Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS

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Abstract

The HIV-1 transactivator of transcription (Tat) is a neurotoxin involved in the pathogenesis of HIV-1 associated neurocognitive disorders (HAND). The neurotoxic effects of Tat are mediated directly via AMPA/NMDA receptor activity and indirectly through neuroinflammatory signaling in glia. Emerging strategies in the development of neuroprotective agents involve the modulation of the endocannabinoid system. A major endocannabinoid, anandamide (N-arachidonoylethanolamine, AEA), is metabolized by fatty acid amide hydrolase (FAAH). Here we demonstrate using a murine prefrontal cortex primary culture model that the inhibition of FAAH, using PF3845, attenuates Tat-mediated increases in intracellular calcium, neuronal death, and dendritic degeneration via cannabinoid receptors (CB 1 R and CB 2 R). Live cell imaging was used to assess Tat-mediated increases in [Ca 2+ ] i , which was significantly reduced by PF3845. A time-lapse assay revealed that Tat potentiates cell death while PF3845 blocks this effect. Additionally PF3845 blocked the Tat-mediated increase in activated caspase-3 (apoptotic marker) positive neurons. Dendritic degeneration was characterized by analyzing stained dendritic processes using Imaris and Tat was found to significantly decrease the size of processes while PF3845 inhibited this effect. Incubation with CB 1 R and CB 2 R antagonists (SR141716A and AM630) revealed that PF3845-mediated calcium effects were dependent on CB 1 R, while reduced neuronal death and degeneration was CB 2 R-mediated. PF3845 application led to increased levels of AEA, suggesting the observed effects are likely a result of increased endocannabinoid signaling at CB 1 R/CB 2 R. Our findings suggest that modulation of the endogenous cannabinoid system through inhibition of FAAH may be beneficial in treatment of HAND.

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Hermes, D. J., Xu, C., Poklis, J. L., Niphakis, M. J., Cravatt, B. F., Mackie, K., … Fitting, S. (2018). Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS. Neuropharmacology, 141, 55–65. https://doi.org/10.1016/j.neuropharm.2018.08.013

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