A paradoxical proinflammatory effect of endocannabinoids in the brain discovered

Summary: While endocannabinoids have been reported to play a role in anti-inflammation in some areas of the brain, a new study reveals they may cause inflammation in the cerebellum.

Source: UPF Barcelona

A new study led by the Neuropharmacology Laboratory -NeuroPhar at UPF shows that increasing endocannabinoids in the brain may cause inflammation in specific brain areas such as the cerebellum, which is associated with problems of fine motor coordination. The results of the study in mice are contrary to what had been observed to date in other areas of the brain where endocannabinoids play an anti-inflammatory role. The article has been published in Brain, Behavior and Immunity.

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

One of the beneficial effects of cannabinoids are their anti-inflammatory properties, which can be useful for treating inflammatory diseases that develop in the brain. To date an increase in the main endocannabinoids –2-arachidonoylglycerol (2AG) and anandamide– had been seen to have an anti-inflammatory role in the brain in general, and the same results have also been observed by focusing the experiments in specific areas such as the hippocampus.

In this new study, the team of researchers led by Andrés Ozaita wondered what happens in the cerebellum, a brain area that has a very important role in coordinating chained and successive movements and motor learning. Their results show that in the cerebellum the opposite occurs from in the rest of the brain because increasing endocannabinoids increases inflammation, and this leads to motor coordination problems in the rodents.

To modulate the levels of endocannabinoids in the mice, the scientists use degradation inhibitors thus causing the latter to accumulate. They specifically inhibited the enzyme monoacylglycerol lipase (MAGL), which is responsible for degrading endocannabinoid 2AG.

This shows microglia activation in the cerebellum
Microglial cells in the cerebellar cortex of the mouse. The image is credited to Pompeu Fabra Universityr.

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

The molecular alterations were not observed in the hippocampus, which points to a particular sensitivity of the cerebellum. In the words of Andrés Ozaita: “the differential response between the cerebellum and the hippocampus may arise from the alternative metabolism of 2-AG accumulated in the two brain areas”.

“We focus specifically on the cerebellum because in a previous study we had seen that THC produced inflammation in this area, leading to deficits in motor coordination, and we wanted to find out if it also occurred by endogenously increasing the endocannabinoids”, states Laura Cutando, co-author of the article.

Overall, the present study reveals the sensitivity of the cerebellum to changes in the signalling of the endocannabinoid system, compared with other areas of the brain like the hippocampus. It also highlights a possible disadvantage of strategies aimed at inhibiting MAGL activity for treating inflammatory disorders. “Increased endocannabinoids to reduce inflammatory processes should probably be supplemented by other conventional anti-inflammatories which, acting synergistically, may prevent inflammation in the cerebellum”, concludes Andrés Ozaita.

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

About this neuroscience research article

Source:
UPF Barcelona
Media Contacts:
Mari Carmen Cebrián – UPF Barcelona
Image Source:
The image is credited to Pompeu Fabra University.

Original Research: Closed access
“Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2”. Sara Martínez-Torres, et a.
Brain, Behavior, and Immunity. doi:10.1016/j.bbi.2019.06.036

Abstract

Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2

Monoacylglycerol lipase (MAGL) is the main enzyme implicated in the degradation of the most abundant endocannabinoid in the brain, 2-arachidonoylglycerol (2-AG), producing arachidonic acid (AA) and glycerol. MAGL pharmacological inhibition with JZL184 or genetic deletion results in an exacerbated 2-AG signaling and reduced synthesis of prostaglandins (PGs), due to the reduced AA precursor levels. We found that acute JZL184 administration, previously described to exert anti-inflammatory effects, and MAGL knockout (KO) mice display cerebellar, but not hippocampal, microglial reactivity, accompanied with increased expression of the mRNA levels of neuroinflammatory markers, such as cyclooxygenase-2 (COX-2). Notably, this neuroinflammatory phenotype correlated with relevant motor coordination impairment in the beam-walking and the footprint tests. Treatment with the COX-2 inhibitor NS398 during 5 days prevented the deficits in cerebellar function and the cerebellar microglia reactivity in MAGL KO, without affecting hippocampal reactivity. Altogether, this study reveals the brain region-specific response to MAGL inhibition, with an important role of COX-2 in the cerebellar deficits associated, which should be taken into account for the use of MAGL inhibitors as anti-inflammatory drugs.

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