BACKGROUND AND PURPOSE Previous findings have indicated that a cannabinoid, such as Δ⁹‐THCV, which has antioxidant properties and the ability to activate CB₂ receptors but to block CB₁, might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson's disease (PD).EXPERIMENTAL APPROACH The ability of Δ⁹‐THCV to reduce motor inhibition and provide neuroprotection was investigated in rats lesioned with 6‐hydroxydopamine and in mice lesioned with lipopolysaccharide (LPS).KEY RESULTS Acute administration of Δ⁹‐THCV attenuated the motor inhibition caused by 6‐hydroxydopamine, presumably through changes in glutamatergic transmission. Moreover, chronic administration of Δ⁹‐THCV attenuated the loss of tyrosine hydroxylase–positive neurones caused by 6‐hydroxydopamine in the substantia nigra, through an effect related to its antioxidant properties (it was reproduced by cannabidiol ‐enriched botanical extract). In addition, CB₂ receptor–deficient mice responded to 6‐hydroxydopamine in a similar manner to wild‐type animals, and CB₂ receptors were poorly up‐regulated in the rat substantia nigra in response to 6‐hydroxydopamine. By contrast, the substantia nigra of mice that had been injected with LPS exhibited a greater up‐regulation of CB₂ receptors. In these animals, Δ⁹‐THCV also caused preservation of tyrosine hydroxylase–positive neurones. This effect probably involved CB₂ receptors as it was also elicited by the selective CB₂ receptor agonist, HU‐308, and CB₂ receptor–deficient mice were more vulnerable to LPS lesions.CONCLUSIONS AND IMPLICATIONS Given its antioxidant properties and its ability to activate CB₂ but to block CB₁ receptors, Δ⁹‐THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms.LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7

The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia. We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2-knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4- dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism. These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols.