Simvastatin Restrains Exacerbation of Epilepsy Figure 3. Hippocampal cytoarchitecture visualized with Nissl staining. A1, A2, A3 and A4 showed hippocampal regions from rats with intracerebroventricular saline injection. B1, B2, B3 and B4 showed regions of hippocampus from KA-injured rat followed by simvastatin treatment. C1, C2, C3 and C4 showed hippocampal regions from KA-injured rat followed by saline-treatment. D showed quantitative data of the number of neurons in DH and CA3. scale bar = 400 mm in A1 (applies to B1, C1, A3, B3, C3); scale bar = 100 mm in A2 (applies to B2, C2, A4, B4, C4 ). (* P,0.05, vs. control group, # P,0.05, vs simvastatin-treated group). doi:10.1371/journal.pone.0024966.g003 57.866.4/min, 5 months: 59.3467.8/min, and 6 months: 61.468.6/min). These results suggest that simvastatin-treatment in injured hippocampus could reduce the abnormal discharge of the epileptic brain. Statin attenuates seizure behavior induced by kainic acid In the present study, we observed seizure behavior (seizure score) at 4-6 months after KA injection (i.c.v) (Fig. 6). The rats were orally treated 0.5 h with simvastatin (1 mg/kg) after KA injection (1.0 ml of KA. i.c.v). Simvastatin attenuated the seizure score. Seizure activity was rated according to the Racine’s scale: Stage I, facial clonus; Stage II, nodding and wet dog shaking; Stage III, unilateral forelimb clonus with lordotic posture; Stage IV, lateral forelimb clonus with rearing; Stage V, bilateral forelimb clonus with rearing, jumping, and falling. Discussion In this study, we found that 14-day simvastatin-treatment immediately after KA-lesion was effective in long-term inhibition of TLE until 6 months, which might be due to the suppression of reactive astrogliosis and neuroinflammation. Simvastatin treat- ment also attenuated aberrant MFS from granular cells in DH, which may lead to decreased discharges of epileptic brain. These findings suggest that simvastatin could reduce KA-induced lesion in hippocampus and simvastatin administration may become a possible intervention for impeding the progression of status epilepticus to chronic epilepsy. Simvastatin inhibits neuroinflammation and reduces reactive astrocytosis Pro-inflammatory cytokines play key roles in the epileptogenic cascade [9–13], [36–38] including seizure-related pathological changes in hippocampus, such as neuronal death, reactive gliosis and abberant mossy fiber sprouting. In rat model of KA-induced epilepsy, injury in hippocampus occurs accompanied by upregula- tion of cytokines including TNF-a and IL-1 in glial cells. Production of cytokines further precedes neuronal degeneration [39], [40]. Reducing TNF-a level by employing thalidomide has showed effective antiepileptic activity [41]. IL-1b, another critical PLoS ONE | www.plosone.org 4 September 2011 | Volume 6 | Issue 9 | e24966