Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy Chuncheng Xie1., Jiahang Sun2., Weidong Qiao1, Dunyue Lu3, Lanlan Wei4, Meng Na1, Yuanyuan Song 1 , Xiaohua Hou 5 , Zhiguo Lin1* 1 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China, 2 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China, 3 Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America, 4 Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang, China, 5 Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China Abstract In this study, we examined the effect of chronic administration of simvastatin immediately after status epilepticus (SE) on rat brain with temporal lobe epilepsy (TLE). First, we evaluated cytokines expression at 3 days post KA-lesion in hippocampus and found that simvastatin-treatment suppressed lesion-induced expression of interleukin (IL)-1b and tumor necrosis factor- a (TNF-a). Further, we quantified reactive astrocytosis using glial fibrillary acidic protein (GFAP) staining and neuron loss using Nissl staining in hippocampus at 4–6 months after KA-lesion. We found that simvastatin suppressed reactive astrocytosis demonstrated by a significant decrease in GFAP-positive cells, and attenuated loss of pyramidal neurons in CA3 and interneurons in dentate hilar (DH). We next assessed aberrant mossy fiber sprouting (MFS) that is known to contribute to recurrence of spontaneous seizure in epileptic brain. In contrast to the robust MFS observed in saline-treated animals, the extent of MFS was restrained by simvastatin in epileptic rats. Attenuated MFS was related to decreased neuronal loss in CA3 and DH, which is possibly a mechanism underlying decreased hippocampal susceptibility in animal treated with simvastatin. Electronic encephalography (EEG) was recorded during 4 to 6 months after KA-lesion. The frequency of abnormal spikes in rats with simvastatin-treatment decreased significantly compared to the saline group. In summary, simvastatin treatment suppressed cytokines expression and reactive astrocytosis and decreased the frequency of discharges of epileptic brain, which might be due to the inhibition of MFS in DH. Our study suggests that simvastatin administration might be a possible intervention and promising strategy for preventing SE exacerbating to chronic epilepsy. Citation: Xie C, Sun J, Qiao W, Lu D, Wei L, et al. (2011) Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy. PLoS ONE 6(9): e24966. doi:10.1371/journal.pone.0024966 Editor: Sophie Mouillet-Richard, INSERM, UMR-S747, France Received May 19, 2011; Accepted August 22, 2011; Published September 19, 2011 Copyright: 2011 Xie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Natural Science Foundation of China (81071215), the Science Foundation of Heilongjiang Province (D201062) and the Foreign Collaboration Project of Heilongjiang Province (WB10B104). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: linzhiguo@hotmail.com . These authors contributed equally to this work. Introduction Epilepsy, characterized by recurrent spontaneous seizures, affects 50 million people worldwide [1]. About 30% of epileptic patients have temporal lobe epilepsy (TLE). TLE, which eventually leads to cognitive deficits, can not be controlled by antiepileptic drugs or surgical removal of epileptic focus [2], [3]. Therefore, there is a need to develop an alternative therapeutic treatment to restrain exacerbation from acute status epilepticus (SE) to chronic epilepsy. TLE is associated with neuropathological changes, including hippocampal sclerosis and neurodegeneration, and extensive reorganization of hippocampal circuits [4–8]. Interventions that reduces inflammation cascade and neuron death have been shown to inhibit abnormal spikes and efficacious for restraining TLE after initial precipitating injury (IPI) [9–13]. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and inhibit cellular synthesis of chole- sterol and isoprenoids [14], [15]. Statins have been recognized for their efficacy in reducing serum cholesterol level and prevention of cardiovascular disease, while growing evidence has shown the efficacy of statins in treating neurodegenerative diseases and possibly traumatic brain injury [16]. The neuroprotective efficacy of statins might be related to their properties such as endothelial protection, antioxidant, anti-platelet effects and anti-inflammatory effects [17]. For instance, statins inhibit a number of inflammatory processes during brain damage and suppress the release of cyto- kines including interleukin (IL)-1b and tumor necrosis factor-a (TNF-a) in neurological diseases or animal disease models, such as human multiple sclerosis [16-18], X-adrenoleukodystrophy [19], experimental autoimmune encephalomyelitis [20], [21], Parkin- son’s disease [22], spinal cord injury [23], brain ischemia [24], [25], Alzheimer’s disease [26], metabolic syndrome [27], and acute brain injury [28–30]. A recent study has compared 9 known statins by analyzing parameters possibly related to neuroprotection. Results suggest that simvastatin presents the best characteristics for neuroprotec- PLoS ONE | www.plosone.org 1 September 2011 | Volume 6 | Issue 9 | e24966