The Role Of IL-1 In The Aberrant Migration Of Hippocampal Newborn Neurons In Adult Rats After Lithium-pilocarione-induced Seizures

Objective:Epilepsy is a disabling neurological disorder characterized by recurring, unprovoked seizures, but the underlying mechanisms remain largely unclear. Recent studies showed that epileptic seizures induced significant inflammatory reaction, and in the local lesion area, the levels of many cytokines increased drastically. Our previous studies also showed that severe seizures induced abnormal migration of newborn neurons in the dentate gyrus from the subgranular zone to the hilus, and these ectopic neurons displayed epileptic discharge, indicating that these neurons might contribute to recurrent seizures. However, it is still unknown whether cytokines are involved in seizures-induced the ectopic migration of new-born neurons. In this study, by employing LiCl-pilocarpine-induced status epilepticus model, we investigated the expression of interleukin-1β(IL-1β) mRNA, one of key factors in inflammatory cascade, after seizures in the dentate gyrus, and examined the effect of IL-1βon the migration of cultured neurons. We aimed to investigate the role of IL-1βin the aberrant migration of newborn neurons and to provide a potential strategy in the treatment of epilepsy.Methods:1. After lithium-pilocarione-induced seizures, all rats were sacrificed at different time-points. By using RT-PCR, IL-1β, IL-1 receptor antagonist (IL-1ra) and IL-1 receptor 1 (IL-1R1) mRNA levels in the dentate gyrus were measured.2. The effects of IL-1βon the migration and growth cone turning guidance of cultured neurons were studied with Boyden chamber assay and Growth cone turning assay, respectively.Results:1. In the intact dentate gyrus, the expression of IL-1β, IL-1ra and IL-1R1 mRNA were in the low levels. After status epilepticus (SE), the expression of cytokines were up-regulated significantly in the acute phase, peaked at 6-12 h (P<0.01), and then declined gradually. IL-1βand IL-1ra expression decreased to the lowest point at 2 weeks, but those were mildly increased compared to the control group. The levels of IL-1βand IL-1ra mRNA were significantly enhanced again 4 weeks later (P<0.05).2. IL-1βcould direct the migration of the cultured neurons in transwell assay. The attractive effect was positively correlated with the concentration of IL-1βin the range of 0.1-10 ng/ml, which could be inhibited by IL-1ra. IL-1βalso affected the direction of neurite and growth cone in growth cone turning assay. Compared to the control, IL-1βwith 1μg/ml triggered an attractive turning of the neurite and growth cone of cultured neurons (P<0.05). Conclusions:1. Expressions of IL-1βand IL-1ra mRNA were elevated in acute and chronic phase of SE, indicating that cytokines were involved in brain damage after epileptic seizures, and might play a role in chronic epilepsy.2. IL-1βcould attract the soma and neurite of neurons in culture, which showed that IL-1βmight contribute to the abnormal migration of neurons after seizures.