TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action remains ambiguous. Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that histone deacetylase 5 plays a key role in the pathological process of depression and the fact that preclinical studies have shown HDAC5 to be a potential antidepressant target, the search for natural drugs or small molecule compounds that can target HDAC5 may be a potential therapeutic strategy for the treatment of depression. In addition, we examined the role of the Brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for neuronal survival and growth, as a potential downstream target of HDAC5. We found downward revision of HDAC5 levels in the hippocampus ameliorated depressive-like behavior in LH (Learned helplessness) mice. Furthermore, injection of HDAC5 overexpressing adenoviral vectors in the hippocampal dentate gyrus of wild-type mice produced a somewhat depressive-like phenotype. Pharmacological, immunofluorescence and biochemical experiments showed that TMP269 could produce antidepressant effects by inhibiting mouse hippocampal HDAC5 and thus modulating its downstream BDNF. Over all, TMP269 mitigated LH-induced depressive-like behaviors and abnormalities in synapse formation and neurogenesis within the hippocampus. These findings suggest potential beneficial effects of TMP269 on depression.

中文翻译：

---

TMP269对小鼠应激抑郁样行为的抗抑郁作用及机制


TMP269是一种IIA类选择性组蛋白脱乙酰酶抑制剂，对中枢神经系统具有保护作用，但其具体作用机制仍不明确。尽管重度抑郁症（MDD）非常普遍，但其病理生理学却知之甚少。最近的证据表明组蛋白脱乙酰酶5在抑郁症的病理过程中发挥着关键作用，并且临床前研究已表明HDAC5是潜在的抗抑郁靶点，寻找能够靶向HDAC5的天然药物或小分子化合物可能是一个潜在的目标治疗抑郁症的治疗策略。此外，我们还研究了脑源性神经营养因子 (BDNF) 作为 HDAC5 潜在下游靶标的作用，BDNF 是神经元存活和生长的重要神经营养因子。我们发现海马体中 HDAC5 水平的下调可以改善 LH（习得性无助）小鼠的抑郁样行为。此外，在野生型小鼠的海马齿状回注射 HDAC5 过表达腺病毒载体会产生某种程度的抑郁样表型。药理、免疫荧光和生化实验表明，TMP269可以通过抑制小鼠海马HDAC5从而调节其下游BDNF产生抗抑郁作用。总体而言，TMP269 减轻了 LH 诱导的抑郁样行为以及海马内突触形成和神经发生的异常。这些发现表明 TMP269 对抑郁症具有潜在的有益作用。