Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by
6-hydroxydopamine, both in vivo and in vitro, which may be relevant to
Parkinson's disease (PD). First, we evaluated whether the administration of
cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of
6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of
dopamine contents and a reduction of
tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in
tyrosine hydroxylase-
mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this
cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same
neuroprotective effect was also produced by
cannabidiol (CBD), another plant-derived
cannabinoid with negligible affinity for
cannabinoid CB1 receptors, suggests that the
antioxidant properties of both compounds, which are
cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether
cannabinoids also provide neuroprotection against the in vitro toxicity of
6-hydroxydopamine. We found that the non-selective
cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the
cannabinoid was directly added to neuronal cultures than when these cultures were exposed to
conditioned medium obtained from mixed glial cell cultures treated with
HU-210, suggesting that the
cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of
cannabinoids against the in vivo and in vitro toxicity of
6-hydroxydopamine, which might be relevant for PD. Our data indicated that these
neuroprotective effects might be due, among others, to the
antioxidant properties of certain plant-derived
cannabinoids, or exerted through the capability of
cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.