Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.
Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.
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DOI：
10.2174/1570162x1206150311161147
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发表时间：
2014
影响因子：
1
通讯作者：
Hauser KF
中科院分区：
文献类型：
--
作者：
Fitting S;Zou S;El-Hage N;Suzuki M;Paris JJ;Schier CJ;Rodríguez JW;Rodriguez M;Knapp PE;Hauser KF
很少有临床前研究比较了用于治疗阿片类药物成瘾与神经艾滋病的相对疗效。在这里，我们比较了美沙酮和丁丙诺啡，和原型阿片类吗啡的能力，以加强神经毒性和促炎（[Ca 2 +]i，ROS，H2 O2，趋化因子）的HIV-1达特在神经元和/或混合神经胶质细胞共培养物的影响。在暴露于达特、等摩尔浓度（500 nM）的吗啡、美沙酮或丁丙诺啡的组合48 h期间，反复观察神经元，发现神经毒性显著高于单独达特的水平。单独丁丙诺啡在500 nM时显示出显著的神经毒性，促使对其在5 nM和50 nM浓度±达特下的神经毒性作用进行额外研究。在与达特组合时，丁丙诺啡显示矛盾的、浓度依赖性的神经毒性和神经保护作用。丁丙诺啡神经毒性与[Ca 2 +]i显著升高一致，但不增加神经胶质细胞ROS或趋化因子释放。达特本身可增加CCL 5/RANTES、CCL 4/MIP-1β和CCL 2/MCP-1的产生。美沙酮和丁丙诺啡单独使用没有效果，但美沙酮与达特相互作用，进一步增加CCL 5/RANTES的产生。在与达特的组合中，所有药物均显著增加胶质细胞[Ca 2 +]i，但ROS仅在与吗啡共暴露时显著增加。总之，神经胶质细胞[Ca 2 +]i、ROS和神经炎性趋化因子的增加不是神经毒性的特别准确的预测因子。尽管有相似之处，阿片类药物在与达特的神经毒性和神经炎症相互作用方面表现出差异。特别是丁丙诺啡，在低浓度下具有部分神经保护作用，这可能是由于其在多种阿片受体上的独特药理学特征。总的来说，结果揭示了可能影响神经艾滋病的成瘾药物之间的差异。
Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca2+]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca2+]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca2+]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca2+]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.