Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Int J Mol Sci. 2023 Sep 27;24(19):14626. doi: 10.3390/ijms241914626.
Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD.
重度抑郁症（MDD）的终生患病率约为 10%，是全球最常见的疾病之一。尽管已经提出了许多 MDD 的发病机制，但 MDD 的发病分子机制和统一假说仍有待确定。在这里，我们研究了酪氨酸硝化是否在实验性 MDD 中起作用，因为酪氨酸硝化可能会影响 MDD 中许多改变的细胞功能。为此，我们通过糖皮质激素应用或慢性环境不可预测的应激来诱导应激，并通过免疫染色和 ELISA 来确定海马中的酪氨酸硝化。通过酶测定测量了过氧化氢酶和过氧化物酶对酪氨酸硝化的作用。我们表明，糖皮质激素和慢性不可预测的环境应激诱导了海马中的酪氨酸硝化。长期用经典抗抑郁药阿米替林或氟西汀治疗应激小鼠可预防酪氨酸硝化。通过静脉内应用抗神经酰胺抗体或重组神经酰胺酶分别中和或降解最近显示可诱导实验性 MDD 的血浆神经酰胺，也可预防酪氨酸硝化。最后，应激后海马中先前显示减少的磷脂酸的应用也逆转了应激诱导的酪氨酸硝化。通过干扰 NO 自由基的形成来抑制酪氨酸硝化至少部分恢复了应激小鼠的正常行为。这些数据表明，酪氨酸硝化可能有助于 MDD 的发病机制，针对该过程可能有助于 MDD 的治疗。
