cannabidiol and Dyskinesia--Drug-Induced

Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient's quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating L-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative L-DOPA exposure. Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms. In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade. In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids. Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.

Topics: Animals; Cannabidiol; Cannabinoids; Dyskinesia, Drug-Induced; Humans; Levodopa; Neuroprotective Agents; Parkinson Disease

The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics. The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors. The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect. Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol. Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662. In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.

Topics: Animals; Antioxidants; Antipsychotic Agents; Behavior, Animal; Brain; Cannabidiol; Corpus Striatum; Dyskinesia, Drug-Induced; Dyskinesias; Female; Haloperidol; Inflammation; Male; Mastication; Mice; Mice, Inbred C57BL; Microglia; Motor Activity; Oxidative Stress; PPAR gamma; Primary Cell Culture; Superoxide Dismutase; Tardive Dyskinesia

Topics: Animals; Anti-Dyskinesia Agents; Arachidonic Acids; Brain; Cannabidiol; Capsaicin; Cyclooxygenase 2; Dyskinesia, Drug-Induced; Endocannabinoids; Extracellular Signal-Regulated MAP Kinases; Histones; Levodopa; Male; Mice, Inbred C57BL; NF-kappa B; Oxidopamine; Parkinsonian Disorders; Polyunsaturated Alkamides; PPAR gamma; Receptor, Cannabinoid, CB1; TRPV Cation Channels; Tyrosine 3-Monooxygenase