Muneer Ather
Islamic International Medical College, Riphah International University, Rawalpindi, Pakistan.
Clin Psychopharmacol Neurosci. 2020 Nov 30;18(4):507-526. doi: 10.9758/cpn.2020.18.4.507.
Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.
在生理条件下,摄入的必需氨基酸色氨酸有95%通过犬尿氨酸途径(KP)进行代谢,以产生普遍存在的辅酶烟酰胺腺嘌呤二核苷酸,满足细胞的能量需求。重要的是,犬尿氨酸途径的中间产物在全身发挥关键作用,包括中枢神经系统。此外,犬尿氨酸途径的代谢产物与多种疾病过程有关,如炎症/免疫紊乱、内分泌/代谢状况、癌症和神经精神疾病。越来越多的研究表明,犬尿氨酸途径在情绪障碍和精神分裂症等主要精神疾病中起致病作用。在炎症过程的触发下,犬尿氨酸途径的神经毒性和神经保护分支之间的平衡被打破。在临床前模型中,这些差异导致出现类似抑郁和精神病的行为。在临床样本中,最近的研究发现了关键的犬尿氨酸途径异常,这使其在主要精神疾病的发病机制中受到牵连。利用这些知识有可能找到有助于识别和预测神经精神疾病的疾病生物标志物。与此同时,针对操纵犬尿氨酸途径的认真研究努力有望发现具有治疗价值的新型药物。在本手稿中,对现有文献进行了深入评估,以了解犬尿氨酸途径在神经精神疾病中的作用机制。得出的结论是,该途径在主要精神疾病的发展中起总体作用,犬尿氨酸途径的代谢产物有可能作为疾病标志物,基于犬尿氨酸途径调节的新药物可以为患有这些难治性疾病的患者带来持久的治愈。