QUINOLINIC ACID AND KYNURENINE PATHWAY METABOLISM IN INFLAMMATORY AND NONINFLAMMATORY NEUROLOGICAL DISEASE
QUINOLINIC ACID AND KYNURENINE PATHWAY METABOLISM IN INFLAMMATORY AND NONINFLAMMATORY NEUROLOGICAL DISEASE
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DOI：
10.1093/brain/115.5.1249
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发表时间：
1992-10-01
期刊：
影响因子：
14.5
通讯作者：
TOURTELLOTTE, WW
中科院分区：
文献类型：
--
作者：
HEYES, MP;SAITO, K;TOURTELLOTTE, WW
神经功能障碍、癫痫发作和脑萎缩发生在广泛的急性和慢性神经系统疾病中。在某些情况下，涉及N-甲基-D-天冬氨酸受体的过度刺激。喹啉酸（QUIN）是一种内源性N-甲基-D-天冬氨酸受体激动剂，通过犬尿氨酸途径由L-色氨酸合成，因此具有介导N-甲基-D-天冬氨酸神经元损伤和功能障碍的潜力。相反，相关代谢物犬尿烯酸是N-甲基-D-天冬氨酸受体的拮抗剂，可调节QUIN的神经毒性作用以及破坏兴奋性氨基酸神经传递。在本研究中，在患有炎性疾病（细菌、病毒、真菌和寄生虫感染、脑膜炎、自身免疫性疾病和败血症）的患者的腰脑脊液（CSF）和死后脑组织中发现QUIN浓度显著增加，与血脑屏障的破坏无关。犬尿烯酸的浓度也增加，但通常程度低于QUIN的增加。相比之下，在慢性神经退行性疾病、抑郁症或肌阵挛性癫痫发作疾病中未发现CSF QUIN增加，而在亨廷顿病和阿尔茨海默病中CSF犬尿烯酸浓度显著较低。在炎性疾病患者中，CSF L-犬尿氨酸的成比例增加和L-色氨酸的减少伴随着CSF QUIN和犬尿烯酸的增加。这些反应与吲哚胺-2，3-双加氧酶的诱导一致，吲哚胺-2，3-双加氧酶是犬尿氨酸途径的第一种酶，其将L-色氨酸转化为犬尿烯酸和QUIN。事实上，在逆转录病毒感染的猕猴的大脑皮层中观察到吲哚胺-2，3-双加氧酶活性和QUIN浓度的增加。特别是那些具有局部炎性损伤的患者。CSF QUIN、犬尿烯酸和L-犬尿氨酸与免疫刺激标志物之间的相关性（新喋呤、白色血细胞计数和IgG水平）表明犬尿氨酸途径代谢加速与脑内免疫刺激程度之间的关系。我们得出结论，炎症性疾病与中枢神经系统内QUIN、犬尿烯酸和L-犬尿氨酸的积累有关，但现有数据不支持QUIN在亨廷顿病或阿尔茨海默病病因学中的作用。结合我们以前的报道，CSF QUIN浓度与HIV-1感染患者神经心理缺陷的客观指标相关，我们假设QUIN和犬尿烯酸是炎症性疾病中神经元功能障碍和神经细胞死亡的介质。因此，减弱犬尿氨酸途径代谢物的神经作用或减弱其合成速率的策略提供了新的治疗方法。
Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized froM L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus. particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation.We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.