| Summary: | Abstract Aim To investigate the effect of estrogen on axon regeneration and neurological recovery after subcortical axon injury, and further explore its underlying molecular mechanisms. Method Subcortical axonal fiber injury model was used in this study. Morris water maze was conducted to detect the learning and memory ability of the rats; modified neurological severity score (mNSS) and beam walking test were performed to evaluate the behavioral; and diffusion tensor imaging (DTI) was used for the determination of recovery after subcortical axonal injury, while Western blotting was performed to detect the expression of p‐Akt, CDK5, p‐Ser262, p‐Ser404, and p‐Thr205. Results Compared with the Sham group, the injury of subcortical axonal fiber resulted in higher mNSS, higher beam walking scores, longer time of escape latency, less number, time and shorter distance of crossing the quadrant, and less FA values. After ovariectomy, the mNSS, beam walking scores, and escape latency reached the peak; inversely, the others reached a minimum. High estrogen treatment reduced the mNSS, beam walking score, and escape latency; improved the number, time, and distance of crossing the quadrant; and increased the FA value. Western blotting results showed that estrogen increased the expression of p‐Akt and decreased the expression of CDK5, p‐Ser262, p‐Ser404, and p‐Thr205. All the changes were counteracted to some extent by Akt inhibitor LY294002. Conclusion After subcortical axonal injury, estrogen could improve the regeneration of axons and improve their functions via regulating the PI3K/Akt/CDK5/Tau pathway.
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