Study reveals paradoxical proinflammatory effect of endocannabinoids in the brain

A new study by the Neuropharmacology Laboratory -NeuroPhar of the UPF shows that the increase of endocannabinoids in the brain can cause inflammation in specific areas of the brain such as the cerebellum, badociated with coordination problems fine motor. The results of the study in mice are contrary to what has been observed so far in other areas of the brain where endocannabinoids play an anti-inflammatory role. The article was published in Brain Behavior and Immunity.

The endocannabinoid system is involved in many physiological functions of the brain, including motor coordination. This system is modulated by externally acquired cannabinoids, such as tetrahydrocannabinol (THC) from the plant Cannabis sativa, and endogenously produced naturally by the body and called endocannabinoids.

One of the beneficial effects of cannabinoids is their anti-inflammatory properties, which can be useful for treating inflammatory diseases that develop in the brain. To date, there has been an increase in the major endocannabinoids – 2-arachidonoylglycerol (2AG) and anandamide – having an anti-inflammatory role in the brain in general, and the same results were observed by focusing on the experiments. areas such as the seahorse.

In this new study, the team of researchers led by Andrés Ozaita asked what is happening in the cerebellum, an area of ​​the brain that plays a very important role in coordinating the chained and successive movements and the Engine learning. Their findings show that in the cerebellum, the opposite occurs in the rest of the brain because the increase in endocannabinoids increases inflammation, resulting in motor coordination problems in rodents.

To modulate endocannabinoid levels in mice, scientists used degradation inhibitors, thereby causing an accumulation of these. They specifically inhibited the enzyme monoacylglycerol lipase (MAGL), responsible for the degradation of the endocannabinoid 2AG.

"Our experiments show that the pharmacological or genetic inhibition of MAGL results in significant deficits in motor coordination and increases inflammation," says Sara Martínez-Torres, first author of the article. "We have seen that this inflammation of the cerebellum is caused by an increase in the enzyme COX2, which is induced during inflammatory processes and produces pro-inflammatory mediators," she adds.

Molecular alterations have not been observed in the hippocampus, suggesting a particular sensitivity of the cerebellum. For Andrés Ozaita: "the differential response between the cerebellum and the hippocampus can come from the alternative metabolism of 2-AG accumulated in the two areas of the brain".

We focus specifically on the cerebellum because a previous study had shown that THC produced inflammation in this area, leading to deficits in motor coordination, and we wanted to know the same by endogenously increasing the endocannabinoids. "

Laura Cutando, co-author of the article

Overall, the present study reveals the sensitivity of the cerebellum to changes in endocannabinoid signaling, as compared to other brain regions such as the hippocampus. It also highlights a possible drawback of strategies to inhibit the activity of MAGL in the treatment of inflammatory disorders. "An increase in endocannabinoids to reduce inflammatory processes should probably be complemented by other conventional anti-inflammatory drugs that, acting synergistically, could prevent inflammation of the cerebellum," Andrés Ozaita concludes.

The study also involved researchers from the Institute of Medical Research of the Mar del Hospital (IMIM), universities of Niigata and Tokyo in Japan and INSERM (France) .