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Figure 7｜EPO promotes neurological recovery after TBI via axon-guided isopathic pathways.
Impairment of spatial recognition memory is an important complication after TBI (Zeng et al., 2020). To test spatial recognition in our mouse model, we performed the MWM test. The representative paths of the mice are shown in Figure 7A. No significant changes in the location-navigation and spatial exploration tests were observed on the first day after TBI, with or without EPO treatment, whereas on days 25–29 after TBI, EPO treatment significantly reduced the escape latency (Figure 7B). In addition, the mNSS score was decreased after EPO administration (Figure 7C). These findings suggest that treatment with EPO may be improve spatial memory and neurological function in a mouse model of TBI.
Given that the term axon guidance was highly enriched in the KEGG results, and that improvement in neural function after TBI could be partly attributable to brain plasticity, we speculated that EPO treatment may promote axonal regeneration (Zhong et al., 2017). To explore whether EPO promotes the recovery of neurological function after TBI through the axon guidance pathway, we assessed the expression of Ephb6 and Wnt5a, two key components of the axon guidance pathway, by co-immunofluorescence and western blotting. Ephrins are axon guidance proteins, and Wnt proteins are also factors in axon development, and both protein families have been studied in the context of CNS injury (Biervert et al., 2001; Miyashita et al., 2009). Our results showed that Ephb6 and Wnt5a colocalized with NeuN in brain tissues, and that the increase in Ephb6 expression and decrease in Wnt5a expression induced by TBI were both reversed by treatment with EPO (Figure 7D and E). These changes in Ephb6 and Wnt5a expression before and after EPO treatment were confirmed by western blotting (Figure 7F). Thus, we conclude that EPO might promote recovery of neurological function after TBI through the axon guidance pathway.