Glial Cells and Their Contribution to the Mechanisms of Action of Cannabidiol in Neuropsychiatric Disorders

Abstract

Cannabidiol (CBD) is a phytocannabinoid with a broad-range of therapeutic potential in several conditions, including neurological (epilepsy, neurodegenerative diseases, traumatic and ischemic brain injuries) and psychiatric disorders (schizophrenia, addiction, major depressive disorder, and anxiety). The pharmacological mechanisms responsible for these effects are still unclear, and more than 60 potential molecular targets have been described. Regarding neuropsychiatric disorders, most studies investigating these mechanisms have focused on neuronal cells. However, glial cells (astrocytes, oligodendrocytes, microglia) also play a crucial role in keeping the homeostasis of the central nervous system. Changes in glial functions have been associated with neuropathological conditions, including those for which CBD is proposed to be useful. Mostly in vitro studies have indicated that CBD modulate the activation of proinflammatory pathways, energy metabolism, calcium homeostasis, and the proliferative rate of glial cells. Likewise, some of the molecular targets proposed for CBD actions are f expressed in glial cells, including pharmacological receptors such as CB1, CB2, PPAR-γ, and 5-HT1A. In the present review, we discuss the currently available evidence suggesting that part of the CBD effects are mediated by interference with glial cell function. We also propose additional studies that need to be performed to unveil the contribution of glial cells to CBD effects in neuropsychiatric disorders.

Neuroprotective Effects of Cannabidiol but Not Δ9-Tetrahydrocannabinol in Rat Hippocampal Slices Exposed to Oxygen-Glucose Deprivation: Studies with Cannabis Extracts and Selected Cannabinoids

“…CBD may operate through components of the endocannabinoid system with low affinity for CB1 and CB2 receptors [ 39 ] or on different neurotransmitter systems and pathways. Other CBD effects may be mediated by direct activation of 5-hydroxytrypamine 1A (5-HT1A) receptors [ 34 , 35 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] and peroxisome proliferator-activated receptorγ (PPARγ) [ 17 , 34 ]. In addition, CBD is shown to have an antagonistic effect against THC [ 35 , 40 ].…”

“…Interestingly, among all the above-highlighted mechanisms, the 5-HT1A receptor seems to be the most strongly implicated in the regulatory effects of CBD on mood and mental diseases [ 40 ]. Several pharmacological approaches with selective receptor antagonists such as WAY-100635 showed that anxiolytic-, antidepressant-, and antipsychotic-like effects of CBD are predominantly mediated by 5-HT1A-Rs [ 41 , 42 , 43 ]. 5-HT1A is a crucial serotonergic receptor subtype involved in many functions of serotonin in the brain, and several works have associated many beneficial actions of CBD to this receptor, in accordance with our results [ 34 , 44 , 45 ].…”

New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders

“…As a result, inhibiting CB2Rs with the antagonist AM630 would prevent the antipsychotic effects of M4 agonists. Preclinical studies also showed that cannabidiol (CBD), another major phytocannabinoid, which is devoid of intoxicating effects, has antipsychotic properties [92][93][94][95] mediated by the activation of CB2Rs [96][97][98]. It should be pointed out that CBD is a non-intoxicating rather than a non-psychoactive constituent in the cannabis plant.…”

Endocannabinoid signaling in oligodendroglia

“…The reports on cannabinoid receptor distribution, signaling and function in oligodendrocytes are still scarce, but several revisions have pointed out the relevance of the endocannabinoid system in oligodendrocyte biology (Haspula & Clark, 2020; Ilyasov et al, 2018; Marinelli et al, 2016; Scarante et al, 2021). Thus, the present review intends to gather and discuss the current knowledge on the presence of cannabinoid receptors in oligodendroglial cells and on how cannabinoids/endocannabinoids affect their function both in cell culture and in vivo.…”