Mechanism Of Quetiapine Ameliorates The Neurodevelopment In The Cortical Dysplasia

Refractory epilepsy imposes a significant clinical, social and economic burdenthroughout the world. Cortical dysplasia (CD) is a malformation of cortical development,which is the most common cause of medically refractory epilepsy in the pediatricpopulation. Myelination, as the process is termed, is the sign of mature brain development,to enable ’saltatory’ impulse propagation. The previous studies found that abnormalmyelinationis one of the important reasons in the formation o f CD. Moreover，thecognitive decline also associated with myelination disturbances. Studies show thatQuetiapine facilitates oligodendrocyte development and prevents mice from myelinbreakdown and behavioral changes.We speculate that Quetiapine may amelioratecognition and reduce seizure threshold to pentylenetetrazol-induced seizures in an animalmodel of CD by facilitating myelin sheath development and preventing myelinbreakdown.Objectives The purpose of this study was to confirm that Quetiapine facilita tes myelin sheathdevelopment, prevents myelin breakdown, ameliorates cognition and reduces seizurethreshold to pentylenetetrazol-induced seizures in an animal model of CD.MethodsWe established the animal model of CD by giving1.8Gy gama-irradiation to E16pregnant rats, using the normal pups as control. According to whether treat with drug ornot, pups can be divided into four groups: control group, CD group, CD+Saline groupand CD+Quetiapine group. The pathologic examination was performed, including HEstaining, Nissl staining, immunohistochemistry and Western Blot. We observed thepathological changes and the expression of MBP in the cerebral cortex and white matter.At1month of age pups were tested using open feld task, elevated plus maze, objectrecognition task, and the Morris water maze task. The tests were measured to assessactivity and cognitive function. We administered pentylenetetrazol intraperitoneally torats at P30at a concentration of25mg per kg of body weight to induce seizure. To useSPSS18.0statistics analysis by mean standard deviation, P<0.05represent significant.Results1.There were10.7%pups in CD group underwent the spontaneous seizures after theirmothers received overdose γ-irradiation at E16. Other pups appeared to be more excitedthan the normal pups. The lamellar structure in the CD group was in chaos and the cortexbecame thinner than the normal pups. Neural nodes can be found in the cerebral cortex,CA1/CA3/CA4region in some rats. Demyelinating and developmental delay can be foundin the CD group. These results revealed that we established the CD animal modelsuccessfully.2.Brain weight and body weight in CD+Quetiapine group was higher than that in CDgroup and lower than that in control group at the same period. These results revealed thatQuetiapine ameliorate developmental delay.3.The open field task and Elevated plus maze task reveal that general activity wasameliorated in CD+Quetiapine group rats. Object recognition task and Morris water maze task reveal that spatial memory and learning was ameliorated in CD+Quetiapine grouprats.4.We investigated whether the susceptibility to pentylenetetrazol-induced seizureswas changed in CD+Quetiapine group. A series of subco nvulsive doses ofpentylenetetrazol (25mg/kg) were administrated intraperitoneally every10min to rats infour different groups. Generalized seizures in the CD group and CD+Saline groupoccurred at signifcantly lower doses of pentylenetetrazol and with signifcantly shorterlatencies than they did in CD+Quetiapine group and control group rats. These resultssuggest that Quetiapine reduces seizure susceptibility and severity.5.MBP immunohistochemistry reveals that MBP level in CD+Quetiapine group washigher than that in CD group at the same period. There is no significant difference withcontrol. MBP Western Blot results are as the same with immunohistochemistry. Theseresults revealed that Quetiapine facilitates myelination in the CD.ConclusionOur results indicate that Quetiapine ameliorates cognition and reduces seizurethreshold to pentylenetetrazol-induced seizures in an animal model of CD by facilitatingmyelin sheath development and preventing myelin breakdown.