Pharmacological induction of CCL5 in vivo prevents gp120-mediated neuronal injury

Abstract

The human immunodeficiency virus (HIV) envelope protein gp120 promotes neuronal injury which is believed to contribute to HIV-associated neurocognitive disorders. Therefore, blocking the neurotoxic effect of gp120 may lead to alternative strategies to reduce the neurotoxic effect of HIV. In vitro, the neurotoxic effect of M-tropic gp120BaL is reduced by the chemokine CCL5, the natural ligand of CCR5 receptors. To determine whether CCL5 reduces the toxic effect of gp120BaL in vivo, animals were intrastriatally injected with lentiviral vectors overexpressing CCL5 prior to an intrastriatal injection of gp120BaL (400 ng). Neuronal injury was determined by silver staining, cleaved caspase-3 and TUNEL. Overexpression of CCL5 decreased gp120-mediated neuronal injury. CCL5 expression can be up-regulated by chronic morphine. Therefore, we examined whether morphine reduces the neurotoxic effect of gp120BaL. Rats stereotaxically injected with gp120BaL into the striatum received saline or chronic morphine for five days (10 mg/kg escalating to 30 mg/kg twice a day). Morphine-treated rats showed a decrease in all markers used to determine neuronal degeneration compared to saline-treated rats. The neuroprotective effect of morphine was significantly attenuated by expressing CCL5 shRNA. Our results suggest that compounds that increase the endogenous production of CCL5 may be used to reduce the pathogenesis of HIV–associated neurocognitive disorders.

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

“…We have previously shown that morphine withdrawal promotes neuronal apoptosis by increasing pro-inflammatory cytokines and microglia (Campbell et al 2015). The present work aims to provide more insights into the neurotoxic mechanisms of morphine withdrawal, by looking at its effect on proBDNF.…”

“…Likewise, withdrawal can increase susceptibility to outside pathogens (Eisenstein et al 2006). For example, opioid withdrawal can reduce the levels of circulating lymphocytes in morphine-dependent macaques (Weed and Steward 2005), or exacerbate the neurotoxic effect of the HIV protein gp120 (Campbell et al 2015). Moreover, an in vitro study of HIV-infected lymphocytes has revealed enhanced HIV replication in both abrupt (cessation of treatment) and precipitated (by naloxone) opioid withdrawal (Desjardins et al 2008).…”

“…Additionally, physical symptoms may be accompanied by neurodegeneration. In fact, in animal models, morphine withdrawal negatively affects synaptic plasticity and neuronal survival (Bandaru et al 2011; Campbell et al 2015), which might be attributed to the neurotoxic effects of proBDNF (Teng et al 2005). …”

The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice

“…Immunohistochemistry for microglia was performed as described with minor alterations (Campbell et al, 2015). Briefly, fixed brains were transferred to 30% sucrose, and serial sections (30 µm) throughout the hippocampus were prepared by a sliding microtome (Microm International, Heidelberg, Germany).…”

<p>The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke</p>

“…56 A neuroprotective effect of CCL5 has also been hypothesized. [125][126][127] Molecular studies in animals (mouse) have shown that CCL5 affects neurons via the CCR3 and CCR5 receptors and can have a direct or indirect protective effect on neurons by inducing the release of neurotrophic factors in the pericerebral area. 128 It has been demonstrated that removal of the CCR5 receptor gene has a protective effect against cerebral ischemia and reperfusion injury.…”