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

El-Hage, Naziraa; Rodriguez, Myosotysb; Podhaizer, Elizabeth M.a; Zou, Shipingc; Dever, Seth M.a; Snider, Sarah E.a; Knapp, Pamela E.a,c,d; Beardsley, Patrick M.a,d; Hauser, Kurt F.a,d

doi: 10.1097/QAD.0000000000000291
Basic Science

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 100 nmol/l and 1 μmol/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.

aDepartment of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia, USA

bDepartment of Microbiology & Immunology, Universidad Central del Caribe, Bayamón, Puerto Rico

cDepartment of Anatomy & Neurobiology, Virginia Commonwealth University, Medical College of Virginia Campus

dInstitute for Drug & Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, USA.

Correspondence to Nazira El-Hage, MS, PhD, Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Richmond, VA 23298-0613, USA. Tel: +1 804 628 7573; fax: +1 804 827 9974; e-mail: nelhage@vcu.edu

Received 7 January, 2014

Revised 26 March, 2014

Accepted 27 March, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.