Transcriptomic identification of CREB1 and FOXO1 activation in neuregulin-1-mediated neuroprotection after stroke

Neuregulin-1 (NRG-1) is a growth factor that has been investigated for its neuroprotective properties following ischemic stroke. While NRG-1 has shown considerable promise in reducing neuronal damage, the molecular mechanisms underlying its protective effects remain unclear. This study aimed to examine the impact of NRG-1 treatment on ischemia-induced gene expression following permanent middle cerebral artery occlusion (MCAO) in rats.

Rats were treated with either NRG-1 or vehicle then sacrificed 3 and 12 h after permanent MCAO. RNA isolated from the peri-infarct cortex (ischemic penumbra) was hybridized to an Affymetrix Rat Genome 2.0 ST Microarray Gene Chip. Gene expression was analyzed using the Affymetrix Transcriptome Analysis Console (TAC) 4.0 software and the STRING Protein-Protein Interaction Networks database.

NRG-1 treatment upregulated transcriptional programs promoting cell survival and anti-inflammatory signaling. CREB1 and FOXO1 transcription factor pathways, which are associated with anti-inflammatory signaling, cell proliferation, reduced apoptosis, and decreased oxidative stress, were upregulated. Consistent with the transcriptomic findings, Luminex multiplex transcription factor assays validated the increased CREB1 and FOXO1 activity in NRG-1-treated MCAO brains.

These findings provide novel insight into the molecular mechanisms by which NRG-1 mediates neuroprotection, highlighting its role in activating transcriptional programs that promote neuronal survival and resilience following ischemic injury.