Heyes M P, Saito K, Jacobowitz D, Markey S P, Takikawa O, Vickers J H
Section on Analytical Biochemistry, National Institute of Mental Health, Bethesda, Maryland 20892.
FASEB J. 1992 Aug;6(11):2977-89. doi: 10.1096/fasebj.6.11.1322853.
Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [13C6]quinolinic acid from [13C6]L-tryptophan, particularly when stimulated by interferon-gamma. Spinal cord slices from poliovirus-inoculated macaques in vitro also converted [13C6]L-tryptophan to [13C6]quinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.
神经毒素喹啉酸在脑内的蓄积发生于广泛的炎性神经系统疾病患者中，可能具有神经病理学意义。据推测，喹啉酸的产生反映了反应性细胞中的细胞因子以及中枢神经系统内炎性细胞浸润对吲哚胺2,3-双加氧酶的局部诱导作用。为验证这一假设，将脊髓内注射脊髓灰质炎病毒的猕猴作为局部炎性神经系统疾病的模型。17天后，脊髓吲哚胺2,3-双加氧酶活性以及脊髓和脑脊液中喹啉酸浓度均与脊髓中的炎症反应程度、神经损伤以及运动麻痹的严重程度成比例增加。脊髓和脑脊液中达到的喹啉酸绝对浓度超过了据报道在体外可杀死脊髓神经元的水平。在作为脊髓灰质炎病毒靶区的顶叶皮质中，吲哚胺2,3-双加氧酶活性和喹啉酸浓度也有较小程度的增加。在并非脊髓灰质炎病毒靶区的额叶皮质中，吲哚胺2,3-双加氧酶未受影响。使用抗人吲哚胺2,3-双加氧酶单克隆抗体，可在脊髓灰质炎病毒感染的脊髓灰质中，结合局部炎性病变，使吲哚胺2,3-双加氧酶主要可视化。体外培养的巨噬细胞/单核细胞可将[13C6]L-色氨酸合成[13C6]喹啉酸，尤其是在受到γ干扰素刺激时。来自接种脊髓灰质炎病毒的猕猴的脊髓切片在体外也可将[13C6]L-色氨酸转化为[13C6]喹啉酸。我们得出结论，中枢神经系统内由L-色氨酸局部合成喹啉酸是在吲哚胺-2,3-双加氧酶诱导之后发生的，尤其是在巨噬细胞/小胶质细胞内。鉴于免疫刺激与神经毒性量喹啉酸合成之间的这种联系，我们提出减轻局部炎症、减少神经活性犬尿氨酸途径代谢产物合成的策略或干扰喹啉酸神经毒性的药物可为炎性神经系统疾病提供新的治疗方法。
