Joseph W. Driver

Introduction. Strokes remain at the forefront of known conditions that cause epilepsy in older adults. With millions of strokes occurring yearly, up to 30% of those affected experience a resultant late-onset seizure and 4-6% of them will develop chronic post-stroke epilepsy (PSE).^1,2 Damage caused by strokes activate a multitude of destructive signaling events causing structural and functional abnormalities in neuronal networks and resulting in glutamate hyperexcitability and seizures.³ As 1/3 of PSE patients are refractory to standard anti-epileptic therapy and no current preventative treatment exists, statin drugs are beginning to be investigated for their neuroprotective effects as novel adjuncts to AEDs and potential therapy to prevent progression to PSE.^1,3,4 Methods. To evaluate the role of statins in NMDAR response and glutamate excitotoxicity, rat cerebellar granule cells were subjected to cholesterol depletion and upon exposure to glutamate, electrophysiological whole cell response was measured via the patch-clamp technique.⁵ Cell desensitization was then determined by measuring NMDA receptor current in the presence of open-channel blocker, MK-801.⁵ Glutamate uptake, with proposed modulation via the MEK/ERK₁ pathway, in the presence of a statin was evaluated using scintillation counting in the presence and absence of MEK/ERK₁ pathway inhibitor, PD98059.⁶ Regarding cell survival, activated Akt was determined by western blotting and quantified by Scion Image software.⁶ Attenuation of neuroinflammation was then assessed by determining involvement of lipocalin-2 and COX2 via western blotting and immunostaining.⁷ Results. Reduced amplitude of NMDAR responses and increases in receptor desensitization were observed in cholesterol-depleted cells compared to control.⁵ Additionally, NMDAR current time course was slowed in cholesterol-depleted cells in presence of MK-801, suggesting less peak open probability of NMDARs in cholesterol-depleted cells.⁵ Furthermore, cholesterol-depletion reduced NMDA uptake and promoted glutamate clearance specifically by activation of ERK₁, causing a neuroprotective effect.⁶ Increased activation of Akt, which promotes cell survival, was also seen in cholesterol-depleted cells.⁶ Lastly, statins were found to attenuate proinflammatory cytokines behind the expression of COX2 that activate glial cells and were responsible for decreased LCN2 expression which attenuates reactive astrocytes and neural cell death.⁷ Discussion. Overall, moderate to high dose statins appear to be beneficial in reducing the risk of development of PSE due to their neuroprotective effects which include decreased neuronal excitotoxicity via modulation of NMDA receptor response and sensitization, modulation of glutamate uptake via the MEK/ERK₁ pathway, decreased neuronal cell death via the Akt cell survival pathway, and reduction of neuroinflammation through effects surrounding lipocalin-2 and COX2.^3-9

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