Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques
Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques
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DOI：
10.1096/fasebj.12.10.881
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发表时间：
1998-07-01
期刊：
影响因子：
4.8
通讯作者：
Markey, SP
中科院分区：
文献类型：
--
作者：
Heyes, MP;Saito, K;Markey, SP
这一点：一项研究调查了HIV感染患者和逆转录病毒感染猕猴的脑和血液中喹啉酸（一种神经毒性的犬尿氨酸途径代谢物）的来源。在脑中，HIV感染患者的喹啉酸浓度升高>300倍，超过脑脊液（CSF）浓度的8.9倍。血清喹啉酸水平升高与CSF和脑实质中喹啉酸水平升高无明显相关性。由于非逆转录病毒诱导的脑炎混淆了人类尸检数据的解释，用逆转录病毒感染的恒河猴来检查喹啉酸积累增加的机制，并确定喹啉酸与脑炎和全身反应的关系。脑中最大的犬尿氨酸途径反应与脑炎相关，并且独立于全身反应。CSF喹啉酸水平也升高，在所有感染的猕猴，但特别是那些与逆转录病毒引起的脑炎。与大脑变化相反，患有脑炎的猕猴与没有脑炎的猕猴之间的任何系统测量没有差异。直接测量来自患有脑炎的猕猴的血液的脑中喹啉酸的量显示，几乎所有喹啉酸（>98%）在脑内局部合成。这些结果证明了诱导吲哚胺-2，3-双加氧酶在加速喹啉酸在脑组织内的局部形成中的作用，特别是在脑炎区域，而不是喹啉酸从脑膜或血液进入脑。针对脑内部位减少QUIN产生的策略是潜在的治疗方法。Heyes，M. P.，齐藤，K.，拉克纳，A.，威利角，澳-地一、Achim，C. L.，马基，S。P. HIV-1感染患者和逆转录病毒感染猕猴脑中神经毒素喹啉酸的来源。
This: study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV-infected patients and retrovirus-infected macaques.In brain, quinolinic acid concentrations in HIV-infected patients were elevated by >300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis: vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3-dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.-Heyes, M. P., Saito, K., Lackner, A., Wiley, C. A., Achim, C. L., Markey, S. P. Sources of the neurotoxin quinolinic acid in the brain of HIV-l-infected patients and retrovirus-infected macaques.