id_883. EFFECTS OF LONG-TERM USE OF 3-HYDROXY-3-METHYLGLUTARYL–COENZYME A REDUCTASE INHIBITORS (STATINS) ON COGNITION AND GLUCOSE METABOLISM IN HYPERCHOLESTEROLEMIC MOUSE MODEL
Emilia Czabrowska1, Joanna Osika1, Oliwia Kmieć1, Hanna Smukowska1, Iga Łobińska1, Aniela Rękawek1, Przemysław Kowiański1,2, Grażyna Lietzau1
1 Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
2 Institute of Health Sciences, Pomeranian University in Słupsk, Bohaterów Westerplatte 64, 76-200 Słupsk, Poland
INTRODUCTION: Statins are widely prescribed for dyslipidemia. Some evidence links long-term statin use to an increased risk of type 2 diabetes mellitus (T2DM) and cognitive impairment.
AIM(S): This study aimed to assess whether long-term statin use induces or exacerbates T2DM and affects memory and learning processes in hypercholesterolemic and non-hypercholesterolemic mice.
METHOD(S): Four-month-old male C57BL/6J mice were randomly assigned to one of two groups: SD (standard diet-fed, n=20) and HCD (high-cholesterol diet-fed, n=28). After 5 months, the mice were gavaged with either simvastatin (SMV, 5 mg/kg) or vehicle (VEH, 0.9% NaCl) for 20 weeks and assigned to four groups: SDVEH, SDSMV, HCDVEH, HCDSMV. To assess if SMV affects diabetic-related parameters, fasting glucose and insulin, insulin tolerance test, and HOMA index were evaluated. Cognitive functions were assessed after 12 weeks using Barnes Maze (BM) and Novel Object Recognition Test (NORT).
RESULTS: Results showed an elevated HOMA-IR value (>1) in SDSMV and SDVEH mice, suggesting mild insulin resistance. This effect was age-related. Glucose levels were elevated in both HCD groups, with no difference between them, indicating that SMV did not affect hyperglycemia. However, HCDSMV mice had significantly lower HOMA-IR compared with HCDVEH (2.7±0.62 vs. 4.2±1.89, p=0.02), indicating that SMV improves insulin sensitivity. BM results showed that HCDSMV mice, compared to HCDVEH mice, had decreased escape latency over the three-day period (p=0.002, p=0.0006 and p=0.01), which suggests that SMV improves spatial learning. Additionally, HCDVEH mice demonstrated impairment of short-term reference memory (p=0.006). SMV administration did not alter this parameter. No group differences were observed in the NORT.
CONCLUSIONS: In conclusion, long-term simvastatin administration did not induce or exacerbate T2DM but improved insulin sensitivity. Additionally, simvastatin reversed HCD-induced spatial learning deficits but had no effect on reference and recognition memory.
FINANCIAL SUPPORT: This study was supported by the National Science Centre (NCN): 2023/07/X/NZ7/01480