BRAIN QUINOLINIC ACID METABOLISM--ROLE IN NEUROPATHOLOGY

在广泛的神经系统疾病中，炎症过程发生并促进神经功能障碍和神经退行性变的进展，包括艾滋病毒相关的痴呆、中风、脊髓损伤、头部创伤、脑膜炎、自身免疫性疾病和脑感染。我们发现被激活的巨噬细胞和小胶质细胞可以合成大量的神经毒素，喹啉酸，并且这种色氨酸代谢物在炎症性神经疾病患者和实验动物的大脑中积累。我们继续寻找：1)喹啉酸生产抑制剂；2)适宜的人体喹啉酸代谢动物模型；3)神经系统疾病进展的合适动物模型，用以评价喹啉酸合成抑制剂。我们的研究结果表明，培养的人巨噬细胞是一个有用的筛选系统，以确定犬尿氨酸途径抑制剂。沙鼠和豚鼠复制了人类喹啉酸代谢的关键特征，而大鼠的不同之处在于它们的巨噬细胞、小胶质细胞和星形胶质细胞在免疫刺激下不产生喹啉酸。大鼠在脑部炎症反应中也没有表现出与人类、沙鼠和豚鼠反应不同的脑喹啉酸水平升高。我们已经确定，在脑局部炎症中，喹啉酸是局部合成的，而不是来自血液。因此，为了减轻脑炎症期间喹啉酸的积累，药物必须进入大脑以阻断局部合成。4-氯-3-羟基氰酸酯仍然是迄今为止在大脑中测试的最有效的喹啉酸合成抑制剂。研究的范围将继续扩大，以包括炎症性神经疾病中其他假定的神经毒性代谢物的评估。

Inflammatory processes occur and contribute to the progression of neurologic dysfunction and neurodegeneration in a broad spectrum of neurologic diseases, including HIV-associated dementia, stroke, spinal cord injury, head trauma, meningitis, autoimmune conditions and brain infections. We have discovered that activated macrophages and microglia synthesize large quantities of the neurotoxin, quinolinic acid, and that this tryptophan metabolite accumulates in brain of patients and experimental animals with inflammatory neurologic diseases. We have continued our search for: 1) inhibitors of quinolinic acid production; 2) appropriate animal models for human quinolinic acid metabolism; 3) appropriate animal models of neurologic disease progression with which to evaluate quinolinic acid synthesis inhibitors. Our results show that human macrophages in culture are a useful screening system to identify kynurenine pathway inhibitors. Gerbils and guinea pigs closely replicate key features of human quinolinic acid metabolism, whereas rats differ in that their macrophages, microglia and astrocytes do not produce quinolinate in response to immune stimuli. Rats also do not show that elevations in brain quinolinic acid levels in response to brain inflammation that characterized human, gerbil and guinea pig responses. We have established that during brain-localized inflammation, quinolinic acid is synthesized locally rather than being derived from blood. Therefore, to attenuate quinolinic acid accumulations during brain inflammation, drugs must enter the brain in order to block local synthesis. 4-Chloro-3-hydroxyanthanilate remains the most potent inhibitor of quinolinic acid synthesis within the brain tested so far. The scope of the investigations will continue to be expanded to include the evaluation of other putative neurotoxic metabolites in inflammatory neurologic diseases.