MTA-SZTE, Neuroscience Research Group, Szeged, Hungary.
Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, Albert Szent-Györgyi Health Centre, University of Szeged, Szeged, Hungary.
Pharmacol Rep. 2020 Apr;72(2):449-455. doi: 10.1007/s43440-020-00067-5. Epub 2020 Mar 12.
Kynurenic acid (KYNA) is an L-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and acetylcholine (Ach). Dysregulation of the kynurenine pathway has been associated with neurodegenerative, neurological, and psychological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, major depressive disorder, and schizophrenia.
The antidepressant-like effects of KYNA were studied with a modified mouse forced swimming test (FST), and the potential involvement of the serotonin (SER), norepinephrine, DA, Ach, N-methyl-D-aspartate, or gamma-aminobutyric acid subunit A (GABA) receptors in its antidepressant-like effect was assayed by modified combination mouse FST. In combination studies, the mice were pretreated with the respective receptor antagonist, cyproheptadine (CPH), phenoxybenzamine, yohimbine, propranolol, haloperidol (HPD), atropine, MK-801, or bicuculline (BCL).
The FST revealed that KYNA reversed immobility, climbing, and swimming times, suggesting the antidepressant-like effects of KYNA. Furthermore, the combination studies showed that CPH prevented the antidepressant-like effects of KYNA on immobility, climbing, and swimming times, whereas HPD reduced climbing time and BCL influenced immobility and climbing times and prevented the effects of KYNA on swimming time.
The results demonstrated, for the first time, the presence of antidepressant-like effects of KYNA in a modified mouse FST. Furthermore, modified combination FST showed that the antidepressant-like actions of KYNA strongly interacted with 5-hydroxytryptamine type 2 SER-ergic receptors, weakly interacted with D, D, D DA-ergic receptors, and interacted moderately with GABA receptors.
犬尿酸（KYNA）是一种 L-色氨酸代谢物，具有神经调节活性，调节神经递质如谷氨酸、多巴胺（DA）和乙酰胆碱（Ach）的释放。犬尿氨酸途径的失调与神经退行性、神经和心理障碍有关，如阿尔茨海默病、帕金森病、亨廷顿病、重度抑郁症和精神分裂症。
通过改良的小鼠强迫游泳试验（FST）研究 KYNA 的抗抑郁样作用，并通过改良的组合小鼠 FST 测定其抗抑郁样作用中涉及的 5-羟色胺（SER）、去甲肾上腺素、DA、Ach、N-甲基-D-天冬氨酸或 γ-氨基丁酸 A 亚基 A（GABA）受体的潜在参与。在组合研究中，用相应的受体拮抗剂赛庚啶（CPH）、苯氧苄胺、育亨宾、心得安、氟哌啶醇（HPD）、阿托品、MK-801 或印防己毒素（BCL）预处理小鼠。
FST 显示 KYNA 逆转了不动、攀爬和游泳时间，表明 KYNA 具有抗抑郁样作用。此外，组合研究表明 CPH 阻止了 KYNA 对不动、攀爬和游泳时间的抗抑郁样作用，而 HPD 降低了攀爬时间，BCL 影响了不动和攀爬时间，并阻止了 KYNA 对游泳时间的影响。
结果首次证明了 KYNA 在改良的小鼠 FST 中具有抗抑郁样作用。此外，改良的组合 FST 表明，KYNA 的抗抑郁样作用与 5-羟色胺 2 型 SER 能受体强烈相互作用，与 D、D、D DA 能受体弱相互作用，与 GABA 受体中度相互作用。
