bFGF promotes neurological recovery from neonatal hypoxic-ischemic encephalopathy by IL-1β signaling pathway-mediated axon regeneration.

introductionNeonatal hypoxia-ischemic brain damage (HIBD) can lead to serious neuron damage and dysfunction, causing a significant worldwide health problem. bFGF as a protective reagent promotes neuron repair under hypoxia/ischemia (HI). However, how bFGF and downstream molecules were regulated in HI remains elusive.

methodsWe established an in vitro HI model by culturing primary cortical neurons and treated with oxygen-glucose deprivation (OGD). We suppressed the expression of bFGF by using siRNA (small interfering RNA) interference to detect the neuronal morphological changes by immunofluorescence staining. To determine the potential mechanisms regulated by bFGF, the change of downstream molecular including IL-1β was examined in bFGF knockdown condition. IL-1β knockout (KO) rats were generated using CRISPR/Cas9-mediated technologies. We used an accepted rat model of HI, to assess the effect of IL-1β deletion on disease outcomes and carried out analysis on the behavior, histological, cellular, and molecular level.

resultsWe identified that OGD can induce endogenous expression of bFGF. Both OGD and knockdown of bFGF resulted in reduction of neuron numbers, enlarged cell body and shortened axon length. We found molecules closely related to bFGF, such as interleukin-1β (IL-1β). IL-1β was up-regulated after bFGF interference under OGD conditions, suggesting complex signaling between bFGF and OGD-mediated pathways. We found HI resulted in up-regulation of IL-1β mRNA in cortex and hippocampus. IL-1β KO rats markedly attenuated the impairment of long-term learning and memory induced by HI. Meanwhile, IL-1β

conclusionsWe showed that IL-1β-mediated axon regeneration underlie the mechanism of bFGF for the treatment of HIBD in neonatal rats. Results from this study would provide insights and molecular basis for future therapeutics in treating HIBD.