El-Hage Nazira, Rodriguez Myosotys, Podhaizer Elizabeth M, Zou Shiping, Dever Seth M, Snider Sarah E, Knapp Pamela E, Beardsley Patrick M, Hauser Kurt F
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.
AIDS. 2014 Jun 19;28(10):1409-19. doi: 10.1097/QAD.0000000000000291.
We explored the antiviral therapeutic potential of ibudilast (AV411, MN-166) and its amino analog, AV1013.
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.
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.
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.
我们探究了异丁司特（AV411，MN - 166）及其氨基类似物AV1013的抗病毒治疗潜力。
我们分析了异丁司特（一种在亚洲已用于临床治疗支气管哮喘、中风后头晕和眼部过敏的非选择性环磷酸腺苷磷酸二酯酶抑制剂）以及AV1013是否能减弱HIV - 1复制，以及在神经元死亡和炎症中与阿片类药物滥用 - HIV - 1共病相关的协同相互作用。
AV411和AV1013抑制HIV - 1在小胶质细胞中的复制，并显著抑制Tat ± 吗啡诱导的肿瘤坏死因子 - α和巨噬细胞移动抑制因子（MIF）的产生、核因子 - κB亚基p65的激活以及神经元死亡。AV411和AV1013在100 nmol/l和1 μmol/l的浓度下可阻止HIV - 1复制并减弱肿瘤坏死因子 - α和MIF的释放；临床剂量下可能达到这些浓度。更重要的是，与吗啡共同暴露并未抵消AV411的抑制作用。
总体而言，我们的数据表明AV411及其氨基类似物AV1013可能是有用的神经保护剂，可对抗由受感染和活化的神经胶质细胞引起的神经毒性，并表明它们可能是治疗阿片类药物滥用人群中HIV相关神经认知障碍的潜在疗法。
