Abstract: Objective To investigate the role of autophagy in estradiol intervention for severe acute spinal cord injury (SCI). Methods A total of 72 adult female Sprague-Dawley rats,weighed 200-220 g,were randomly divided into 3 groups (n=24).Severe SCI models were established with an artery clip (15 g closing force) in model group and intervention group.The intervention group received an intramuscular injection of estradiol benzoate every other day one week before injury and last into sacrifice.The Basso,Beattie,Bresnahan (BBB) open field locomotor rating scale were performed on 7,14,21 and 28 days after SCI to evaluate the functional recovery of locomotion.Real-time PCR and Western blot analysis were used to detect the expression of autophagy marker and Immunohistochemical staining for LC3 was performed using spinal cord sections obtained on days 3 after SCI. Results High dose of estradiol significantly improved locomotor recovery in vivo;the BBB scores in the intervention group were higher than that in the model group on 14,21,and 28 days after spinal cord injury.The expression of LC3 and Beclin-1 in model groups were higher than sham group at 3 days after SCI;E2 treatment inhibited the expression at both mRNA and protein level.Conversely,the expression levels of autophagy substrates protein P62 in the model group was significantly reduced when compared with the sham group.However,the expression was increased when treated with estradiol.Immunohistochemical result indicated that the enhanced immunoreactivity for LC3 in motor neurons after SCI was repressed when treated with high dose of estradiol. Conclusion The neuroprotective effects of E2 in SCI is related to the restraint of excessive autophagy.