Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine

摘要

OBJECTIVE:: We explored the antiviral therapeutic potential of ibudilast (AV411, MN-166) and its amino analog, AV1013. METHODS:: We analyzed whether Ibudilast, a nonselective cyclic AMP phosphodiesterase inhibitor that has been used clinically in Asia for bronchial asthma, poststroke dizziness, and ocular allergies, and AV1013, attenuate HIV-1 replication and the synergistic interactions seen with opiate abuse-HIV-1 comorbidity in neuronal death and inflammation. RESULTS:: AV411 and AV1013 inhibited replication by HIV-1 in microglia and significantly suppressed Tat ± morphine-induced tumor necrosis factor-α and MIF production, the activation of the nuclear factor-kappa B subunit p65, and neuronal death. AV411 and AV1013 prevented HIV-1 replication, and attenuated tumor necrosis factor-α and MIF release at concentrations of 100nmol/l and 1μmol/l, which are likely achievable at clinical doses. More importantly, co-exposure with morphine did not negate the inhibitory actions of AV411. CONCLUSION:: Collectively, our data suggest that AV411 and its amino analog, AV1013, may be useful neuroprotective agents counteracting neurotoxicity caused by infected and activated glia, and implicate them as potential therapies for the management of HIV-associated neurocognitive disorders in an opioid-abusing population.