Simvastatin Restrains Exacerbation of Epilepsy Figure 5 Simvastatin-treatment decreased the frequency of abnormal spikes of epileptic brain. Representative EEG recordings from saline-treated group and simvastatin-treated group at 4 months (A), 5 months (B) and 6 months (C). Quantitative data was presented in (D). *P,0.05, vs. the saline-treated group. doi:10.1371/journal.pone.0024966.g005 the change of astrocytic potassium and calcium-signaling. Reactive astrocytosis is also a source of cytokines including IL-1b, TNF-a, and IL-6 [53]. Reactive astrocytosis may exacerbate inflammation by inducing the migration of other leukocytes into the injured site, interrupting blood-brain-barrier function [54], [55], and produc- ing reactive oxygen species[56], [57] and cytotoxic edema [58]. Therefore, we also investigated the effect of simvastatin-treatment on the extent of reactive astrocytosis after KA-lesion. Our result showed that simvastatin-treatment reduced GFAP-positive astro- cytes in both DH and CA3 area in the hippocampus where neuron loss mainly occurred. This simvastatin-mediated suppression of astrocytosis may contribute to inhibition of neuroinflammation and neuronal loss, thus exert a neuroprotective role in KA-induced injury. Simvastatin attenuates aberrant MFS into the DSGL In both human and animal models of epilepsy, due to the degeneration of pyramidal neurons in CA3 and interneurons in DH, axons of the granular cells (mossy fiber) lose their normal connecting targets and sprout abnormally, which is called aberrant MFS. The extent of MFS is influenced by the degree of neuron loss in CA3 and DH. [59–61]. This is supported by observation that intense MFS occurred associated with extensive loss of CA3 pyramidal neurons and hilar neurons in not only animal models of TLE but also TLE patients. [61], [62–64]. Therefore, decreased neuronal death after simvastatin-treatment in injured hippocam- pus may contribute to reducing MFS. Aberrant sprouting of mossy fiber into DSGL in KA-injured hippocampus is known to contribute to spontaneous seizures [62– 65]. The extent of MFS has been correlated with increased seizure susceptibility of spontaneous seizures [64], [66], [67]. Therefore, we speculate that a lasting suppression of aberrant MFS is likely to reduce the recurrent excitation and seizure susceptibility. In this study, we showed that KA-injured animals with 2-week admin- istration of simvastatin presented a significant decrease in the frequency of discharge in 4–6 month after KA-lesions, which was concurrent with restrained MFS in DG. This observation suggests that simvastatin-treatment could reduce the abnormal discharge of the epileptic brain possibly through restraining the excitation connection derived from aberrant MFS. In addition to MFS, high frequency of spontaneous recurrent motor seizures (SRMS) is also associated with other features of chronic epilepsy, such as extensive loss of inhibitory interneurons in hilar area [68], [69] and changes in neurotransmitters expression by granule cells [70]. PLoS ONE | www.plosone.org 6 September 2011 | Volume 6 | Issue 9 | e24966