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Combination of atorvastatin and ezetimibe reduces neuronal cell death and cerebral hemorrhage in rat model with transient hemispheric ischemia

  • 서동기 (아주대학교 일반대학원)

초록/요약

Despite the high mortality and morbidity associated with ischemic stroke, no neuroprotective agents have been identified that can provide satisfactory results. Among these, statins have shown efficacy in various clinical contexts, including the management of hyperlipidemia, metabolic syndrome, and cardiovascular disease. In clinical practice, ezetimibe is often added to statins as a modulator with lipid- lowering, anti-inflammatory and neuroprotective properties. Nevertheless, higher doses of statins have been demonstrated in clinical trials to be significantly associated with an increased risk of cerebral hemorrhage, despite their efficacy in lowering cholesterol and conferring neuroprotective benefits. The occurrence of statin-induced hemorrhage has been well-documented in previous SPARCL (The Stroke Prevention by Aggressive Reduction of Cholesterol Levels) study. Therefore, in this study, we will investigate the inhibition of cerebral hemorrhage and additional neuroprotective effects of combination therapy with statins and ezetimibe in an ischemia-reperfusion rodent model. The rats were randomly assigned to one of six experimental groups. The groups were as follows: a sham group, a vehicle group without drug, a statin-only group (20 mg/kg), an ezetimibe-only group (10 mg/kg), a high-dose statin group (20 mg/ The remaining groups were a low-dose statin group (10 mg/kg) and an ezetimibe group (10 mg/kg) (n=5 to 11, respectively). Ischemia- reperfusion was induced by transient middle cerebral artery occlusion (t-MCAO) 90- minute model. The survival rate, body weight, and neurological behaviors were evaluated from 7 days preoperatively to 3 days postoperatively after the procedure. Drugs were administered one hour before these assessments. The animals were then sacrificed 3 days after the procedure, and an experiment was conducted immediately to confirm the histological changes (neuronal cell death, inflammation, vessel permeability). As a consequence, the infarct volume was markedly diminished in the sole statin and low- dose statin combination ezetimibe groups in comparison to the vehicle control. Similarly, the low-dose statin combination ezetimibe group demonstrated a significant reduction in neuronal damage (NeuN-positive cells) in the cortex when compared to the vehicle control. Furthermore, the results of cell apoptosis (cresyl violet negative) demonstrated significant differences within the aforementioned group. The results of the GFAP-positive test, which is used as an astrocyte activation marker, demonstrated a notable discrepancy between the drug groups and the vehicle control group about the inflammatory response. However, the Iba-1 results, which indicate microglia activation, did not yield statistically significant findings across all drug groups. No significant results were observed in the RECA-1 assay, which assesses vascular damage. However, the MMP-2 assay, which monitors vessel permeability, revealed notable differences between the ezetimibe group and the low-dose statin combination ezetimibe group, compared to the vehicle control. In conclusion, the findings of this study support the hypothesis that the use of low-dose statins is beneficial when statins are used in combination with ezetimibe in ischemic reperfusion stroke environments. Furthermore, the results suggest that low-dose statin combination therapy in ischemic reperfusion environments may have additional neuroprotective effects in the context of stroke. Keyword: statin, ezetimibe, ischemic-reperfusion, neuroprotection, hemorrhage

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목차

INTRODUCTION 1
MATERIAL AND METHODS 5
A. Animal care procedures 5
B. Animal models 5
C. Group of experimental animals 6
D. Neurological animal behavior assessment 6
E. Brain infarct size measurement 7
F. Tissue sampling 7
G. Immunohistochemistry 8
H. Cresyl violet staining 9
I. Statistical analysis 9
RESULTS 11
A. Selection of duration of medication 11
B. A comparison of the impact of reducing infarct volume and neuron apoptosis with regard to drug dosage and combination 13
C. A comparison of the impact of reducing inflammation with regard to drug dosage and combination 16
D. A comparative analysis of the influence of reducing vessel damage and hemorrhage on drug dosage and combination 18
DISCUSSION 21
CONCLUSION 25
REFERENCE 26
국문요약 32

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