The Effects Of Antiepileptic Drugs On Early Brain Development Of Rats And The Possible Mechanisms

【Objective】To study the effects of antiepileptic drugs (AEDs)on the cognition of rats of different brain development age, and to explore the possible mechanisms underlying these secondary effects.【Methods】Wistar rats, at the age of postnatal day 8 (P8) and P15 received intragastric administration of phenobarbital (PB, 30mg/kg, qd),valproate sodium (VPA, 150mg/kg, bid),topiramate (TPM, 40mg/kg, bid) respectively for 7 consecutive days, and the control group were given Carboxymethylcellulose solution (CMC) in which the drugs were dissolved. At the termination of drugs administration, the rats were divided equally into two groups. One group were used for the flowing test: measurement of drug plasma concentrations of PB and VPA and brain weight, the location of apoptotic cells by using terminal deoxynucleotidyl dUTP nick end-labeling (TUNEL) of brain sections in situ, the observation of morphological changes of synapses by electron microscopy, the test of synaptophysin(SYP) and brain-derived neurotrophic factor (BDNF) in the brain sections by immunohistochemistry. Another group of rats were allowed to survive to adulthood. At 7 days after drugs administration terminated and on postnatal day 60 (P60), these rats were tested with Morris Water Maze to evaluate the learning and memory ability of spatial field. At the end of this test, the rats were sacrificed for the test of SYP of brain tissue.【Results】(1) Comparing with the control group of the same age, in rats which received PB,VPA from postnatal day 8, the incidence of apoptosis in temporal lobe and hippocampus CA3 regions increased obviously (p＜0.01). The weight of brains and the expression of synaptophysin in the hippocampus CA3 regions and BDNF in temporal lobe and hippocampus CA3 regions significantly decreased (p＜0.01). Escape latency for searching platform increased significantly and frequency of passing through the platform significantly decreased(p＜0.01). On P65, the brain weight and the expression of synaptophysin were still obviously decreased compared to the control group (p＜0.05). (2) In rats which received PB,VPA from postnatal day 15, as compared with the control group, there were no significant differences in the incidence of apoptosis in temporal lobe and hippocampus CA3 regions, brain weight, the expression of synaptophysin in the hippocampus CA3 regions, the expression of BDNF in temporal lobe and hippocampus CA3 regions and there were no obvious ultrastructure changes of synapse observed by electron microscope. There were also no statistical significance diffrences in escape latency for searching submerged platform and frequency of passing through the platform. (3) In rats which received TPM from postnatal day 8 and 15, as compared with the control group, there were no significant differences in the incidence of apoptosis in temporal lobe and hippocampus, brain weight, the expression of synaptophysin in the hippocampus CA3 regions, the expression of BDNF in temporal lobe and hippocampus CA3 regions and there were no obvious ultrastructure change of synapse observed by electron microscope. There were also no statistical significance diffrences in escape latency for searching submerged platform and frequency of passing through the platform.【Conclusions】(1) During brain growth spurt, PB and VPA could enchance apoptosis of neurocytes, affect the growth of synapse, and thus decrease the brain weight, cause cognitive disfunctions. And this kind of morphological and functional impairments were proved to be irreversible. (2) There is a sensitive period for PB and VPA to affect brain development and cognition, aider the end of brain growth spurt, the administration of PB and VPA, did not produce obvious impairments on brain development and cognition. (3) TPM cause no obvious structural or functional impairments on brain during brain growth spurt and could be used as an ideal antiepileptic drug given to developing children of little age. (4) The decreased expression of BDNF in nerve cells and its' affects on synapse play important roles in the impairments of developing brain and cognition resulting from PB and VPA administration.