Role of Cdk5-CRMP pathway in sevoflurane-induced dendritic developmental disorder of neurons in prefrontal cortex of neonatal rats

AIM: To investigate the effect of sevoflurane (Sevo) on the dendritic development in prefrontal cortex (PFC) of neonatal rats and the role of cyclin dependent kinase 5 (Cdk5)- collapsin response mediator protein (CRMP) pathway in it. METHODS: Eighty-eight postnatal day 7 Sprague Dawley (SD) rats were randomly divided into 4 groups (n=22): Air+NS group, Air+roscovitine (Ros) group, Sevo+NS group and Sevo+Ros group. The rats in Air+NS group and Air+Ros group were exposed to the air for 4 h, while the rats in the other 2 groups were exposed to 2.8% sevoflurane for 4 h. The rats received intraperitoneal injection of 150 μL normal saline 15 min before exposure in the Air+NS group and Sevo+NS group, while the rats in the Air+Ros group and Sevo+Ros group received intraperitoneal injection of 150 μL roscovitine (in DMSO solution, 10 mg/kg) 15 min before exposure. At the end of exposure, the cortices of the rat brain were collected and the protein levels of P35, P25, Cdk5, CRMP1, CRMP2, CRMP4 and p-CRMP2 Ser522 in PFC were detected by Western blot. On the postnatal day 30, the rat brains were sectioned for Golgi-Cox staining and morphological analysis of dendrites in the PFC neurons. Open-field test and contextual fear conditioning test were performed on postnatal days 25~27 and 31~32, respectively. RESULTS: Compared with Air+NS group, the expression of P35 in the Sevo+NS group was significantly decreased, and the expression of P25 was dramatically increased (P <0.05), whereas roscovitine partly reversed the changes above induced by sevoflurane (P <0.05). The expression of Cdk5 was not significantly different among all groups. Compared with the Air+NS group, the expression of CRMP1, 2, and 4 in the Sevo+NS group were decreased, and the protein level of p-CRMP2 Ser522/CRMP2 was increased (P <0.05), whereas roscovitine partly reversed the changes above induced by sevoflurane (P <0.05), except for the expression of CRMP2. Compared with Air+NS group, the total dendrite length, secondary dendritic length and interactions on 60 and 80 μm shells in the Sevo+NS group were decreased (P <0.01), whereas roscovitine partly reversed the changes above induced by sevoflurane (P <0.05). Compared with Air+NS group, the percentage of freezing time in the Sevo+NS group was decreased (P <0.01), whereas roscovitine partly reversed the changes induced by sevoflurane (P <0.05). No significant difference among groups in the open-field test was observed. CONCLUSION: Sevoflurane exposure disturbed dendritic development of neurons in PFC, learning and memory ability of neonatal rats, which may be mediated by Cdk5-CRMP pathway.