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. 2024 Aug 10;17(8):1054.
doi: 10.3390/ph17081054.

Nifedipine Improves the Ketogenic Diet Effect on Insulin-Resistance-Induced Cognitive Dysfunction in Rats

Affiliations

Nifedipine Improves the Ketogenic Diet Effect on Insulin-Resistance-Induced Cognitive Dysfunction in Rats

Nancy M Abdel-Kareem et al. Pharmaceuticals (Basel). .

Abstract

Insulin resistance, induced by high fructose consumption, affects cognitive function negatively. Nifedipine may be suggested for neurological disorders. This study aimed to assess the effect of nifedipine with either a normal diet (ND) or a ketogenic diet (KD) in cognitive dysfunction. Male Wistar rats received 10% fructose in drinking water for 8 weeks to induce insulin resistance. Rats received nifedipine (5.2 mg/kg/day; p.o.) later with ND or KD for an additional five weeks. One and two-way ANOVAs were used in analyzing the data. Reversion to the ND improved insulin resistance and lipid profile, besides brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 beta (GSK3β), and insulin-degrading enzyme (IDE) levels. Rats fed KD alone and those that received nifedipine with KD did not show similar improvement in the previously mentioned parameters as the ND group. However, nifedipine-ND rats showed improvement in cognitive behavior and insulin resistance. Treatment with nifedipine-KD ameliorated GSK3β, amyloid β (Aβ), and tau protein levels. As the nifedipine-KD combination succeeded in diminishing the accumulated Aβ and tau protein, KD may be used for a while due to its side effects, then nifedipine treatment could be continued with an ND. This conclusion is based on the finding that this combination mitigated insulin resistance with the associated improved behavior.

