Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways

Abstract

Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination. Recently a combination of Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated. In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells. These effects were mediated through CB1 and CB2 receptors inasmuch as, THC+CBD failed to ameliorate EAE in mice deficient in CB1 and CB2. THC+CBD treatment also caused a decrease in the levels of brain infiltrating CD4+ T cells and pro-inflammatory molecules (IL-17, INF-γ, TNF-α, IL-1β, IL-6, and TBX21), while increasing anti-inflammatory phenotype such as FoxP3, STAT5b, IL-4, IL-10, and TGF-β. Also, the brain-derived cells showed increased apoptosis along with decreased percentage in G0/G1 phase with increased percentage in G2/M phase of cell cycle. miRNA microarray analysis of brain-derived CD4+ T cells revealed that THC+CBD treatment significantly down-regulated miR-21a-5p, miR-31-5p, miR-122-5p, miR-146a-5p, miR-150-5p, miR-155-5p, and miR-27b-5p while upregulating miR-706-5p and miR-7116. Pathway analysis showed that majority of the down-regulated miRs targeted molecules involved in cycle arrest and apoptosis such as CDKN2A, BCL2L11, and CCNG1, as well as anti-inflammatory molecules such as SOCS1 and FoxP3. Additionally, transfection studies involving miR-21 and use of Mir21 −/− mice suggested that while this miR plays a critical role in EAE, additional miRs may also be involved in THC+CBD-mediated attenuation of EAE. Collectively, this study suggests that combination of THC+CBD suppresses neuroinflammation and attenuates clinical EAE development and that this effect is associated with changes in miRNA profile in brain-infiltrating cells.

Cannabis Sativa Revisited - Crosstalk between microRNAs Expression, Inflammation, Oxidative Stress and Endocannabinoid Response System in Critically Ill Patients with Sepsis

“…A similar study carried out by Ma et al reported that microRNA-124 influences and controls the activity of TNF-α, TLR6, and MyD88 [150]. Moreover, they observed a reduction in NF-κB activity induced by microRNA-223, through the minimization of the expression of p65 phosphorylation [160]. Qi et al showed that microRNA-210, through its interaction with the p50 segment of NF-κB, reduces the expression of proinflammatory mediators induced by LPS [161].…”

Effects of cannabis oil extract on immune response gene expression in human small airway epithelial cells (HSAEpC): implications for chronic obstructive pulmonary disease (COPD)

“…It is speculated that the mixture of compounds in the cannabis oil extract used in these studies may have been more capable of eliciting a Th2 immune response than purified cannabidiol. In support of this, a mixture containing both cannabidiol and tetrahydrocannabinol promoted a Th2 and anti-inflammatory immune response in a murine experimental autoimmune encephalomyelitis model (Al-Ghezi et al 2019). It was noted that neither cannabidiol nor tetrahydrocannabinol alone was capable of eliciting the beneficial immune response.…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…These and other authors have been studying limonene effects in the context of its impacts in the CNS. For instance, limonene has shown to exhibit anxiolytic effect increasing hippocampal dopamine levels and serotonin in the prefrontal cortex [75]. Considering the information above exposed, this is just one of the many compounds to be still addressed in this review that are natural and abundant in different plants, which could be used as potential therapeutics for diseases dependent on the inflammatory and oxidative-stress processes.…”

“…We just established that phytocannabinoids demonstrate different pharmacological effects, and it can get even more intriguing and complex when we focus on previous data describing that the combined use of some phytocannabinoids can possibly increase the positive effects proportionate by them. For instance, the use of CBD associated with ∆9-THC promoted downregulation of the neuroinflammatory process in animal models of multiple sclerosis (MS) [75], besides, reducing pain [76] and muscle spasticity in MS patients [75]. Importantly, CBD attenuated the psychotropic effects of THC when used in a combined form [75].…”

“…For instance, the use of CBD associated with ∆9-THC promoted downregulation of the neuroinflammatory process in animal models of multiple sclerosis (MS) [75], besides, reducing pain [76] and muscle spasticity in MS patients [75]. Importantly, CBD attenuated the psychotropic effects of THC when used in a combined form [75]. This last piece of data supports the hypothesis that CBD binds to an allosteric site on CB1R that is functionally distinct from the active site for 2-AG and THC [77].…”