Inhibition of the Epigenetic Regulator REST Ameliorates Ischemic Brain Injury
Cerebral ischemia is known to activate the repressor element-1 (RE1)-silencing transcription factor (REST) which silences neural genes via epigenetic remodeling and promotes neurodegeneration. We presently determined if REST inhibition derepresses target genes involved in synaptic plasticity and promotes functional outcome after experimental stroke. Following transient focal ischemia induced by middle cerebral artery occlusion (MCAO) in adult rats, REST expression was upregulated significantly from 12 h to 1 day of reperfusion compared to sham control. At 1 day of reperfusion, REST protein levels were increased and observed in the nuclei of neurons in the peri-infarct cortex. REST knockdown by intracerebral REST siRNA injection significantly reduced the post-ischemic expression of REST and increased the expression of several REST target genes, compared to control siRNA group. REST inhibition also decreased post-ischemic markers of apoptosis, reduced cortical infarct volume, and improved post-ischemic functional recovery on days 5 and 7 of reperfusion compared to the control siRNA group. REST knockdown resulted in a global increase in synaptic plasticity gene expression at 1 day of reperfusion compared to the control siRNA group and significantly increased several synaptic plasticity genes containing RE-1 sequences in their regulatory regions. These results demonstrate that direct inhibition of the epigenetic remodeler REST prevents secondary brain damage in the cortex and improves functional outcome potentially via de-repression of plasticity-related genes after stroke.
KeywordsCerebral ischemia Transcription factor Synaptic plasticity Neurodegeneration BDNF Neuron-restrictive silencing factor
This study was funded by the National Institute of Health grant no. R21NS095192, RO1 NS099531, and RO1 NS101960.
Compliance with Ethical Standards
Human and Animal Rights and Informed Consent
All surgical procedures were approved by the Research Animal Resources and Care Committee of the University of Wisconsin-Madison, and the rats were cared for in accordance with the Guide for the Care and Use of Laboratory Animals (U.S. Department of Health and Human Services Publication 86-23, revised).
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