Effect Of CX3CL1, Placental Growth Factor And Norbin In Epileptic Pathogeneses

Objective: Recent studies indicated that inflammatory processeswithin the brain constitute a common and crucial mechanism in thepathophysiology of epilepsy. CX3CL1(Chemokine C-X3-C motif ligand1)is highly expressed in the central nervous system and participates ininflammatory responses. It has been suggested that angiogenesis andblood-brain-barrier damage are involved in the pathophysiology of epilepsy.Placental growth factor (PIGF) plays a role in angiogenesis andneuroprotection. This study aimed to investigate expression pattern ofCX3CL1in epilepsy and its relationship with neuronal loss. Expression ofPIGF was examined in both patients and animal model.Methods: Double immunolabeling, immunohistochemistry andimmunoblotting study show that CX3CL1and PIGF expression in temporalneocortex of temporal lobe epilepsy (TLE) patients. In rat model ofepilepsy, induced by Lithium Chloride-pilocarpine, examine the CX3CL1and PIGF expression in hippocampus and adjacent cortex of epileptic rats.In addition, enzyme linked immunosorbent assay revealed that the concentrations of CX3CL1in cerebrospinal fluid (CSF) and serum inepileptic patients, patients with neurosis and patients with inflammatoryneurological diseases. Moreover, Hematoxylin-eosin (HE) stainingdemonstrated neuronal loss in the brain of patients and animal model.Finally, the expression of TNF-related apoptosis-inducing ligand (TRAIL)was examined in both patients and animal model.Results: CX3CL1expression was upregulated in temporal neocortexof TLE patients. In rat model of epilepsy, CX3CL1upregulation started at6hours after epilepsy, the relatively high expression maintained until60days. The concentrations of CX3CL1in CSF and serum were higher inepileptic patients than in patients with neurosis, but were lower than inpatients with inflammatory neurological diseases. Moreover, there weresignificant neuronal loss in the brain of epileptic patients and animal model.Finally, the expression of TRAIL was significantly increased in bothpatients and animal modelPIGF expression was significantly elevated in patients with TLE thanin control. TLE patients with initial injuries had significantly higher PIGFlevel than those without initial injuries. In the rat model, PIGF upregulationstarted at6hours after status epilepticus and maintained at significant highlevel for up to60days.Conclusion: CX3CL1is significantly up-regulated after epilepsy, theneuronal loss is apparent in epileptic patients and rats. Consistent withneuronal death, TRAIL is significantly increased in both patients andanimal model. Our results indicate that TRAIL may play a role inCX3CL1-induced cell death, CX3CL1may serve as a possible biomarkerof brain inflammation in epilepsy.PIGF is significantly up-regulated after epilepsy. The augmentation of brain PIGF is associated with development of epilepsy. Objective: Norbin, also called neurochondrin or NCDN, is widelydistributed in neuronal tissues. Norbin promote neurite extension inNeuro2a cells, is a negative regulator of Ca2+/calmodulin-dependentprotein kinase II (CaMKII) phosphorylation and essential for the spatiallearning process. Norbin is an important endogenous modulator of mGluR5.In addition, the nervous system-specific homozygous gene disruptionresulted in epileptic seizure. Epilepsy is related to mGluR5, CaMKII andneurite extension aberrantly. The study aimed to understand the expressionand role of Norbin in hippocampus and cortex of epileptic human and rats.Methods: Double immunolabeling, immunohistochemistry andimmunoblotting study show that Norbin expression in temporal neocortexof temporal lobe epilepsy (TLE) patients. In rat model of epilepsy, inducedby lithium Chloride-pilocarpine, examine the Norbin expression inhippocampus and adjacent cortex of epileptic rats. In addition,adeno-associated viral vector-induced overexprssion of Norbin inhippocampus of rats and induced status epilepticus (SE) by lithiumChloride-pilocarpine, and observe the epileptic ethology.Results: Norbin expression was downregulated in temporal neocortexof TLE patients. In rat model of epilepsy, Norbin downregulation afterepilepsy, the relatively low expression maintained until60days. p-CaMKIIwas increased in temporal neocortex of TLE patient and in chronic periodof epileptic rats; Norbin and mGluR5were coexpressed in epileptic tissue.AAV-induced overexpression of Norbin in hippocampus of rats affectedthe epileptic ethology. Conclusion: Norbin is significantly down-regulated after epilepsy.Overexpression of Norbin in hippocampus of rats affects the epilepticethology. Norbin may participate in epileptic pathology by modulatingmGluR5, regulateing CaMKII phosphorylation or other mechanism.