A Failure to Normalize Biochemical and Metabolic Insults During Morphine Withdrawal Disrupts Synaptic Repair in Mice Transgenic for HIV-gp120
A Failure to Normalize Biochemical and Metabolic Insults During Morphine Withdrawal Disrupts Synaptic Repair in Mice Transgenic for HIV-gp120
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DOI：
10.1007/s11481-011-9289-0
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发表时间：
2011-12-01
影响因子：
6.2
通讯作者：
Haughey, Norman J.
中科院分区：
文献类型：
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作者：
Bandaru, Veera Venkata Ratnam;Patel, Neha;Haughey, Norman J.
HIV感染者的药物滥用加速了HIV相关神经认知障碍（HAND）的发作和进展。阿片类药物是一类常被滥用的药物，与神经毒性HIV蛋白具有相互作用，可促进神经胶质功能障碍、神经元损伤和死亡。虽然神经毒性HIV蛋白和吗啡的联合作用已在慢性和急性吗啡使用的情况下进行了广泛研究，但对HIV蛋白在药物戒断期间的作用知之甚少。由于阿片类药物戒断可以诱导相当大的神经元应激，我们确定了阿片类药物（吗啡）对脑氧化还原平衡，鞘脂代谢和突触完整性的影响，在慢性和戒断条件下，在非转基因小鼠（nTg），并在小鼠转基因的HIV-外壳蛋白gp 120（gp 120 tg）。在nTg小鼠中，我们发现慢性吗啡增加了脑氧化能力，并诱导了突触损伤，这些损伤在药物戒断过程中基本上被逆转。gp 120 tg小鼠对慢性吗啡表现出类似的反应，但在药物戒断期间，氧化能力降低和突触损伤未能正常化。在nTg小鼠，脑鞘脂含量不受吗啡在慢性或戒断条件。在gp 120 tg小鼠中，鞘脂代谢存在基线扰动，表现为鞘磷脂减少，生物活性脂质神经酰胺蓄积。gp 120 tg小鼠的鞘脂代谢对吗啡具有高度反应性。慢性吗啡增加鞘磷脂含量，从而减少神经酰胺。在停药期间，这些作用逆转，鞘磷脂水平降低，神经酰胺随之增加。我们解释这些发现表明，吗啡戒断过程中的神经元修复在gp 120的设置中受到抑制，其机制涉及持续的氧化损伤和高反应性中间体神经酰胺的积累。
Drug abuse in HIV-infected individuals accelerates the onset and progression of HIV-associated neurocognitive disorders (HAND). Opiates are a class of commonly abused drugs that have interactive effects with neurotoxic HIV proteins that facilitate glial dysfunction, neuronal damage and death. While the combined effects of neurotoxic HIV proteins and morphine have been extensively studied in the setting of chronic and acute morphine use, very little in known about the effects of HIV proteins during drug withdrawal. Since opiate withdrawal can induce considerable neuronal stress, we determined the effects of opiates (morphine) on brain redox balance, sphingolipid metabolism and synaptic integrity during both chronic and withdrawal conditions in non-transgenic mice (nTg), and in mice transgenic for the HIV-coat protein gp120 (gp120tg). In nTg mice, we found that chronic morphine increased brain oxidative capacity and induced synaptic damage that was largely reversed during drug withdrawal. Gp120tg mice showed a similar response to chronic morphine, but the diminished oxidative capacity and synaptic damage failed to normalize during drug withdrawal. In nTg mice, brain sphingolipid content was not affected by morphine during chronic or withdrawal conditions. In gp120tg mice there was a baseline perturbation in sphingolipid metabolism that manifest as decreased sphingomyelin with accumulations of the bioactive lipid ceramide. Sphingolipid metabolism was highly reactive to morphine in gp120tg mice. Chronic morphine increased sphingomyelin content with a consequent reduction in ceramide. During drug withdrawal, these effects reversed, and sphingomyelin levels were reduced with consequent increases of ceramide. We interpret these findings to suggest that neuronal repair during morphine withdrawal is inhibited in the setting of gp120 by mechanisms that involve sustained oxidative insult and accumulations of the highly reactive intermediate ceramide.