A Novel Histone Deacetylase 6 Inhibitor, 4-FHA, Improves Scopolamine-Induced Cognitive and Memory Impairment in Mice

Overview

Journal Biomol Ther (Seoul)

Specialty Pharmacology

Date 2025 Feb 11

PMID 39933949

Authors

Jee-Yeon Seo

Jisoo Kim

Yong-Hyun Ko

Bo-Ram Lee

Kwang-Hyun Hur

Young Hoon Jung

Hyun-Ju Park

Seok-Yong Lee

Choon-Gon Jang

Affiliations

Soon will be listed here.

Abstract

Although histone deacetylase 6 (HDAC6) is considered a therapeutic target for Alzheimer's disease (AD), its role in cholinergic dysfunction in AD patients remains unclear. This study investigated the effects of ()-3-(2-(4-fluorostyryl)thiazol-4-yl)--hydroxypropanamide (4-FHA), a new synthetic HDAC6 inhibitor, on cognitive and memory impairments in a scopolamine-induced-AD mouse model. Behaviorally, 4-FHA improved scopolamine-induced memory impairments in the Y-maze, passive avoidance, and Morris water maze tests. In addition, 4-FHA ameliorated scopolamine-induced cognitive impairments in the novel object recognition and place recognition tests. Furthermore, 4-FHA increased acetylation of α-tubulin (a major HDAC6 substrate); the expression of BDNF; and the phosphorylation of ERK 1/2, CREB, and ChAT in the hippocampus of scopolamine-treated mice. In summary, according to our data 4-FHA, an HDAC6 inhibitor, improved the cognitive and memory deficits of the AD mouse model by normalizing BDNF signaling and synaptic transmission, suggesting that 4-FHA might be a potential therapeutic candidate for AD.

References

Park H, Kwon H, Lee J, Cho E, Lee Y, Moon M . β-Amyrin Ameliorates Alzheimer's Disease-Like Aberrant Synaptic Plasticity in the Mouse Hippocampus. Biomol Ther (Seoul). 2019; 28(1):74-82. PMC: 6939697. DOI: 10.4062/biomolther.2019.024. View

Ding Y, Kang A, Tang Q, Zhao Y . Inhibition of HDAC6 expression decreases brain injury induced by APOE4 and Aβ co‑aggregation in rats. Mol Med Rep. 2019; 20(4):3363-3370. DOI: 10.3892/mmr.2019.10571. View

Therriault J, Zimmer E, Benedet A, Pascoal T, Gauthier S, Rosa-Neto P . Staging of Alzheimer's disease: past, present, and future perspectives. Trends Mol Med. 2022; 28(9):726-741. DOI: 10.1016/j.molmed.2022.05.008. View

Kim B, Jha S, Seo J, Jeong C, Lee S, Lee S . MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus. Biomol Ther (Seoul). 2020; 28(6):519-526. PMC: 7585641. DOI: 10.4062/biomolther.2020.041. View

Dompierre J, Godin J, Charrin B, Cordelieres F, King S, Humbert S . Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci. 2007; 27(13):3571-83. PMC: 6672116. DOI: 10.1523/JNEUROSCI.0037-07.2007. View

Ko Y, Kwon S, Hwang J, Kim K, Seo J, Nguyen T . The Memory-Enhancing Effects of Liquiritigenin by Activation of NMDA Receptors and the CREB Signaling Pathway in Mice. Biomol Ther (Seoul). 2017; 26(2):109-114. PMC: 5839488. DOI: 10.4062/biomolther.2016.284. View

Yang Y, Chen C, Wu C, Huang W, Kuo T, Kuan M . NBM-T-L-BMX-OS01, Semisynthesized from Osthole, Is a Novel Inhibitor of Histone Deacetylase and Enhances Learning and Memory in Rats. Evid Based Complement Alternat Med. 2013; 2013:514908. PMC: 3625590. DOI: 10.1155/2013/514908. View

Hempen B, Brion J . Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease. J Neuropathol Exp Neurol. 1996; 55(9):964-72. DOI: 10.1097/00005072-199609000-00003. View

Wang Q, Zhang X, Guo Y, Pang Y, Li J, Zhao Y . Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss. Zool Res. 2023; 44(4):712-724. PMC: 10415773. DOI: 10.24272/j.issn.2095-8137.2022.473. View

10.

Wu Q, Huang Q, Guan H, Zhang X, Bao M, Bendahmane M . Comprehensive Genome-Wide Analysis of Histone Acetylation Genes in Roses and Expression Analyses in Response to Heat Stress. Genes (Basel). 2022; 13(6). PMC: 9222719. DOI: 10.3390/genes13060980. View

11.

Wang C, Kavalali E, Monteggia L . BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell. 2021; 185(1):62-76. PMC: 8741740. DOI: 10.1016/j.cell.2021.12.003. View

12.

Jo H, Shim K, Jeoung D . Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. Int J Mol Sci. 2022; 23(17). PMC: 9455701. DOI: 10.3390/ijms23179592. View

13.

Kwon S, Ma S, Joo H, Lee S, Jang C . Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice. Biomol Ther (Seoul). 2014; 21(6):462-9. PMC: 3879918. DOI: 10.4062/biomolther.2013.074. View

14.

Bai P, Mondal P, Bagdasarian F, Rani N, Liu Y, Gomm A . Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease. Acta Pharm Sin B. 2022; 12(10):3891-3904. PMC: 9532562. DOI: 10.1016/j.apsb.2022.05.017. View

15.

Zhu Y, Feng M, Wang B, Zheng Y, Jiang D, Zhao L . New insights into the non-enzymatic function of HDAC6. Biomed Pharmacother. 2023; 161:114438. DOI: 10.1016/j.biopha.2023.114438. View

16.

Cheon S, Koo B, Kim S, Kam E, Nam J, Kim E . Scopolamine promotes neuroinflammation and delirium-like neuropsychiatric disorder in mice. Sci Rep. 2021; 11(1):8376. PMC: 8052461. DOI: 10.1038/s41598-021-87790-y. View

17.

Zhang F, Su B, Wang C, Siedlak S, Mondragon-Rodriguez S, Lee H . Posttranslational modifications of α-tubulin in alzheimer disease. Transl Neurodegener. 2015; 4:9. PMC: 4448339. DOI: 10.1186/s40035-015-0030-4. View

18.

Alarcon J, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel E . Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004; 42(6):947-59. DOI: 10.1016/j.neuron.2004.05.021. View

19.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schluter O, Bradke F . Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease. EMBO Mol Med. 2012; 5(1):52-63. PMC: 3569653. DOI: 10.1002/emmm.201201923. View

20.

Yoon E, Choi Y, Park D . Improvement of Cognitive Function in Ovariectomized Rats by Human Neural Stem Cells Overexpressing Choline Acetyltransferase via Secretion of NGF and BDNF. Int J Mol Sci. 2022; 23(10). PMC: 9146967. DOI: 10.3390/ijms23105560. View