Modulation of the
endocannabinoid system has emerged as an effective approach for the treatment of many neurodegenerative and neuropsychological diseases. However, the underlying mechanisms are still uncertain. Using a repetitive
mild traumatic brain injury (mTBI) mouse model, we found that there was an impairment in locomotor function and working memory within two weeks post-injury, and that treatment with
MJN110, a novel inhibitor of the principal 2-arachidononyl
glycerol (2-AG) hydrolytic
enzyme monoacylglycerol lipase dose-dependently ameliorated those behavioral changes. Spatial learning and
memory deficits examined by Morris water maze between three and four weeks post-TBI were also reversed in the drug treated animals. Administration of
MJN110 selectively elevated the levels of 2-AG and reduced the production of
arachidonic acid (AA) and
prostaglandin E2 (
PGE2) in the TBI mouse brain. The increased production of proinflammatory
cytokines, accumulation of astrocytes and microglia in the TBI mouse ipsilateral cerebral cortex and hippocampus were significantly reduced by
MJN110 treatment. Neuronal cell death was also attenuated in the drug treated animals.
MJN110 treatment normalized the expression of the
NMDA receptor subunits NR2A and NR2B, the
AMPA receptor subunits GluR1 and GluR2, and the GABAA receptor subunits α1, β2,3 and γ2, which were all reduced at 1, 2 and 4 weeks post-injury. The reduced inflammatory response and restored
glutamate and
GABA receptor expression likely contribute to the improved motor function, learning and memory in the
MJN110 treated animals. The
therapeutic effects of
MJN110 were partially mediated by activation of CB1 and CB2
cannabinoid receptors and were eliminated when it was co-administered with DO34, a novel inhibitor of the 2-AG biosynthetic
enzymes. Our results suggest that augmentation of the endogenous levels of 2-AG can be therapeutically useful in the treatment of TBI by suppressing
neuroinflammation and maintaining the balance between excitatory and inhibitory neurotransmission.