Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 110, Issue -, Pages 14-24Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2017.08.003
Keywords
Parkinson's disease; MPTP; KML29; PF-3845; Monoacylglycerol lipase; Fatty acid amide hydrolase
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Funding
- Boehringer Ingelheim Ulm University BioCenter [BIU N2]
- International Graduate School in Molecular Medicine Ulm (IGradU) [DFG GSC-270]
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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 MPIP/probenecid-induced Cnr2 expression without any effects on neurotrophin expression. Investigation of treatment-native 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 MPFP/probenecid-induced effects on striatal dopamine levels which were accompanied by an increase in 2-AG levels. (C) 2017 Elsevier Ltd. All rights reserved.
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