The phytocannabinoid 9-THCV as a neuroprotective and anti-dyskinetic agent in experimental models of Parkinson's disease

KEIFMAN, ETTEL; JAVIER FERNÁNDEZ-RUIZ; ISABEL ESPADAS; CONCEPCIÓN GARCÍA; SONIA BURGAZ; CRISTINA PALOMO-GARO; MORATALLA, ROSARIO

Madrid

Congreso; 19° Reunión Anual de la Sociedad Española de Iinvestigación en Canabinoides; 2018

Sociedad Española de Investigacion sobre Canabinoides

As found for 9-THC, the phytocannabinoid 9-THCV is also antioxidant and a CB2 receptor agonist, but, in contrast, at doses lower than 5 mg/kg, it behaves as a CB1 receptor antagonist rather than an agonist. Such profile is particularly attractive for the treatment of Parkinson?s disease (PD), as 9-THCV may serve to alleviate akinetic symptoms due to its action as a CB1 receptor antagonist, as well as to provide neuroprotection due to its antioxidant activity and its capability to activate CB2 receptors, as we already described (García et al., Brit J Pharmacol 163, 1495-1506 (2011)). Its neuroprotective properties were particularly evident in an inflammation-driven model of PD, but they were rather modest in 6-hydroxydopamine-lesioned mice (García et al., Brit J Pharmacol 163, 1495-1506 (2011)). In the present study, we investigated whether the combination of 9-THCV (2 mg/kg, i.p.) with cannabidiol (CBD; 3 mg/kg, i.p.), may enhance its neuroprotective effect in these mice. As a second objective, we investigated the anti-dyskinetic potential of 9-THCV (2 mg/kg, i.p.), a property relevant for any antiparkinsonian agent. This had not been investigated before for this phytocannabinoid. As regards to the first objective, the treatment with Δ9-THCV completely reduced the paresis of the contralateral forepaw in the cylinder test and partially reversed the motor inhibition observed in lesioned mice in a computer-aided actimeter, effects that were likely caused by the capability of 9-THCV to preserve nigrostriatal neurons (measured by tyrosine hydroxylase immunostaining). It is important to remark that, although significant, some of these beneficial effects were relatively modest. Δ9-THCV with CBD combination did not produce any improvement in the neuroprotective properties of 9-THCV alone. As a second objective, we investigated the capability of Δ9-THCV to attenuate L-DOPA-induced dyskinesia in Pitx3-/- aphakia mice, a genetic model of dopaminergic deficiency. The daily treatment of these mice with L-DOPA for two weeks progressively increased the time spent in abnormal involuntary movements, as well as elevated the horizontal and vertical activities measured in a computer-aided actimeter, signs that reflected the dyskinetic state of these mice. Interestingly, when combined with L-DOPA from the first injection, Δ9-THCV delayed the appearance of all these signs, being these benefits associated with a partial normalization in two molecular markers, FosB protein and the histone pAcH3 (measured by immunohistochemistry), that have been found to be elevated in the basal ganglia in L-DOPA induced dyskinesia. In addition, Δ9-THCV was also effective in attenuating the extent of dyskinesia when administered for five days once the dyskinetic signs were already present (two weeks after the onset of L-DOPA treatment). In summary, our data support the anti-dyskinetic potential of Δ9-THCV, in addition to its promising neuroprotective properties that, however, could not be enhanced by a combined treatment with CBD. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for PD patients.