Upregulation of Foxo3a protects neurons against hypoxia-ischaemia injury

A series of transcription factors have been profiled in ischaemic stroke. Forkhead box protein O 3a (FoxO3a), which belongs to the family of transcription factors, is characterised by a forkhead DNA-binding domain. However, the role of FoxO3a and circFoxO3, which is encoded from FOXO3 gene in stroke, remains unelucidated.

A rat model of middle cerebral artery occlusion (MCAO)/reperfusion was applied, and rat neuroblastoma B35 cells were treated with cobalt chloride to mimic cellular hypoxia in vitro. FoxO3a (or circFoxO3a) was manipulated to assess the infarction volume and apoptotic proteins.

Brain infarction was enlarged in ischaemia/reperfusion compared with simple ischaemia treatment. The protein level of FoxO3a increased significantly in MCAO and subsequently decreased following reperfusion. Increased FoxO3a expression was also found in CoCl₂ treatment at 24 h and 48 h. Downregulation of FoxO3a significantly promoted apoptosis, while upregulation of FoxO3a reduced apoptosis. Further biochemical analysis demonstrated that protein expression level of caspase-3, caspase-9, and Bax were upregulated following FoxO3a inhibition but downregulated following FoxO3a overexpression. Moreover, upregulated FoxO3a level was consistent with enhanced circFoxO3 expression both in vivo and in vitro.

Both FoxO3a and circFoxO3 are upregulated in ischaemic stroke, which associates with the apoptosis pathway. Hence, FoxO3a and circFoxO3 might be protective factors against hypoxia/ischaemia-induced neuronal damage.