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The Journal of Neuroscience, August 24, 2005, 25(34):7813-7820; doi:10.1523/JNEUROSCI.2347-05.2005

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Cellular/Molecular
Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

David A. Karanian,^1,2,3 Queenie B. Brown,¹ Alexandros Makriyannis,³ Therese A. Kosten,^4,5 and Ben A. Bahr^1,2,3

¹Department of Pharmaceutical Sciences and ²Bioinformatics and Biocomputing Institute, University of Connecticut, Storrs, Connecticut 06269, ³Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, ⁴Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, and ⁵Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB₁ receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB₁ signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB₁ agonist AM356 (R-methanandamide). AM374/AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB₁-linked MAPK signaling, and (3) were blocked by a selective CB₁ antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB₁ receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

Key words: AM374; AM404; cannabinoid CB₁ receptor; endocannabinoid system; hippocampus; neuroprotection

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Received April 15, 2005; accepted July 6, 2005.

This article has been cited by other articles:

				D. A. Karanian, S. L. Karim, J. T. Wood, J. S. Williams, S. Lin, A. Makriyannis, and B. A. Bahr Endocannabinoid Enhancement Protects against Kainic Acid-Induced Seizures and Associated Brain Damage J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1059 - 1066. [Abstract] [Full Text] [PDF]

				C. Benito, J. P. Romero, R. M. Tolon, D. Clemente, F. Docagne, C. J. Hillard, C. Guaza, and J. Romero Cannabinoid CB1 and CB2 Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis J. Neurosci., February 28, 2007; 27(9): 2396 - 2402. [Abstract] [Full Text] [PDF]

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