Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K+ current

Abstract Methamphetamine (Meth) abuse not only increases the risk of human immunodeficiency virus-1 (HIV-1) infection, but exacerbates HIV-1-associated neurocognitive disorders (HAND) as well. The mechanisms underlying the co-morbid effect are not fully understood. Meth and HIV-1 each alone interacts with microglia and microglia express voltage-gated potassium (K V ) channel K V 1.3. To understand whether K V 1.3 functions an intersecting point for Meth and HIV-1, we studied the augment effect of Meth on HIV-1 glycoprotein 120 (gp120)-induced neurotoxic activity in cultured rat microglial cells. While Meth and gp120 each alone at low (subtoxic) concentrations failed to trigger microglial neurotoxic activity, Meth potentiated gp120-induced microglial neurotoxicity when applied in combination. Meth enhances gp120 effect on microglia by enhancing microglial K V 1.3 protein expression and K V 1.3 current, leading to an increase of neurotoxin production and resultant neuronal injury. Pretreatment of microglia with a specific K V 1.3 antagonist 5-(4-Phenoxybutoxy)psoralen (PAP) or a broad spectrum K V channel blocker 4-aminopyridine (4-AP) significantly attenuated Meth/gp120-treated microglial production of neurotoxins and resultant neuronal injury, indicating an involvement of K V 1.3 in Meth/gp120-induced microglial neurotoxic activity. Meth/gp120 activated caspase-3 and increased caspase-3/7 activity in microglia and inhibition of caspase-3 by its specific inhibitor significantly decreased microglial production of TNF-α and iNOS and attenuated microglia-associated neurotoxic activity. Moreover, blockage of K V 1.3 by specific blockers attenuated Meth/gp120 enhancement of caspase-3/7 activity. Taking together, these results suggest an involvement of microglial K V 1.3 in the mediation of Meth/gp120 co-morbid effect on microglial neurotoxic activity via caspase-3 signaling.