The Study On The Mechanism Of BDNF In Cognitive Dysfunction Caused By Propofol In Neonatal Rats

Part 1 Effect of propofol anesthesia on the expression of the ratio of pro BDNF/ m BDNF in hippocampus and long-term spatial learning/ memory functions in neonatal ratsOBJECTIVE To investigate the effect of propofol anesthesia on the expression of the ratio of pro BDNF/ m BDNF in hippocampus in neonatal rats within 72 h and 30 d and the relationship with long-term spatial learnig/memory functions.METHODS 108 SD rats aged 7 days weighing 12-16 g were randomly divided into 3 groups(n=36 each):group C were intraperitoneally injected with 0.9% normal saline 7.5ml/kg once a day for 7 days,group P1 were injected normal saline 7.5ml/kg once a day for 6 days and propofol 75mg/kg on the last day, group P2 were recived propofol 75mg/kg once a day for 7 days.Fifteen minutes after the last intraperitoneal injection, blood gas analysis and blood glucose were detected of 6 rats in each group.The hippocampal tissues were taken at 6,24,48,72 h and 30 d to measure BDNF m RNA, pro BDNF and m BDNF by RT-PCR and Western blot after the completion of the injection. Learning and memory functions were assessed using Morris water maze at 25 days old of rats.RESULTS The indexes of blood gas and blood glucose of 3 groups were in normal range.The expression of BDNF m RNA and m BDNF in Group C were gradually increased in hippocampus, the pro BDNF and the ratio of pro BDNF/m BDNF were gradually decreased. In group P1,the BDNF m RNA and m BDNF were down-regulated, the ratio of pro BDNF/m BDNF were increased(P<0.05),the escape latency was prolonged, space exploration time was shortened compared with group C(P<0.05); in group P2 the BDNF m RNA and m BDNF were significantly down-regulated,the pro BDNF and the ratio of pro BDNF/m BDNF were observably increased(P<0.05),the escape latency was distinctly prolonged, space exploration time was apparently shortened(P<0.05).CONCLUSION A single propofol anesthesia reduced the expression of BDNF m RNA and m BDNF in the hippocampal in neonatal rats. But it do no significant effect on pro BDNF. The ratio of pro BDNF and m BDNF increases slightly. So it impaired learning and memory functions of infancy in rats. Repeated propofol anesthesia can also significantly increased the expression of pro BDNF. The ratio of pro BDNF and m BDNF increased further than before. Eventually the learning and memory function of infancy in rats reduced apparently.Part 2 The effect of m BDNF /Akt/CREB and pro BDNF/Rho A signaling imbalances in cognitive dysfunction caused by propofol in neonatal ratsOBJECTIVE To investigate the effect of m BDNF /Akt/CREB,pro BDNF/ Rho A signaling imbalances in cognitive dysfunction caused by propofol in neonatal ratsMETHODS Rats aged 7 days weighing 12-16 g were randomly divided into 6 groups(n=12 each): group C were intraperitoneally injected with 0.9% normal saline for 7 days, group P1 were injected normal saline for 6 days and propofol on the 7th day, group P2 were recived propofol for 7 days, group T、K and D were given propofol for 7 days and then respectively injected with the inhibitor of P75 NTR receptor TAT-Pep5、the inhibitor of Trk B receptor K252 a and the solvent DMSO. Blood gas analysis and blood glucose were detected of 6 rats in each group. The other 6 rats in each group were subjected to Morris water maze to access learning and memory functions at age of 25 d and decapitated after the tests. The hippocampal tissues were taken to measure m BDNF /Akt/CREB,pro BDNF/ Rho A by Western blot.RESULTS Compared with group C, the escape latency was prolonged(P<0.05), space exploration time was shortened in group P1 and more obvious in P2. Compared with group D, the escape latency was prolonged, space exploration time was shortened in the inhibitor of Trk B receptor group(group K)(P<0.05), the escape latency was shortened, space exploration time was prolonged in the inhibitor of P75 NTR receptor group(group T)(P<0.05). The expression of m BDNF /Akt/ CREB in hippocampus were decreased in group P1 and distinctly decreased in group P2(P<0.05). The pro BDNF/ Rho A in hippocampus were increased in group P1 and gradually increased in group P2(P<0.05).Compared with group D, the Akt/ CREB were down-regulated in group K, the Rho A were reduced in group T(P<0.05).CONCLUSION Propofol anesthesia supressed the anti-apoptosis signal pathway of m BDNF /Akt/ CREB and enhanced the apoptosis signal pathway of pro BDNF/Rho A in the hippocampal in neonatal rats, which may be one of the mechanism by which propofol leads to long-term cognitive dysfunction.