Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors

Abstract

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.

Immune Responses Regulated by Cannabidiol

“…In vivo, CBD has been shown to decrease microglial accumulation in the spinal cord in diabetic mice, 81 which might contribute to attenuation of neuropathic pain, and CBD decreased haloperidol-induced activation of reactive microglial cells. 97 CBD's suppression of TNF-a production from microglial cells in vitro was mediated by A 2A adenosine receptors in EOC-20 mouse microglial cells (0.5-5 lm) 89 or rat retinal microglial cells (1 lM). 91 CBD Effects in Autoimmune Disease Models EAE and MS The immunosuppressive and neuroprotective mechanisms of CBD make it an ideal therapeutic candidate for MS, a neurodegenerative autoimmune disease of the CNS that affects *2.5 million people worldwide.…”

“…143 A few other T cell-derived cytokines have been shown to be targets of CBD. As noted above, IL-6 is a critical target of CBD in many cells and tissues, 82,84,86,97,[125][126][127][128]132 many of which are innate cells. However, IL-6 was also suppressed by CBD (5 lM) using encephalitogenic T cells stimulated by APCs and MOG 35-55 in vitro, 144 and ''IL-6 signaling'' as a critical pathway suppressed by CBD.…”

“…CBD's effects have also been shown to be mediated by peroxisome proliferator-activated receptor gamma (PPAR-c) using PPAR-c antagonists in models of b amyloid neuroinflammation, 92 apoptosis, 93,94 dinitrobenzene sulfonic acid (DNBS)-induced colitis, 95 human ulcerative colitis, 96 LPS activation of microglial cells, 97 and hypoxia-ischemia model of neuroinflammation. 98 There are several reports that CBD acts through the serotonin 5-HT1a receptor (Table 1).…”

“…An important part of this question is whether CBD-induced FAAH inhibition generates anandamide metabolites that bind to various receptors to mediate some of the immune suppressive or anti-inflammatory effects of CBD. Coupled with the observation that some of the effects of CBD can be attenuated with PPAR-c antagonists, [92][93][94][95][96][97][98] the possibility exists that CBD-mediated anandamide production drives the subsequent production of (yet unidentified) metabolites that activate PPAR-c. Another critical determination needed for many of the receptor studies is identification of the cell type(s) on which the receptors are expressed, which are mediating the CBD effects. Second, although combined cannabinoids were not a major focus of this review, it will be critical to determine the CBD contribution to immune function compromise in cannabis and/or combined pharmaceuticals such as Sativex.…”

Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts

“…In contrast to the psychoactive constituent tetrahydrocannabinol (THC), CBD demonstrates no direct effect at cannabinoid receptors 1 and 2 (CB 1 and CB 2 ) but modulates the effect of agonists suggesting an allosteric function 2 . In addition, CBD binds to PPARγ, GPR3/6/12/18/55, TRPV1/2, TRPA1, 5-hydroxytryptamine receptor, and mitochondrial proteins [3][4][5][6][7][8][9][10][11] . Despite its promiscuous pharmacology, CBD is well tolerated even when given in high concentrations 12,13 .…”