Objective: To examine the potential efficacy of statin treatment in reducing the risk of poststroke seizures. Methods: In this cohort study, patients with a first-ever ischemic stroke and no history of epilepsy before stroke were enrolled. After a mean follow-up period of 2.5 years, a follow-up assessment was performed to identify poststroke epilepsy. Logistic regression and Cox regression analyses were used to assess the relationship between statin use and poststroke early-onset seizures or poststroke epilepsy. Results: Of 1,832 enrolled patients, 63 (3.4%) patients had poststroke early-onset seizures and 91 (5.0%) patients had poststroke epilepsy. Statin use was associated with a lower risk of poststroke early-onset seizures (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.20–0.60, p < 0.001), and this reduced risk was seen mainly in patients who used a statin only in the acute phase (OR 0.36, 95% CI 0.20–0.62, p < 0.001). No significant association was found between statin use and poststroke epilepsy (OR 0.81, 95% CI 0.52–1.26, p = 0.349). In 63 patients who presented with early-onset seizures, statin use was associated with reduced risk of poststroke epilepsy (OR 0.34, 95% CI 0.13–0.88, p = 0.026). Conclusions: Statin use, especially in the acute phase, may reduce the risk of poststroke early-onset seizures. In addition, statin treatment may prevent the progression of initial poststroke seizure-induced neurodegeneration into chronic epilepsy. Because of the observational nature of the study, more studies are needed to confirm the results. Classification of evidence: This study provides Class III evidence that in patients with a first-ever ischemic stroke, the early use of statins reduces the risk of early poststroke seizures.

Background: Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na⁺/H⁺ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Methods: Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Results: Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP⁺ astrocytes and Iba1⁺ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Conclusion: Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.