Abstract
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.
Highlights
IntroductionA stroke, called a cerebrovascular accident, is the rapid loss of brain function due to disturbance in the blood supply to the brain
To understand how HDAC1 activator (HA) has a neuroprotective effect on the ischemic brain, we further examined the DNA damage level in cerebral ischemia rats with immunofluorescent staining for NeuN and γH2AX to validate the underlying Histone deacetylase 1 (HDAC1)-mediated mechanism in stroke pathogenesis
We confirmed that ischemic insult leads to the decreased enzymatic activity of HDAC1, and HA treatment with the compound 5104434 can restore
Summary
A stroke, called a cerebrovascular accident, is the rapid loss of brain function due to disturbance in the blood supply to the brain. It is one of the most lethal diseases. It was the second leading cause of death worldwide in 2016, accounting for 10.1%. Because of its high morbidity and mortality rates, a stroke causes physical and physiological stress to individuals and imposes high economic burdens on families and social resources
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