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Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

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Neurotherapeutics

Abstract

Advances in the understanding of the endogenous cannabinoid system have led to several therapeutic indications for new classes of compounds that enhance cannabinergic responses. Endocannabinoid levels are elevated during pathogenic conditions, and inhibitors of endocannabinoid inactivation promote such on-demand responses. The endocannabinoids anandamide and 2-arachidonoyl glycerol have been implicated in protective signaling against excitotoxic episodes, including seizures. To better understand modulatory pathways that can exploit such responses, we used the new generation compound AM6701 that blocks both the anandamide-deactivating enzyme fatty acid amide hydrolase (FAAH) and the 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase (MAGL) with equal potency. Also studied was the structural isomer AM6702 which is 44-fold more potent for inhibiting FAAH versus MAGL. When applied before and during kainic acid (KA) exposure to cultured hippocampal slices, AM6701 protected against the resulting excitotoxic events of calpain-mediated cytoskeletal damage, loss of presynaptic and postsynaptic proteins, and pyknotic changes in neurons. The equipotent inhibitor was more effective than its close relative AM6702 at protecting against the neurodegenerative cascade assessed in the slice model. In vivo, AM6701 was also the more effective compound for reducing the severity of KA-induced seizures and protecting against behavioral deficits linked to seizure damage. Corresponding with the behavioral improvements, cytoskeletal and synaptic protection was elicited by AM6701, as found in the KA-treated hippocampal slice model. It is proposed that the influence of AM6701 on FAAH and MAGL exerts a synergistic action on the endocannabinoid system, thereby promoting the protective nature of cannabinergic signaling to offset excitotoxic brain injury.

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Acknowledgments

The authors thank Ana Charalambides and Tyler Loehr for their laboratory assistance, and Alyson Bahr for editing services. The work was supported by the National Institutes of Health (grants DA07215, R44 DA023737, and R25 GM077634), the Oliver Smithies Grant from the North Carolina Biotechnology Center (Research Triangle Park, NC), and by funds supporting the William C. Friday Chair. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Conflict of interest

B.A.B. and A.M. are consultants for a company developing novel fatty acid amide hydrolase (FAAH) inhibitors.

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Authors and Affiliations

  1. Biotechnology Research and Training Center, William C. Friday Laboratory, University of North Carolina Pembroke, Pembroke, North Carolina, 28372, USA

    Vinogran Naidoo, Johnathan R. Locklear, Pamela Marie P. Quizon, Emily E. Graves & Ben A. Bahr

  2. Department of Biology, University of North Carolina Pembroke, Pembroke, North Carolina, USA

    Vinogran Naidoo & Ben A. Bahr

  3. Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, Connecticut, USA

    David A. Karanian & Ben A. Bahr

  4. Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA

    David A. Karanian, Subramanian K. Vadivel, JodiAnne T. Wood, Mahmoud Nasr, Vidyanand Shukla & Alexandros Makriyannis

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  1. Vinogran Naidoo
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  2. David A. Karanian
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Naidoo, V., Karanian, D.A., Vadivel, S.K. et al. Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology. Neurotherapeutics 9, 801–813 (2012). https://doi.org/10.1007/s13311-011-0100-y

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