QUINOLINIC ACID ACCUMULATION AND FUNCTIONAL DEFICITS FOLLOWING EXPERIMENTAL SPINAL-CORD INJURY
QUINOLINIC ACID ACCUMULATION AND FUNCTIONAL DEFICITS FOLLOWING EXPERIMENTAL SPINAL-CORD INJURY
复制标题
DOI：
10.1093/brain/118.3.735
复制
发表时间：
1995-06-01
期刊：
影响因子：
14.5
通讯作者：
HEYES, MP
中科院分区：
文献类型：
--
作者：
BLIGHT, AR;COHEN, TI;HEYES, MP
喹啉酸 (QUIN) 是一种兴奋毒性色氨酸代谢物，由活化的巨噬细胞产生。 QUIN 的积累与多种人类神经系统疾病，特别是炎症性疾病的病因有关。为了确定 QUIN 是否是一种内源性神经毒素，需要减少 QUIN 合成的药物，以及 QUIN 水平增加与神经系统疾病相关的动物模型。豚鼠脊髓的压缩损伤会导致继发性神经功能缺损，与炎症和巨噬细胞激活有关。我们评估了 4-氯-3-羟基邻氨基苯甲酸 (4Cl-3HAA)（一种 3-羟基邻氨基苯甲酸-3,4-双加氧酶抑制剂）是否会减少该模型中 QUIN 的积累并影响神经功能缺损的进展。腹腔注射 4Cl-3HAA（每 12 小时 100 mg/kg）可减轻损伤后脊髓中 QUIN 的积累，并减轻迟发性功能缺陷的严重程度。腹腔注射巨噬细胞毒素二氧化硅也可以降低 QUIN 水平并减轻神经功能缺损。将Cl-3HAA直接硬膜下注入受损脊髓（50μM，1μl/h）会立即加剧功能损伤，这表明注入物具有直接毒性作用。这些研究表明，脊髓损伤的豚鼠构成了一个有用的模型，可用于研究在 CNS 炎症条件下增加中枢神经系统 (CNS) QUIN 水平的机制，并评估旨在减少 CNS 内 QUIN 和其他潜在致病介质积累的药物的神经化学和神经学效应。结果与 QUIN 在脊髓损伤后继发性功能损伤的发病机制中的贡献作用一致，尽管不能排除 4Cl-3HAA 具有独立于 QUIN 的额外作用的可能性。需要进一步的研究来确定 4Cl-3HAA 的有益作用是否持续。虽然尚不清楚继发性炎症过程是否会显着导致人类脊髓损伤的神经功能缺损，但减少 QUIN 积累的策略作为治疗靶点值得考虑和评估。
Quinolinic acid (QUIN) is an excitotoxic tryptophan metabolite that is produced by activated macrophages. Accumulations of QUIN are implicated in the aetiology of a broad spectrum of human neurological diseases, particularly inflammatory conditions. To determine whether and QUIN is an endogenous neurotoxin requires agents that reduce and QUIN synthesis, and animal models where QUIN levels increase in association with neurological disease. Compression injury of the spinal cord of guinea pigs results in secondary neurological deficits, related to inflammation and macrophage activation. We evaluated whether 4-chloro-3-hydroxyanthranilate (4Cl-3HAA), an inhibitor of 3-hydroxyanthranilate-3,4-dioxygenase reduces QUIN accumulations in this model and influences the progression of neurological deficits. Intraperitoneal injections of 4Cl-3HAA (100 mg/kg every 12 h) attenuated QUIN accumulations in spinal cord following injury, and reduced the severity of delayed functional deficits. Intraperitoneal injections of the macrophage toxin, silica, also reduced QUIN levels and attenuated neurological deficits. A direct subdural infusion of Cl-3HAA into the injured spinal cord (50 mu M, 1 mu l/h) promptly exacerbated functional impairments, which suggests that the infusate had direct toxic effects. These studies demonstrate that guinea pigs with spinal cord injury constitute a useful model to study the mechanisms that increase central nervous system (CNS) QUIN levels in conditions of CNS inflammation, and to evaluate the neurochemical and neurological effects of agents designed to reduce the accumulations of QUIN and other potential pathogenic mediators within the CNS. The results are consistent with a contributory role for QUIN in the pathogenesis of secondary functional impairments following spinal cord injury, although the possibility that 4Cl-3HAA had additional effects independent of QUIN cannot be excluded. Further studies are required to determine whether the beneficial effects of 4Cl-3HAA are sustained While it is unknown whether secondary inflammatory processes contribute significantly to neurological deficits in human spinal cord injury, strategies that reduce the accumulation of QUIN are worthy of consideration and evaluation as a therapeutic target.