Fatty Acid Binding Proteins (FABPs) as Putative Endocannabinoid Targets for Neuroprotection

Abstract

Fatty Acid Binding Proteins (FABPs) as Putative Endocannabinoid Targets for Neuroprotection æRubin Jiang, Han Zhou, Karrie Chan, Sergiy I. Tyukhtenko, Richard W. Mercier, Mark Williams, æLingling Shen, De-Ping Yang, Jianxin Guo, Alexandros Makriyannis æCenter for Drug Discovery, Northeastern University æThe endocannabinoid anandamide (arachidonoylethanolamine, AEA) has been demonstrated in vivo to be a neuroprotective agent against excitotoxicity and neuronal injury. Recently, it was reported that blockage of fatty acid binding proteins (FABPs), particularly brain FABP (FABP7) and epidermal FABP (FABP5), can significantly elevate brain anandamide levels. Thus, selective FABP inhibitors provide a potential neuroprotective therapeutic modality through enhancement of endocannabinoid signaling. We have successfully expressed recombinant human FABP7 and FABP5 in Escherichia coli. Multidimensional nuclear magnetic resonance (NMR) spectroscopy was used to characterize the binding of FABP7 with anandamide and other endocannabinoids. æOur NMR data demonstrated that a non-lipid ligand, BMS309403, as well as AEA bind tightly to human-brain FABP. Moreover, we have developed a high throughput ligand screening protocol for FABPs. æAcknowledgements: This work was supported by NIH grants DA003801 (A.M.), DA007215 (A.M.), DA007312 (A.M.), and DA032020 (J.G.) from the National Institute on Drug Abuse.