Simvastatin Restrains Exacerbation of Epilepsy Figure 4. Comparison of KA-lesion induced MFS using Timm’s staining in DH. The extent of aberrant MFS in saline-treated group with severe hippocampal injury (A1and A2), simvastatin-treated group with moderate hippocampal injury (B1 and B2) and in comparison with rats with intracerebroventricular saline injection (C1 and C2), visualized by Timm’s histochemical staining. Quantitative data for width and density of sprouting into DSGL were presented in (D and E). GCL, granule cell layer, UB, upper blade; LB, lower blade. Scale bars = 500 mm in A1 and 200 mm in A2. (*P,0.05, vs. the simvastatin-treated group). doi:10.1371/journal.pone.0024966.g004 cytokine involved in epileptogenesis, has been reported to increase seizure susceptibility in rats brain [42]. Intracerebral injection of high dose IL-1b, which is sufficient to generate limbic seizures in wild type mice, fails to cause seizures in transgenic mice with deficient IL-1b receptors [43]. The effect of IL-6 in epileptic brain is still controversial. Some studies indicate that IL-6 might be neuroprotective through activating the synthesis of corticotrophin and glucocorticoids, and initiating an anti-inflammatory feedback loop [44], [45]. Therefore, manipulating level of cytokines in inflammatory cascades could have a potential effect on KA- induced injury. Previous studies suggest a role of simvastatin in suppression of cytokines by regulating nuclear factor-kB transcription pathway [46] and decreasing isoprenylation protein involved in cellular signaling [47] or Rac1/PI3K/PKB-dependent caspase-1 activa- tion [48]. In this study, we observed simvastatin-induced decrease in IL-1 b and TNF-a in injured hippocampus as early as 3 days after KA-lesion. The reduction of IL-1 b and TNF-a in early stage after injury attenuates secondary inflammation damage, which may contribute to the improvement of pathological changes in hippocampus. Our founding supports the hypothesis that simvastatin-mediated early suppression of the inflammatory cascade may result in a marked reduction in secondary neuronal damage after SE. Evidence has also shown that simvastatin-treatment increases brain-derived neurotrophic factor (BDNF)expression in hippo- campus after traumatic brain injury (TBI) [34]. Moreover, supplementation of BDNF attenuates astrocytosis and IL-1b expression after status epilepticus [49]. Therefore, the neuropro- tective effect of simvastatin observed in this study may be also related to increased BDNF level that prevents neurons from lesion- induced degeneration. Thus, both anti-inflammation and neuro- trophy effect of simvastatin may contribute to its neuroprotective role found in our study. Astrocytes also play a critical role in epileptogenesis [50–52], particularly in chronic relapsing forms, which is associated with PLoS ONE | www.plosone.org 5 September 2011 | Volume 6 | Issue 9 | e24966