4.7 Article

Restoration of HDAC1 Enzymatic Activity after Stroke Protects Neurons from Ischemia/Reperfusion Damage and Attenuates Behavioral Deficits in Rats

Journal

Publisher

MDPI
DOI: 10.3390/ijms221910654

Keywords

HDAC1; stroke; DNA damage; apoptosis; mNSS; cylinder test

Funding

  1. E-DA Hospital, Kaohsiung, Taiwan [EDAHP108025, EDAH109029, EDAH109039, EDAHP110001, EDAHP110032, EDAHS109003]
  2. I-Shou University, Kaohsiung, Taiwan [ISU-110-IUC-07, ISU 110-S-01]
  3. Ministry of Science and Technology, Taiwan [109-2320-B-214-001]

Ask authors/readers for more resources

A compound named 5104434 has shown potential in stroke therapy by selectively restoring HDAC1 enzymatic activity and protecting neurons to reduce ischemic damage.
A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

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