Abstract：
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.
摘要：
TMP269，一种具有选择性的IIA类组蛋白去乙酰化酶抑制剂，对中枢神经系统有保护作用，然而，其具体的作用机制仍然模棱两可。尽管重度抑郁症（MDD）非常普遍，对其病理生理学了解甚少。最近的证据表明，组蛋白去乙酰化酶5在抑郁症的病理过程中起着关键作用，事实上，临床前研究表明HDAC5是一个潜在的抗抑郁靶点。寻找能够靶向HDAC5的天然药物或小分子化合物可能是治疗抑郁症的潜在治疗策略.此外,我们检查了脑源性神经营养因子（BDNF）的作用，神经元存活和生长的重要神经营养因子,作为HDAC5的潜在下游靶标。我们发现海马中HDAC5水平的下调改善了LH（学习无助）小鼠的抑郁样行为。此外，在野生型小鼠的海马齿状回中注射过表达HDAC5的腺病毒载体产生了类似抑郁的表型。药理学,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而产生抗抑郁作用。总的来说，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对抑郁症的潜在有益作用。
