The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

Abstract

SummaryAim and methodsDifferent types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells. With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.ResultsThe synthetic cannabinoid agonist WIN55212.2 at 1 μM increased the myelin basic protein mRNA and protein expression in vitro. During cuprizone‐induced acute demyelination, the administration of 0.5 mg/kg WIN55212.2 confers more myelinated axons, increased the expression of retinoid X receptor alpha, and declined nogo receptor expression. Controversially, 1 mg/kg of the drug increased the number of demyelinated axons and reduced the expression of nerve growth factor inducible, calreticulin and myelin‐related genes coupling specifically with a decrease in 2′,3′‐cyclic nucleotide 3′ phosphodiesterase expression.ConclusionThe cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro. Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone‐induced demyelination, while 1 mg/kg aggravates the demyelination process.

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

“…In the prefrontal cortex (PFC), there was an increase in CB receptor 1 binding that coincided with reduced levels of monoacylglycerol lipase, extracellular signal‐regulated kinase, and cyclic adenosine monophosphate response element‐binding protein, which are all critically involved in CB signaling . WIN55 212.2, a CB receptor agonist, increased OPC proliferation in vitro, as well as MBP messenger RNA and protein expression in mice, whereas blocking the metabolism of endogenous CBs decreased OL excitotoxicity and demyelination in vitro, and preserved myelin integrity in a demyelinating mouse model . EtOH exposure alters CB ligands in several brain areas related to memory and addiction (e.g., PFC and amygdala).…”

Dose-dependent effect of cannabinoid WIN-55,212-2 on myelin repair following a demyelinating insult

“…Conversely, histological analysis of the demyelinated area revealed that CNS myelination was slightly compromised when 0.5 mg/Kg of WIN was administered. Similarly, a previous study revealed that the cannabinoid WIN at 0.5 mg/ Kg confers neuroprotection against demyelination while the administration of the drug at 1 mg/Kg aggravates the process 5 . Despite this, it is widely accepted that the cannabinoid receptors modulate the severity of demyelination in distinct experimental animal models 5,32 .…”

“…Similarly, a previous study revealed that the cannabinoid WIN at 0.5 mg/ Kg confers neuroprotection against demyelination while the administration of the drug at 1 mg/Kg aggravates the process 5 . Despite this, it is widely accepted that the cannabinoid receptors modulate the severity of demyelination in distinct experimental animal models 5,32 . The administration of CPZ for three weeks led to a pronounced inflammatory reaction by activating the recruitment of microglia and astroglial cells in the demyelinated area 10,33 .…”

“…Despite this, several independent groups have demonstrated that the activation of CB 1 receptors in outer mitochondrial membranes regulates respiratory chain complexes and thus, mitochondrial biogenesis (for review see 40 ). Thus, it might be speculate that the drug at 0.5 mg/kg dosage could possess a therapeutic effect probably by protecting neurons against CPZ-induced neurotoxicity through the stimulation of copper-zinc superoxide dismutase enzyme 39 or by promoting the differentiation of oligodendrocytes 5 . On the other hand, 1 mg/kg of the drug had a deleterious effect, presumably related to an inhibitory effect of G i /G o -proteins expressed in neurons as our group postulated on previously 5 .…”

“…MS is a chronic inflammatory disorder of the CNS characterized by inflammation and progressive axonal neurites injury terminating in neurodegeneration 2 . The use of the main active component of marijuana, Δ9-tetrahydrocannabinol (THC), has a broad range of therapeutic effects for a variety of medical conditions, including pain, anxiety, glaucoma, and emesis, and also possesses a neuroprotective effect [3][4][5][6] . For our research, we chose the cannabinoid agonist WIN-55,212-2, since this chemical compound has been shown to possess better efficacy at CB 1 -receptor (Ki = 1.9 nM) than THC (Ki = 41 nM) and shows greater binding affinity to CB 1 than CB 2 7,8 .…”