RESUMEN
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.
Asunto(s)
Antidepresivos , Depresión , Ratones Endogámicos C57BL , Estrés Psicológico , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ratones , Masculino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Estrés Psicológico/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histona Desacetilasas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Conducta Animal/efectos de los fármacosRESUMEN
Depression is a prevalent and debilitating psychiatric illness. However, the antidepressant drugs currently prescribed are only effective in a limited group of patients. Histone modifications mediated by histone acetylation are considered to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors may be involved in the pathogenesis of depression and the underlying mechanism of the antidepressant therapeutic action. Here, we first conducted virtual screening of histone deacetylase-5 (HDAC5) inhibitors against HDAC5, a target closely related to depression, and identified compound T2943, further verifying its inhibitory effect on enzyme activities in vitro. After stereotaxic injection of T2943 into the hippocampus of mice, the antidepressant effect of T2943 was evaluated using behavioral experiments. We also used different proteomic and molecular biology analyses to determine and confirm that T2943 promoted histone 3 lysine 14 acetylation (H3K14ac) by inhibiting HDAC5 activity. Following the overexpression of adenoviral HDAC5 in the hippocampus of mice and subsequent behavioral analyses, we confirmed that T2943 exerts antidepressant effects by inhibiting HDAC5 activity. Our findings highlight the efficacy of targeting HDAC5 to treat depression and demonstrate the potential of using T2943 as an antidepressant.
Asunto(s)
Histonas , Proteómica , Humanos , Antidepresivos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismoRESUMEN
As a major coastal economic province in the east of China, it is of great significance to clarify the temporal and spatial patterns of regional development in Shandong Province in recent years to support regional high-quality development. Nightlight remote sensing data can reveal the spatio-temporal patterns of social and economic activities on a fine pixel scale. We based the nighttime light patterns at three spatial scales in three geographical regions on monthly nighttime light remote sensing data and social statistics. Different cities and different counties in Shandong Province in the last 10 years were studied by using the methods of trend analysis, stability analysis and correlation analysis. The results show that: (1) The nighttime light pattern was generally consistent with the spatial pattern of construction land. The nighttime light intensity of most urban, built-up areas showed an increasing trend, while the old urban areas of Qingdao and Yantai showed a weakening trend. (2) At the geographical unit scale, the total nighttime light in south-central Shandong was significantly higher than that in eastern and northwest Shandong, while the nighttime light growth rate in northwest Shandong was significantly highest. At the urban scale, Liaocheng had the highest nighttime light growth rate. At the county scale, the nighttime light growth rate of counties with a better economy was lower, while that of counties with a backward economy was higher. (3) The nighttime light growth was significantly correlated with Gross Domestic Product (GDP) and population growth, indicating that regional economic development and population growth were the main causes of nighttime light change.