Development of a novel histone deacetylase inhibitor unveils the role of HDAC11 in alleviating depression by inhibition of microglial activation

Soo Yeon Baek; Jeehee Lee; Taegwan Kim; Hyelim Lee; Hoon-Seong Choi; Hahnbeom Park; Minseob Koh; Eunha Kim; Michael E Jung; Dimitrios Iliopoulos; Jeong-Yeon Lee; Jonghoon Kim; Sanghee Lee

doi:10.1016/j.biopha.2023.115312

Development of a novel histone deacetylase inhibitor unveils the role of HDAC11 in alleviating depression by inhibition of microglial activation

Biomed Pharmacother. 2023 Oct:166:115312. doi: 10.1016/j.biopha.2023.115312. Epub 2023 Aug 9.

Authors

Soo Yeon Baek¹, Jeehee Lee², Taegwan Kim³, Hyelim Lee¹, Hoon-Seong Choi⁴, Hahnbeom Park¹, Minseob Koh⁵, Eunha Kim⁶, Michael E Jung⁷, Dimitrios Iliopoulos⁸, Jeong-Yeon Lee⁹, Jonghoon Kim¹⁰, Sanghee Lee¹¹

Affiliations

¹ Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea.
² Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, South Korea.
³ Department of Chemistry and Integrative Institute of Basic Science, Soongsil University, Seoul 06978, South Korea.
⁴ Research Animal Resources Center, Research Resources Division, Korea Institute of Science and Technology, Seoul 02792, South Korea.
⁵ Department of Chemistry, Pusan National University, Busan 46241, South Korea.
⁶ Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea.
⁷ Department of Chemistry & Biochemistry, University of California at Los Angeles (UCLA), Los Angeles, CA 90095-1569, USA.
⁸ Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA.
⁹ Department of Pathology, College of Medicine, Hanyang University, Seoul 04763, South Korea.
¹⁰ Department of Chemistry and Integrative Institute of Basic Science, Soongsil University, Seoul 06978, South Korea. Electronic address: jhkim19@ssu.ac.kr.
¹¹ Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, South Korea. Electronic address: slee19@kist.re.kr.

PMID: 37567072
DOI: 10.1016/j.biopha.2023.115312

Abstract

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.

Keywords: Depressive disorder; HDAC inhibitor; Microglial activation; Neuroinflammation.

MeSH terms

Animals
Brain / drug effects
Brain / metabolism
Depression* / drug therapy
Depression* / genetics
Depression* / metabolism
Histone Deacetylase Inhibitors* / pharmacology
Histone Deacetylases / metabolism
Mice
Microglia* / drug effects
Microglia* / metabolism

Substances

Histone Deacetylase Inhibitors
Histone Deacetylases
Hdac11 protein, mouse