BRAIN QUINOLINIC ACID METABOLISM--ROLE IN NEUROPATHOLOGY

炎症过程会发生，并有助于疾病的进展。 广泛的神经功能障碍和神经退行性变 神经系统疾病，包括艾滋病毒相关性痴呆症、中风、脊柱 脊髓损伤、头部创伤、脑膜炎、自身免疫性疾病和脑 感染。我们发现激活的巨噬细胞和小胶质细胞 合成大量的神经毒素，喹啉酸，以及 这种色氨酸代谢物在患者的大脑中积聚， 患有炎症性神经系统疾病的实验动物。我们有 我们继续寻找：1)喹啉酸生产的抑制剂； 2)合适的人体喹啉酸代谢动物模型；3) 合适的神经系统疾病进展的动物模型 目的：评价喹啉酸合成抑制剂。 我们的结果表明，培养的人巨噬细胞是一种有用的 犬尿氨酸途径抑制剂的筛选系统。沙鼠和 豚鼠紧密复制人喹啉酸的主要特征 代谢，而大鼠的不同之处在于它们的巨噬细胞、小胶质细胞和 星形胶质细胞不会对免疫刺激产生喹啉。 大鼠也没有显示出大脑中喹啉酸水平的升高 对脑部炎症的反应，这是人类、沙鼠和 豚鼠的反应。我们已经确定，在大脑定位的过程中 炎症，喹啉酸是在局部合成的，而不是 从血液中提取的。因此，要弱化喹啉酸 在脑部炎症期间蓄积，药物必须进入大脑 以阻止局部合成。4-氯-3-羟基安非他酯残留物 大脑中最有效的喹啉酸合成抑制剂 目前为止已经测试过了。调查的范围将继续是 扩展到包括对其他假定的神经毒性的评估 炎症性神经系统疾病中的代谢物。(前身为LCS)

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. (Formerly LCS)