用了CB（1）受体激动剂花生四烯酸-2-氯乙酰胺（ACEA），CB（2）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 ，所有人都通过ip管理每天施用ACEA或WIN55,212-2并不能逆转病变侧的6-羟基多巴胺诱导的多巴胺（DA）消耗，而HU-308的恢复很小，支持CB（2）可能参与，但CB（ 1）受体。 AM404在患侧显着恢复了6-羟基多巴胺诱导的DA消耗和酪氨酸羟化酶缺陷。这可能是由于AM404的抗氧化特性引起的，而AM404的抗氧化特性是由于其结构中存在酚基而引起的，而不是AM404阻断大麻素转运蛋白的能力，因为另一种缺乏抗氧化特性的转运蛋白抑制剂UCM707没有产生相同的效果。在非病变对侧结构中未观察到这些影响。我们还检查了在这种PD大鼠模型中CBD提供神经保护作用的时机。我们发现，正如在病灶后立即给予治疗一样，CBD能够如预期的那样恢复6-羟基多巴胺诱导的DA耗竭，但是当治疗在1周后开始时，CBD未能恢复原状。此外，CBD的作用暗示了铜，锌超氧化物歧化酶的mRNA水平上调，铜，锌超氧化物歧化酶是内源防御氧化应激的关键酶。总而言之，我们的研究结果表明，具有抗氧化剂大麻素受体独立特性的那些大麻素可提供针对PD中发生的黑质纹状体多巴胺能神经元进行性退化的神经保护作用。此外，CB（2）（但不是CB（1））受体的激活或其他其他机制也可能在某种程度上有助于大麻素在这种疾病中的潜能。

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