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  • Modulation of the cannabinoid system

    2022-09-08

    Modulation of the cannabinoid system has been reported to exert anti-parkinsonian properties through different mechanisms. On one hand, cannabinoids have neuroprotective properties in different rodent models of PD, both through a CB1/CB2 receptor-independent mechanism (Lastres-Becker et al., 2005) and by modulating glial cell activity in a manner that involves CB2 receptors (Price et al., 2009, Fernández-Suárez et al., 2014, Aymerich et al., 2016). On the other hand, pharmacological modulation of the endocannabinoid anandamide (AEA) showed promise in terms of the symptomatic treatment of the disease (Kreitzer and Malenka, 2007, More and Choi, 2015, Celorrio et al., 2016). In this study, we questioned whether modulating GPR55 could have anti-parkinsonian effects, either neuroprotective or symptomatic. CBD was proposed to have a neuroprotective action in the 6-OHDA rat model through a CB1/CB2 receptor-independent mechanism, probably due to its antioxidant properties (Lastres-Becker et al., 2005, García-arencibia et al., 2006). By contrast, we found that CBD lacked neuroprotective activity in the MPTP mouse model and it even exacerbated the effect of MPTP by increasing the loss of dopaminergic terminals in the striatum. CBD also worsened the performance of control animals in the rotarod test. MPTP and 6-OHDA are the most widely used neurotoxins to induce a nigrostriatal lesion in animal models: 6-OHDA causes massive oxidative stress and respiratory inhibition due to free radical formation; MPTP impairs mitochondrial respiration by inhibiting complex I of the Gemcitabine transport chain (Schober, 2004). The different type of cell death induced by these two neurotoxins, the acute administration of 6-OHDA compared to the chronic administration of MPTP, and the different techniques used to evaluate the preservation of the nigrostriatal pathway (TH mRNA and activity vs stereology) might account for the differences observed in these models. Thus, caution must be taken when proposing CBD as a neuroprotective agent since the specific type of cell death might determine the beneficial or deleterious properties of this compound. Although Ryberg et al. showed results consistent with antagonism of GPR55 (Ryberg et al., 2007), CBD exerts effects via serotonin 1A (Russo et al., 2005) and cannabinoid (see McPartland et al., 2015 for review) receptors, and it has been reported as allosteric modulator of CB1 receptors (Laprairie et al., 2015). Therefore, CBD effects in-vivo may result from a combination of actions in overlapping regulatory systems. Our data show that the improvement in motor behavior in animals treated with Abn-CBD could not be explained by the preservation of the nigrostriatal pathway or by a compensatory effect in DA metabolism. The strong expression of GPR55 in the basal ganglia led us to explore the possibility that Abn-CBD might act through these receptors to induce symptomatic relief from the motor symptoms. Using the haloperidol-induced catalepsy mouse model, Abn-CBD exhibited a clear anti-cataleptic effect that was reversed by GPR55 antagonists but not by antagonists of CB1, CB2 or GPR18 receptors. Two agonists of GPR55 with a different chemical structure to that of Abn-CBD also had anti-cataleptic properties. The mechanism of action to induce a motor deficit in the chronic MPTP mouse model and in the haloperidol-induced catalepsy model is different. In the chronic MPTP mouse model, MPTP is administered twice a week with probenecid, which reduces the renal clearance of MPTP leading to a sustained toxic response that result in dopaminergic neuron loss and a permanent decrease in striatal dopamine levels. We considered that the behavior analyzed at 16 h after the last dose of Abn-CBD (24 h after MPTPp) would still be under the influence of MPTP and the Abn-CBD. In fact, animals treated with MPTP and Abn-CBD showed a motor behavior clearly different from animals receiving only MPTP, which indicates that at 16 h after the last dose the effect of Abn-CBD was still detectable. The haloperidol-induced catalepsy mouse model is a transient model. Haloperidol is an antagonist of D2 receptors, but it does not affect striatal dopamine levels. The results obtained using these two different models are consistent with Abn-CBD improving PD-related motor deficits. Furthermore, a careful analysis of motor behavior in two independent GPR55 deficient mice provided clear evidence that GPR55 has a subtle but defined modulatory influence on motor control (Wu et al., 2013, Meadows et al., 2015, Bjursell et al., 2016), consistent with the expression of GPR55 in brain areas important to motor function. Together, these results indicate that GPR55 is involved in the anti-parkinsonian properties of Abn-CBD, constituting the first evidence that GPR55 could be considered as a therapeutic target for PD.