Researchers have found that Delta9-tetrahydrocannabinol and cannabidiol (CBD), two plant-derived cannabinoids, are neuroprotective in an animal model of Parkinson’s disease (PD), presumably because of their antioxidant properties.
The neuroprotective effects of a series of cannabinoid-based compounds with more selectivity for different elements of the cannabinoid signaling system in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine were evaluated for the research purposes.
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 were used and 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 minor recovery supporting a likely involvement of CB2 but not CB1 receptors.
AM404 produced a significant recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side, possibly caused by the antioxidant properties of AM404. The AM404 properties are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter as another transporter inhibitor devoid of antioxidant properties, UCM707, did not produce the same effect.
The researchers also evaluated the timing for the effect of CBD in offering 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion. However, it failed to do that when treatment was initiated a week later. Moreover, 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 short, the results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties offer neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. Furthermore, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, may also contribute to some extent to the potential of cannabinoids in Parkinson’s disease.
The study was conducted by García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J. from Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Brain Res., 2007 Feb 23;1134(1):162-70