Virus-Host Interactions that Lead to Epilepsy

描述（由申请人提供）：中枢神经系统（CNS）的病毒感染通常导致脑炎。病毒性脑炎是癫痫（反复发作）的显著危险因素。癫痫的发病率约为1-3%，在美国约有2.5 x 106人，在全世界有超过5.0 x 107人。简单地说，癫痫发作是由于大脑内兴奋性和抑制性输入之间的不平衡造成的。脑炎及其引起的损伤，特别是对海马体的损伤，可以改变这些联系。感染引发的癫痫性疾病通常对许多已建立的抗癫痫药物是难治的。大约30%的癫痫患者对现有的抗癫痫药物无效。因此,

DESCRIPTION (provided by applicant): Viral infections of the central nervous system (CNS) often result in encephalitis. Viral encephalitis is a marked risk factor for epilepsy (recurrent seizures). Epilepsy has an incidence of about 1-3% and affects about 2.5 x 106 Americans and more than 5.0 x 107 individuals worldwide. Simplistically, seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage, particularly to the hippocampus, can alter these connections. Infection-initiated seizure disorders are often refractory to many established antiepileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new and novel biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in acute seizures and later epilepsy. These viruses include herpes viruses such as human herpes virus type-6 as well as influenza viruses, West Nile virus, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with acute seizures. A problem that has plagued this field is that a good experimental animal model has not been available to investigate how viral encephalitis and acute seizures can subsequently lead to epilepsy. Previous animal models have used rabbits, rats and mice infected with different viruses. These animals develop encephalitis where acute seizures are observed, but infected animals succumb to the infection or do not subsequently develop spontaneous seizures, making it difficult to investigate the viral etiology of epilepsy. Theiler's murine encephalomyelitis virus (TMEV) is a murine neurotropic picornavirus. We feel it is important to study virus-host interactions using the virus in its naturl host. We have developed a new and novel model where TMEV- infected C57BL/6 mice develop acute seizures between day 3 and 10 post infection. Early infiltrating macrophages producing interleukin (IL)-6 are implicated in the development of acute seizures. Viral antigen positive cell (neurons) are cleared by day 14 and viral genomes are undetectable in the CNS of mice by about day 28 post infection. Therefore, mice recover from the acute seizures and, after a variable latent period, mice start to have recurrent seizures (epilepsy). This is the first infectin driven model of temporal lobe epilepsy. In Specific Aim 1, we will elucidate the mechanism of the induction of seizures. In Specific Aim 2, we propose to define the functional link between IL-6 and changes in neuronal excitability. In Specific Aim 3, we will investigate the effects of wogonin and minocycline, compounds that block (IL-6-producing) macrophage infiltration into the CNS, on both acute seizures and recurrent seizures when administered at various time points post infection with the goal of prevention, interrupting or reversing the occurrence of acute and/or recurrent seizures.