Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death

Abstract

Statins are inhibitors of HMG-CoA reductase that have been recently recognized as antiinflammatory and neuroprotective drugs. Herein, we investigated anti-excitotoxic and anti-seizure effects of statins by using kainic acid (KA)-rat seizure model, an animal model for temporal lobe epilepsy and excitotoxic neurodegeneration. We observed that pretreatment with Lipitor (atorvastatin) effeiciently reduced KA-induced seizure activities, hippocampal neuron death, monocyte infiltration and proinflammatory gene expression. In addition, we also observed that lovastatin treatment attenuated KA-or glutamate-induced excitotoxicity of cultured hippocampal neurons. These observations suggest a potential for use of statin treatment in modulation of seizures and other neurological diseases associated with excitotoxicity.

Bi-lateral changes to hippocampal cholesterol levels during epileptogenesis and in chronic epilepsy following focal-onset status epilepticus in mice

“…3. Discussion Previous studies have suggested that the statin class of cholesterol synthesis inhibitors are capable of protecting against hippocampal injury in models of seizure--induced neuronal death (He et al, 2006, Lee et al, 2008, Piermartiri et al, 2009, Rangel et al, 2005and Xie et al, 2011. Statin treatment has been shown to reduce cell death in the hippocampus in mice with quinolinic acid--induced seizures and in rats with pilocarpine and KA--induced seizures.…”

“…Lovastatin treatment does not prevent hippocampal damage caused by intra--amygdala KA--induced status epilepticus Statins have been reported to have potent neuroprotective effects against seizure--induced neuronal death in rats (Lee et al, 2008, Ohyama et al, 2006and Rangel et al, 2005. To test if lovastatin treatment has such an effect in the present model, mice were treated for three consecutive days with lovastatin using a dose previously shown to lower brain cholesterol in animal models (Lee et al, 2008). On the fourth day, mice received lovastatin before and after being subjected to KA--induced status epilepticus, and then received lovastatin again on the two subsequent days.…”

“…We recently reported that brief seizures in mice increase the expression of StAR--related lipid transfer domain containing 4 (Stard4), which can bind cholesterol and is involved in intracellular cholesterol transport ( Hatazaki et al, 2007). A number of studies have also explored the effects of statins on seizure--induced neuronal death ( He et al, 2006, Lee et al, 2008and Xie et al, 2011. Statins competitively inhibit the rate--limiting enzyme in cholesterol synthesis, 3--hydroxy--3--methylglutaryl coenzyme--A reductase (HMGCR), and are a commonly prescribed as cholesterol--lowering agent.…”

“…Statins competitively inhibit the rate--limiting enzyme in cholesterol synthesis, 3--hydroxy--3--methylglutaryl coenzyme--A reductase (HMGCR), and are a commonly prescribed as cholesterol--lowering agent. Atorvastatin has been reported to reduce hippocampal neuronal death in rodent models of excitotoxicity in vivo ( Lee et al, 2008 andPiermartiri et al, 2009) and lovastatin treatment of rats reduced sterol levels and increased neuronal survival after status epilepticus ( He et al, 2006).…”

“…Brains were collected 72 h after status epilepticus. Because previous studies have reported that statins can alter seizure severity ( Lee et al, 2008), the EEG was recorded for 40 min after KA injection until administration of the anticonvulsant lorazepam and quantified to define the durations of injury--causing electrographic seizures. Lovastatin treatment had no observable effect on the duration or severity of electrographic seizures during status epilepticus induced by intra--amygdala KA ( Fig.…”