Chair and Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 20-090 Lublin, Poland.
Cells. 2024 Aug 26;13(17):1424. doi: 10.3390/cells13171424.
Cytoprotective and neurotoxic kynurenines formed along the kynurenine pathway (KP) were identified as possible therapeutic targets in various neuropsychiatric conditions. Memantine, an adamantane derivative modulating dopamine-, noradrenaline-, serotonin-, and glutamate-mediated neurotransmission is currently considered for therapy in dementia, psychiatric disorders, migraines, or ischemia. Previous studies have revealed that memantine potently stimulates the synthesis of neuroprotective kynurenic acid (KYNA) in vitro via a protein kinase A-dependent mechanism. Here, the effects of acute and prolonged administration of memantine on brain kynurenines and the functional changes in the cerebral KP were assessed in rats using chromatographic and enzymatic methods. Five-day but not single treatment with memantine selectively activated the cortical KP towards neuroprotective KYNA. KYNA increases were accompanied by a moderate decrease in cortical tryptophan (TRP) and L-kynurenine (L-KYN) concentrations without changes in 3-hydroxykynurenine (3-HK) levels. Enzymatic studies revealed that the activity of cortical KYNA biosynthetic enzymes ex vivo was stimulated after prolonged administration of memantine. As memantine does not directly stimulate the activity of KATs' proteins, the higher activity of KATs most probably results from the increased expression of the respective genes. Noteworthy, the concentrations of KYNA, 3-HK, TRP, and L-KYN in the striatum, hippocampus, and cerebellum were not affected. Selective cortical increase in KYNA seems to represent one of the mechanisms underlying the clinical efficacy of memantine. It is tempting to hypothesize that a combination of memantine and drugs could strongly boost cortical KYNA and provide a more effective option for treating cortical pathologies at early stages. Further studies should evaluate this issue in experimental animal models and under clinical scenarios.
细胞保护和神经毒性的犬尿氨酸途径 (KP) 形成的犬尿氨酸被认为是各种神经精神疾病的可能治疗靶点。 目前，作为调节多巴胺、去甲肾上腺素、血清素和谷氨酸介导的神经递质的金刚烷衍生物，美金刚被认为可用于痴呆、精神障碍、偏头痛或缺血的治疗。 先前的研究表明，美金刚通过蛋白激酶 A 依赖性机制在体外强烈刺激神经保护型犬尿氨酸酸 (KYNA) 的合成。 在这里，使用色谱和酶方法在大鼠中评估了美金刚的急性和长期给药对大脑犬尿氨酸的影响以及大脑 KP 中的功能变化。 五天而不是单次美金刚处理选择性地激活了皮质 KP 以产生神经保护性 KYNA。 KYNA 增加伴随着皮质色氨酸 (TRP) 和 L-犬尿氨酸 (L-KYN) 浓度的适度降低，而 3-羟基犬尿氨酸 (3-HK) 水平没有变化。 酶研究表明，长期给予美金刚后，皮质 KYNA 生物合成酶的活性被刺激。 由于美金刚不会直接刺激 KATs 蛋白的活性，因此 KATs 的更高活性很可能是由于相应基因的表达增加所致。 值得注意的是，纹状体、海马体和小脑的 KYNA、3-HK、TRP 和 L-KYN 浓度不受影响。 选择性的皮质 KYNA 增加似乎代表了美金刚临床疗效的机制之一。 可以假设美金刚与药物的联合使用可以强烈促进皮质 KYNA，并为早期治疗皮质病变提供更有效的选择。 应在实验动物模型和临床情况下进一步研究这个问题。
