cART has been proven effective in controlling HIV-1, however HAND remains a significant problem in patient treatment. HIV-1 Tat is a neurotoxin that contributes to the development of HAND and its effects are mediated via AMPAR/NMDAR activity. Enhanced cannabinoid signaling activity in various neurodegeneration models has been shown to be neuroprotective. PF3845, an inhibitor of FAAH activity, increases anandamide levels and produces increased neuronal survival and anti-inflammatory effects in mice with minimal side effects.

PF3845 attenuates calcium equilibrium disruption, neuronal death, and dendritic degeneration via CB1R and CB2R mediated pathways. Incubation with CB1R and CB2R antagonists revealed that PF3845 calcium effects were CB1R dependent, while reduction of neuronal death and degeneration was CB2R dependent. PF3845 application led to increased levels of AEA, as well as increased levels of PEA. Our findings suggest that activation of the endogenous cannabinoid system through inhibition of FAAH may be beneficial in treatment of HAND.