Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 166, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2023.115312
Keywords
HDAC inhibitor; Microglial activation; Neuroinflammation; Depressive disorder
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In this study, a novel HDAC inhibitor, 5, was developed and shown to suppress microglial activation and alleviate depression-like behavior by inducing autophagy and inhibiting nitric oxide production. These findings suggest HDAC11 as a potential therapeutic target for depressive disorder.
Histone deacetylases (HDACs) are key epigenetic regulators and classified into four subtypes. Despite the various roles of each HDAC isoform, the lack of selective HDAC inhibitors has limited the elucidation of their roles in biological systems. HDAC11, the sole class-IV HDAC, is highly expressed in the brain, however, the role of HDAC11 in microglia is not fully understood. Based on the modification of MC1568, we developed a novel HDAC inhibitor, 5. Interestingly, 5 suppresses lipopolysaccharide-induced microglial activation by the initiation of autophagy and subsequent inhibition of nitric oxide production. Furthermore, we demonstrated that 5 significantly alleviates depression-like behavior by inhibiting microglial activation in mouse brain. Our discovery reveals that specific pharmacological regulation of HDAC11 induces autophagy and reactive nitrogen species balance in microglia for the first time, which makes HDAC11 a new therapeutic target for depressive disorder.
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