Campbell Lee A, Avdoshina Valeriya, Day Chris, Lim Seung T, Mocchetti Italo
Department of Pharmacology and Physiology, Laboratory of Preclinical Neurobiology, Georgetown University Medical Center, Washington, D.C. 20057, USA; Department of Neuroscience, Laboratory of Preclinical Neurobiology, Georgetown University Medical Center, Washington, D.C. 20057, USA.
Department of Neuroscience, Laboratory of Preclinical Neurobiology, Georgetown University Medical Center, Washington, D.C. 20057, USA.
Neuropharmacology. 2015 May;92:98-107. doi: 10.1016/j.neuropharm.2015.01.009. Epub 2015 Jan 23.
The human immunodeficiency virus (HIV) envelope protein gp120 promotes neuronal injury which is believed to cause 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.
人类免疫缺陷病毒（HIV）包膜蛋白gp120会促进神经元损伤，据信这会导致HIV相关神经认知障碍。因此，阻断gp120的神经毒性作用可能会带来减少HIV神经毒性作用的替代策略。在体外，趋化因子CCL5（CCR5受体的天然配体）可降低M嗜性gp120BaL的神经毒性作用。为了确定CCL5在体内是否能降低gp120BaL的毒性作用，在向纹状体内注射gp120BaL（400 ng）之前，先向动物纹状体内注射过表达CCL5的慢病毒载体。通过银染、裂解的半胱天冬酶-3和TUNEL法来确定神经元损伤情况。CCL5的过表达减少了gp120介导的神经元损伤。慢性吗啡可上调CCL5的表达。因此，我们研究了吗啡是否能降低gp120BaL的神经毒性作用。将gp120BaL立体定向注射到纹状体的大鼠接受生理盐水或慢性吗啡注射五天（10 mg/kg，每天两次，剂量递增至30 mg/kg）。与生理盐水处理的大鼠相比，吗啡处理的大鼠用于确定神经元变性的所有标志物均有所减少。表达CCL5的短发夹RNA可显著减弱吗啡的神经保护作用。我们的结果表明，增加CCL5内源性产生的化合物可能用于减少HIV相关神经认知障碍的发病机制。
