Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease.

The modulation of the brain endocannabinoid system has been identified as an option to treat neurodegenerative diseases including Parkinson's disease (PD). Especially the elevation of endocannabinoid levels by inhibition of hydrolytic degradation represents a valuable approach. To evaluate whether monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) inhibition could be beneficial for PD, we examined in parallel the therapeutic potential of the highly selective MAGL inhibitor KML29 elevating 2-arachidonoylglyerol (2-AG) levels and the highly selective FAAH inhibitor PF-3845 elevating anandamide (AEA) levels in a chronic methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/probenecid) mouse model of PD. Chronic administration of KML29 (10 mg/kg) but not PF-3845 (10 mg/kg) attenuated striatal MPTP/probenecid-induced dopamine depletion. Furthermore, KML29 induced an increase in Gdnf but not Bdnf expression, whereas PF-3845 decreased the MPTP/probenecid-induced Cnr2 expression without any effects on neurotrophin expression. Investigation of treatment-naïve striatal mRNA levels revealed a high presence of Gdnf and Mgll in contrast to Bdnf and Faah. Treatment of primary mouse microglia with 2-AG increased Gdnf but not Bdnf expression, suggesting that microglia might mediate the observed KML29-induced increase in Gdnf. In summary, pharmacological MAGL but not FAAH inhibition in the chronic MPTP/probenecid model attenuated the MPTP/probenecid-induced effects on striatal dopamine levels which were accompanied by an increase in 2-AG levels.

Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1G93A mouse model of ALS. We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro. In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue.

Monoacylglycerol lipase (MAGL) is part of the endocannabinoid and the prostaglandin signaling system. MAGL degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) into glycerol and arachidonic acid. MAGL-induced arachidonic acid is the primary source for prostaglandin synthesis in the brain. 2-AG mainly induces neuroprotective and anti-inflammatory effects, whereas prostaglandins are related to pro-inflammatory effects inducing neurotoxicity. Therefore, inhibition of MAGL represents a promising target for neurological diseases characterized by inflammation. However, as 2-AG is an agonist for the cannabinoid receptor 1 (CB1), inhibition of MAGL might be associated with unwanted cannabimimetic effects. Here, we show that oral administration of KML29, a highly selective inhibitor of MAGL, induced large and dose-dependent changes in 2-AG levels in vivo in brain and spinal cord of mice. Of note, MAGL inhibition by KML29 induced a decrease in prostaglandin levels in brain and most peripheral tissues but not in the spinal cord. MAGL expression was highest in fat, liver and brain, whereas the cytosolic phospholipase A2 (cPLA2), a further enzyme responsible for arachidonic acid production, was highly expressed in spinal cord, muscle and spleen. In addition, high doses (10 mg/kg) of KML29 induced some cannabimimetic effects in vivo in the tetrad test, including hypothermia, analgesia and hypomotility without induction of cataleptic behavior. In summary, inhibition of MAGL by KML29 represents a promising strategy for targeting the cannabinoid and prostaglandin system of the brain with only a moderate induction of cannabimimetic effects.