Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmaceutiche, Sezione di Fisiologia e Farmacologia, Università di Milano, Milano, Italy.
Department of Life Sciences and Biotechnologies, University of Ferrara, Ferrara, Italy; Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Italy.
Brain Behav Immun. 2020 Oct;89:440-450. doi: 10.1016/j.bbi.2020.07.031. Epub 2020 Jul 26.
The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle. The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF) and homozygous knock-in BDNF Val66Met (BDNF) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF mice compared to BDNF mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.
脑源性神经营养因子（BDNF）Val66Met 多态性与认知和精神障碍的易感性增加有关，并且对某些治疗方法的反应降低。然而，这些损伤的机制目前尚不完全清楚。值得注意的是，犬尿氨酸途径的改变也与认知和精神障碍有关。此外，最近的证据表明，体育锻炼可以通过控制肌肉中的犬尿氨酸代谢来促进有益的效果。本研究旨在评估犬尿氨酸途径是否在久坐不动和运动的野生型（BDNF）和纯合 knock-in BDNF Val66Met（BDNF）小鼠中受到不同调节。我们发现，BDNF 小鼠的血浆和海马中犬尿氨酸酸和 IDO1 的海马 mRNA 水平以及 KAT2 蛋白水平升高，而运动并没有调节这些水平。相反，与 BDNF 小鼠相比，BDNF 小鼠的比目鱼肌中的 KAT1 蛋白水平降低，而比目鱼肌中的 MCP1 mRNA 和海马中的 GFAP 蛋白水平升高，运动则降低了这些水平。运动仅增加了 BDNF 小鼠的血浆犬尿氨酸水平，而增加了比目鱼肌和海马中的 KAT1 和 KAT4 蛋白水平，无论基因型如何。最后，我们发现运动仅能增强 BDNF 小鼠的海马依赖性记忆。总之，我们的结果显示 BDNF 小鼠中的犬尿氨酸途径过度激活，这可能提示了 BDNF Val66Met 携带者报告的认知缺陷的潜在机制。
