Ramipril and ketogenic diet response in cognitive dysfunction of insulin-resistant rats

Nancy Mahmoud Abdel Kareem^1*Shimaa Elshazly²May Abd El Fattah³Sawsan Zaitone⁴Thanaa Elmasry⁵Asmaa Saleh⁶Enas Abd El-Haleim³

• ¹Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sinai University – Arish Branch, Arish 45511, Egypt, Arish, Egypt
• ²Department of Pharmacology & Toxicology, Faculty of Pharmacy, Zagazig University,, Zagazig, Egypt
• ³Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
• ⁴Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
• ⁵Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sinai University – Arish Branch, Arish 45511,, Arish, Egypt
• ⁶Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia., Riyadh, Saudi Arabia

Introduction: High fructose consumption induces insulin resistance (IR), which impairs cognitive functions. Recent studies have recommended the use of ramipril for the treatment of neurological disorders. In the current study, the effects of ramipril on cognitive dysfunction were compared in IR rats fed a ketogenic diet (KD) or normal diet (ND).Methods: Fructose (10%) dissolved in drinking water was administered to the rats for 8 weeks to induce experimental IR. Ramipril (2 mg/kg daily; p.o.) was administered along with the ND or KD for an additional 5 weeks. Cognitive dysfunction was assessed at the end of the experiment using the Morris water maze (MWM) test. One-way and two-way analyses of variance were used for comparisons.Results: The IR+ND group-as a diet control group-displayed a significant improvement in IR at the end of week 13 (1.63±0.12 vs. 1.35±0.06 in normal rats) as determined by the homeostasis model assessment of IR. Further, brain-derived neurotrophic factors, lipid profile, insulin-degrading enzyme activities, and glycogen synthase kinase-3β activity were significantly ameliorated. The IR + KD and IR + ND + ramipril groups did not show significant improvements in most of the measured parameters compared to the normal and IR + ND groups. Notably, the IR + ND + ramipril group demonstrated significantly reduced tau protein and amyloid β (Aβ) levels. Differently, the IR + KD + ramipril group displayed ameliorated metabolic parameters (e.g., the IR index was 1.74±0.13 vs.3.34±0.28 in the IR + ND + ramipril group and that of serum triglycerides was 58.17±1.85 vs. 97.5±2.09 in the IR + ND + ramipril group) with no improvement in the cognitive function parameters.Discussion: Ramipril may be best indicated for the treatment of KD because of its preferable peripheral and central effects. However, KD may be administered for a while, as it can treat accumulated Aβ and tau protein and patients must be aware of its adverse effects.