Endocannabinoid Metabolism and Traumatic Brain Injury.

Dexiao Zhu,Chu Chen,Fei Gao

doi:10.3390/cells10112979

Abstract

Traumatic brain injury (TBI) represents a major cause of morbidity and disability and is a risk factor for developing neurodegenerative diseases, including Alzheimer’s disease (AD). However, no effective therapies are currently available for TBI-induced AD-like disease. Endocannabinoids are endogenous lipid mediators involved in a variety of physiological and pathological processes. The compound 2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid with profound anti-inflammatory and neuroprotective properties. This molecule is predominantly metabolized by monoacylglycerol lipase (MAGL), a key enzyme degrading about 85% of 2-AG in the brain. Studies using animal models of inflammation, AD, and TBI provide evidence that inactivation of MAGL, which augments 2-AG signaling and reduces its metabolites, exerts neuroprotective effects, suggesting that MAGL is a promising therapeutic target for neurodegenerative diseases. In this short review, we provide an overview of the inhibition of 2-AG metabolism for the alleviation of neuropathology and the improvement of synaptic and cognitive functions after TBI.

Highlights

Traumatic brain injury (TBI) is defined as a disruption of brain function caused by external forces, including falls, blows, or blasts
We discussed the beneficial effects of the inhibition of 2-AG metabolism in TBI-induced Alzheimer’s disease (AD)-like neuropathology
We focused on monoacylglycerol lipase (MAGL), as it is the key enzyme hydrolyzing 2-AG in the brain

Summary

Introduction

Traumatic brain injury (TBI) is defined as a disruption of brain function caused by external forces, including falls, blows, or blasts. TBI causes immediate tissue damages, and induces potential long-term biochemical and neuropathological changes, including oxidative stress, excitotoxicity, disruption of blood–brain barrier (BBB) permeability, neuroinflammatory responses, and cognitive deficits [3]. The brain damage following TBI can be divided into primary and secondary injury (Figure 1). Primary injury results directly from the external mechanical disruption of brain tissue, occurs at the time of the insult, and is usually not alterable. The secondary injury is usually reversible and occurs within seconds or minutes following the primary damage. These secondary injuries can persist for minutes, days, or years. SSeeccoonnddaarryy iinnjjuurryy iinnvvoollvveess aaccaassccaaddeeooffppaatthhoopphhyyssiioollooggiiccaall pprroocceesssseessininccluluddininggnneueurorioninflfalmammmataotroyryrersepsopnosnes,etsa,utapuhposhpohsoprhyolraytiloanti,oTnD, PT-D4P3 -a4g3garegggarteigoant,iaonnd, aAnβd aAcβcuamccuulmatuiolnat.iTonh.esTehneseeurnoepuartohpoalothgoicloagl icchaalncgheasnfgoelslofwolilnogwTinBgI lTeBaIdlteoadnetuornoeduergoedneegraentieorna,tsioynn,aspytnicdapystifcudnyctsifounn,catniodnc, oagnnditciovgendieticvleindee. cline

Endocannabinoid 2-AG Synthesis and Metabolism

Alleviation of TBI-Induced Neuropathology by Inactivation of MAGL

Summary