Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3′-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.

Microglia participate in innate inflammatory responses within the central nervous system. The highly conserved microRNA-9 (miR-9) plays critical roles in neurogenesis as well as axonal extension. Its role in microglial inflammatory responses, however, remains poorly understood. Here we identify a unique role of miR-9 in mediating the microglial inflammatory response via distinct signalling pathways. MiR-9-mediated regulation of cellular activation involved downregulated expression of the target protein, monocyte chemotactic protein-induced protein 1 (MCPIP1) that is crucial for controlling inflammation. Results indicate that miR-9-mediated cellular activation involved signalling via the NF-κB pathway, but not the β-catenin pathway.

HIV-associated increase in monocyte adhesion and trafficking is exacerbated by cocaine abuse. The underlying mechanisms involve cocaine-mediated up-regulation of adhesion molecules with subsequent disruption of the blood brain barrier (BBB). Recently, a novel activated leukocyte cell adhesion molecule (ALCAM) has been implicated in leukocyte transmigration across the endothelium. We now show that up-regulation of ALCAM in the brain endothelium seen in HIV+/cocaine drug abusers paralleled increased CD68 immunostaining compared with HIV+/no cocaine or uninfected controls, suggesting the important role of ALCAM in promoting leukocyte infiltration across the BBB. Furthermore, ALCAM expression was increased in cocaine-treated mice with concomitant increase in monocyte adhesion and transmigration in vivo, which was ameliorated by pre-treating with the neutralizing antibody to ALCAM, lending further support to the role of ALCAM. This new concept was further confirmed by in vitro experiments. Cocaine mediated induction of ALCAM in human brain microvascular endothelial cells through the translocation of sigma receptor to the plasma membrane, followed by phosphorylation of platelet-derived growth factor (PDGF)-β receptor. Downstream activation of mitogen-activated protein kinases, Akt, and NF- κB pathways resulted in induced expression of ALCAM. Functional implication of up-regulated ALCAM was confirmed using cell adhesion and transmigration assays. Neutralizing antibody to ALCAM ameliorated this effect. Taken together, these findings implicate cocaine-mediated induction of ALCAM as a mediator of increased monocyte adhesion/transmigration into the CNS.

Neuroinflammation associated with advanced HIV-1 infection is often exacerbated in cocaine-abusing, HIV-infected patients. The underlying mechanisms could, in part, be attributed to the increased impairment of blood brain barrier integrity in the presence of cocaine. Plateletderived growth factor (PDGF) has been implicated in several pathologic conditions, specifically attributable to its potent mitogenic effects. Its modulation by drug abuse, however, has received very little attention. In the present study, we demonstrated cocaine-mediated induction of PDGF-BB in human brain microvascular endothelial cells through the binding to its cognate receptor. Furthermore, this effect was mediated, with subsequent activation of mitogen-activated protein kinases and Egr-1 pathways, culminating ultimately into increased expression of PDGF-BB. Cocaine exposure resulted in increased permeability of the endothelial barrier, and this effect was abrogated in mice exposed to PDGF-BB neutralizing antibody, thus underscoring its role as a vascular permeant. In vivo relevance of these findings was further corroborated in cocaine-treated mice that were administered neutralizing antibody specific for PDGF-BB as well as in Egr IntroductionAlthough the advent of combined antiretroviral therapy has significantly decreased the incidence of HIV-associated neurocognitive disorders (HANDs), the prevalence of the disease is actually increasing. Drug abuse has been implicated as a contributing risk factor for increased neuroinflammation associated with HIV-1 infection. Intriguingly, cocaine has been shown to open up the blood-brain barrier (BBB). 1-3 BBB is critical for the maintenance of central nervous system (CNS) homeostasis and for the regulation of the neuronal microenvironment. However, under conditions of barrier disruption as in HIV-1 infection, virus can enter the CNS through infected leukocytes likely via the Trojan horse mechanism.Zhang et al 3 have demonstrated that cocaine-mediated effects on the BBB are complex, including both direct proapoptotic effects on the endothelial cells as well as indirect paracrine effects that are manifested by proinflammatory modulators such as chemokines and cytokines. Cocaine plays a critical role in HIV-1 neuroinvasion, thus accelerating the progression of HAND. [1][2][3] Because the chemokine/growth factor platelet-derived growth factor (PDGF) has been shown in previous reports to be upregulated in the areas around the blood vessels in the brains of macaques with simian immunodeficiency virus infection, 4 we hypothesized that cocaine-mediated disruption of the endothelial barrier could involve PDGF. Adding further validity to this hypothesis was a recent report by Su et al 5 suggesting the role of a novel mediator of the PDGF family as a cerebrovascular permeant in ischemic stroke. Other investigators have also demonstrated the effects of PDGF on endothelial cells. [6][7][8] PDGF comprises a family of proteins that are the products of 4 genes (A-D) that are highly conserved throughout the anim...

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