Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, CRBS 1, Rue Eugène Boeckel, 67000 Strasbourg, France.
Int J Mol Sci. 2021 Jun 28;22(13):6974. doi: 10.3390/ijms22136974.
Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1-0.4 µM in A and A), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.
黄尿酸（XA）是犬尿氨酸途径（KP）的代谢产物，由饮食或微生物色氨酸在大脑中合成，通过载体介导的转运穿过血脑屏障。XA 和犬尿氨酸（KYNA）是 KP 的两种结构相关化合物，在中枢神经系统中以微摩尔浓度存在，被怀疑调节神经精神和/或神经退行性疾病的一些病理生理机制。特别是，包括 XA 脑分布（从嗅球和小脑的 1µM 到 A 和 A 的 0.1-0.4µM）、释放及其与 G 蛋白依赖性 XA 受体、谷氨酸转运体和代谢型受体的相互作用在内的各种数据强烈支持 XA 具有信号转导和/或神经调节作用。然而，尽管母体分子 KYNA 因其对纹状体多巴胺释放的抑制作用而被认为可能与神经精神障碍有关，但 XA 对大脑多巴胺活性的影响仍不清楚。在这里，我们证明急性局部/微透析输注 XA 剂量依赖性地刺激大鼠前额叶皮层中的多巴胺释放（存在 20µM XA 时增加四倍）。这种刺激作用被 XA 受体拮抗剂 NCS-486 阻断。有趣的是，我们的结果表明，外周/腹腔内给予 XA，已被证明能增强脑内 XA 浓度（腹腔内给予 50mg/kg XA 后增加约 200%），也能诱导皮层和纹状体中多巴胺释放的剂量依赖性增加。此外，我们的体内电生理研究表明，XA 的重复/每日给药使腹侧被盖区中自发放电的多巴胺能神经元数量减少 43%。在黑质中，XA 处理不会改变放电神经元的数量。总的来说，我们的结果表明，XA 可能与 KYNA 一起产生一个 KYNA/XA 比值，这可能对大脑正常的多巴胺活性起着至关重要的决定作用。这种比值的失衡可能导致与几种脑疾病相关的多巴胺功能障碍，包括精神病和药物依赖。