Keywords: cognitive dysfunction; fructose; insulin resistance; ketogenic diet; nifedipine.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Effect of the normal diet (ND) and the ketogenic diet (KD) with or without nifedipine (5.2 mg/kg/day, p.o.) on the body weight difference, Final weight of IR at the end of the experiment— their weights after 8 weeks’ treatment with 10% fructose in insulin-resistant (IR) rats. Data are represented as median and interquartile percent (25–75%) and analyzed using one-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats; # p ≤ 0.05 vs. IR + ND; @ p ≤ 0.05 vs. IR + ketogenic diet; and + p ≤ 0.05 vs. IR + ND + nifedipine group.
Figure 2
Figure 2
Effect of 10% fructose treatment after 8 weeks on the oral glucose tolerance test (OGTT). Blood glucose levels were evaluated before glucose administration and after administration of 2.5 mg/kg glucose at 30, 60, and 90 min. Results are represented as the median and interquartile range (min. to max.) (n = 6) and analyzed using two-way ANOVA followed by the Bonferroni test, with * p ≤ 0.05 vs. normal rats.
Figure 3
Figure 3
Effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on the behavioral response in IR rats. Results are represented as median and interquartile range (min. to max.) (n = 6) and analyzed using two-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats.
Figure 4
Figure 4
Effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on serum lipid profile: (a) Cholesterol, (b) triglycerides, (c) high-density lipoprotein (HDL), and (d) low-density lipoprotein (LDL) (d) in (IR) rats. Results are represented as median and interquartile range (min. to max. with all points) (n = 6) and analyzed using one-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats; # p ≤ 0.05 vs. IR + ND; and @ p ≤ 0.05 vs. IR + ketogenic diet.
Figure 5
Figure 5
Effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on the brain-derived neurotrophic factor (BDNF) in the brain hippocampus of IR rats. Results are represented as median and interquartile range (25–75%) (n = 6) and analyzed using one-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats.
Figure 6
Figure 6
Effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on (a) glycogen synthase kinase-3 beta (GSK3β) and (b) insulin-degrading enzyme (IDE) in the brain hippocampus of IR rats. Results are represented as median and interquartile range (25–75%) (n = 6) and analyzed using one-way ANOVA followed by the Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats; # p ≤ 0.05 vs. IR + ND; @ p ≤ 0.05 vs. IR + ketogenic diet; and + p ≤ 0.05 vs. IR + ND + nifedipine group.
Figure 7
Figure 7
Effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on histopathological examinations of insulin-resistant rats. Photomicrographs of hematoxylin-and-eosin-stained (a): for cerebral cortex and (b): for hippocampus slices from various groups. (A) Brain tissue that is uniform and without any neuronal damage. Grade 0 for both tissues. (B) The perineuronal edema and neurons with pyknotic nuclei (black arrows), Rosenthal fibers may be seen in gliosis (black arrowheads) regions, and the red arrows represent red neurons for both cerebral cortex and hippocampus, 75% of brain tissue. Grade 3 for both tissues. (C) Red arrows indicate that there are a few scattered red neurons, for both the cerebral cortex and hippocampus. For the cerebral cortex only, tissue edema (red arrowheads) is seen. The red neurons are sparsely distributed (red arrow). Perineuronal edema (black arrows), tissue edema (red arrowheads), and gliosis (black arrowheads) are all seen, 25% of brain tissue. Grade 2 for both tissues. (D) The red neurons are sparsely distributed (red arrow). Perineuronal edema (black arrows), tissue edema (red arrowheads), and gliosis in cerebral cortex only (black arrowheads) are all seen in both tissues, 45% of brain tissue. Grade 3 for cerebral cortex and 15% of brain tissue for hippocampus. Grade 2. (E) Neurons in cerebral cortex and hippocampus with pyknotic nuclei and perineuronal edema are seen (black arrows), 10% of brain tissue. Grade 1 for both tissues. There are gliosis regions with Rosenthal fibers in cerebral cortex only (black arrowheads). There are red neurons (shown by red arrows). Pictures captured at magnification power ×40 for cerebral cortex and ×20 for hippocampus.
Figure 8
Figure 8
(a,b) (A) Weak focal levels of Aβ (black arrows). (B) Significant increase in levels of Aβ (black arrows). (C) Significant reduction in levels of Aβ (black arrows). (D) Significant increase in levels of Aβ (black arrows). (E) Weak focal levels of Aβ (black arrows). Pictures captured at magnification power ×40 for cerebral cortex and 20× for hippocampus. (c,d) (A) Weak levels of tau in the cytoplasm of a few neuron cells (black arrows). (B) There is an increase in the levels of tau in many neurons (black arrows). (C) There is a reduction in the levels of tau in many neurons (black arrows). (D) There is an increase in the levels of tau in many neurons (black arrows). (E) There are weak levels of tau in cytoplasm of some neurons (black arrows) in cerebral cortex while a significant increase in the levels of tau in cytoplasm of some neurons (black arrows). Pictures captured at magnification power ×40 for cerebral cortex and 20× for hippocampus. Statistical analysis showed the effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on immunohistochemical staining of cerebral cortex and hippocampal levels of amyloid β (Aβ) (e,f) and tau protein (g,h) of insulin-resistant rats. Results are represented as median and interquartile range (25–75%) (n = 6) and analyzed by one-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats; # p ≤ 0.05 vs. IR + ND; @ p ≤ 0.05 vs. IR + ketogenic diet; and + p ≤ 0.05 vs. IR + ND + nifedipine group.
Figure 8
Figure 8
(a,b) (A) Weak focal levels of Aβ (black arrows). (B) Significant increase in levels of Aβ (black arrows). (C) Significant reduction in levels of Aβ (black arrows). (D) Significant increase in levels of Aβ (black arrows). (E) Weak focal levels of Aβ (black arrows). Pictures captured at magnification power ×40 for cerebral cortex and 20× for hippocampus. (c,d) (A) Weak levels of tau in the cytoplasm of a few neuron cells (black arrows). (B) There is an increase in the levels of tau in many neurons (black arrows). (C) There is a reduction in the levels of tau in many neurons (black arrows). (D) There is an increase in the levels of tau in many neurons (black arrows). (E) There are weak levels of tau in cytoplasm of some neurons (black arrows) in cerebral cortex while a significant increase in the levels of tau in cytoplasm of some neurons (black arrows). Pictures captured at magnification power ×40 for cerebral cortex and 20× for hippocampus. Statistical analysis showed the effect of the ND and KD with or without nifedipine (5.2 mg/kg/day, p.o.) on immunohistochemical staining of cerebral cortex and hippocampal levels of amyloid β (Aβ) (e,f) and tau protein (g,h) of insulin-resistant rats. Results are represented as median and interquartile range (25–75%) (n = 6) and analyzed by one-way ANOVA followed by Tukey–Kramer test, with * p ≤ 0.05 vs. normal rats; # p ≤ 0.05 vs. IR + ND; @ p ≤ 0.05 vs. IR + ketogenic diet; and + p ≤ 0.05 vs. IR + ND + nifedipine group.
Figure 9
Figure 9
A schematic presentation for the results of the study.

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The authors would like to thank AlMaarefa University, Riyadh, Saudi Arabia for supporting this research.

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