A role for spermine oxidase as a mediator of reactive oxygen species production in HIV-Tat-induced neuronal toxicity

Abstract

Chronic oxidative stress, which occurs in brain tissues of HIV-infected patients, is involved in the pathogenesis of HIV-associated dementia. Oxidative stress can be induced by HIV-1-secreted proteins, either directly or indirectly through the release of cytotoxic factors. In particular, HIV-1 Tat is able to induce neuronal death by interacting with and activating the polyamine-sensitive subtype of the NMDA receptor (NMDAR). Here, we focused on the role of polyamine catabolism in Tat-induced oxidative stress in human neuroblastoma (SH-SY5Y) cells. First, Tat was found to induce reactive oxygen species production and to affect cell viability in SH-SY5Y cells, these effects being mediated by spermine oxidase (SMO). Second, Tat was observed to increase SMO activity as well as decreasing the intracellular spermine levels. Third, Tat-induced SMO activation was completely prevented by the NMDAR antagonist MK-801, clearly indicating an involvement of NMDAR stimulation. Finally, pretreatment of cells with N-acetylcysteine, a scavenger of H₂O₂, and with MK-801 was able to completely inhibit reactive oxygen species formation and to restore cell viability. Altogether, these data strongly suggest a role for polyamine catabolism-derived H₂O₂ in neurotoxicity as elicited by Tat-stimulated NMDAR.

Keywords: CHL; Free radicals; Glutathione; HAD; HAND; HIV-1 Tat; HIV-associated dementia; HIV-associated neurocognitive disorders; L-NAME; MDL; N(1), N(4)-bis(2,3-butadienyl)-1,4-butanediamine; N(ω)-Nitro-L-arginine methyl ester hydrochloride; N-acetylcysteine; N-methyl-d-aspartate; N-methyl-d-aspartate receptor; NAC; NMDA; NMDA receptor; NMDAR; Oxidative stress; ROS; Reactive oxygen species; SH-SY5Y cells; SMO; Spd; Spermine oxidase; Spm; chlorhexidine digluconate; reactive oxygen species; spermidine; spermine; spermine oxidase.