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A Reversible FAAH Inhibitor Exhibits Efficient Bioavailability While Enhancing Neuroprotective Endocannabinoid Responses
Author(s) -
Karanian David Anthony,
Butler David,
Makriyannis Alexandros,
Bahr Ben
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1132-c
Subject(s) - neuroprotection , endocannabinoid system , fatty acid amide hydrolase , cannabinoid receptor , excitotoxicity , cannabinoid , postsynaptic potential , pharmacology , anandamide , kainic acid , chemistry , neuroscience , glutamate receptor , biology , receptor , biochemistry , antagonist
The cannabinoid system has been implicated in protection against many disease states including excitotoxicity. As an alternative to the direct action of CB1 receptor agonists, we have shown that inhibitors of fatty acid amide hydrolase (FAAH) and anandamide transport enhance endocannabinoid responses, resulting in cellular protection as well as improved behavioral and memory performance in excitotoxic rats (Karanian et al., J. Neurosci. 25:7813, 2005). Here, a reversible FAAH inhibitor (AM5206; 0–8 mg/kg) was injected IP into rats, resulting in rapid activation of the ERK/MAPK pathway in many brain regions including hippocampus. The dose‐dependent effect on signaling corresponds with AM5206's dose response on reducing the severity of kainic acid (KA)‐induced seizures. The drug was injected 5 min after KA, and seizures were measured over a 4‐h period. The KA‐induced seizures were associated with a loss of synaptic markers and breakdown of the cytoskeletal protein spectrin measured 24 h post‐insult. Pre‐ and postsynaptic markers were protected by AM5206, the result comparable to control levels. Interestingly, levels of the postsynaptic marker GluR2/3 were strongly correlated with reduced seizure scores (r=−0.66, p<0.001). AM5206 also protected against cytoskeletal damage, and the protective effects were comparable to those found with the irreversible FAAH inhibitor AM374. In developmental studies, AM5206 also exhibited neuroprotective effects in PND9 and PND23 animals subjected to KA insult. These data show that AM5206 crosses the blood brain barrier, enhances endocannabinoid responses, and promotes repair. Work supported by DA07312, DA07215, and DA09158.