Eriodictyol Ameliorates Biochemical and Histopathological Abnormalities in the Hippocampal Brain Region of Fructose/Streptozotocin-Induced Type-2 Diabetic Rats

Abstract

Eriodictyol offers essential protection to the brain but its effect in diabetes-induced neurologic dysfunction is poorly known. Diabetes was induced in male Wistar rats by administering 10% fructose in the drinking water for fourteen days followed by single intraperitoneal injection of 40 mg/kg body weight streptozotocin. Separate groups of diabetic rats were post-treated with varying doses of eriodictyol (0.25, 0.5 and 1.0 mg/kg) for 14 days. Thereafter, the animals were sacrificed; the hippocampi were carefully separated and processed for biochemical estimations and histopathological examination. The weight, blood glucose level, and glycated hemoglobin were determined using standard methods. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), Acetylcholinesterase (AChE) and  Na⁺/K⁺-ATPase activities were evaluated. Reduced glutathione (GSH), protein carbonyl (PC) levels and the extent of lipid peroxidation (LPO) were also evaluated. Also, histopathological examination was carried out on the hippocampi brain region. Eriodictyol significantly (p<0.0001) reduced the high blood glucose level and glycated hemoglobin in the diabetic rats. There was a significant (p<0.0001) increase in SOD, CAT, GPx, Na⁺/K⁺-ATPase activities and weight as well as GSH level but, decrease in AChE activity and extent of LPO, and PC levels of diabetic rats post-treated with the flavonoid. These results were consistent with the histopathological findings which showed significant attenuation of neuronal cell death in diabetic rats post-treated with the flavonoid. The data established for the first time, the ameliorative potential of eriodictyol on oxidative imbalance and histopathological changes against fructose/stz-induced type-2 diabetic rats.

References

1. Antar, S.A.; Ashour, N.A.; Sharaky, M.; Khattab, M.; Ashour, N.A.; Zaid, R.T.; Al-Karmalawy, A.A. Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments. Biomed. Pharmacother. 2023, 168, 115734.
2. Kropp, M.; Golubnitschaja, O.; Mazurakova, A.; Koklesova, L.; Sargheini, N.; Vo, T.T.K.S.; Thumann, G. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications—risks and mitigation. EPMA J. 2023, 14 (1), 21–42.
3. Bellary, S.; Kyrou, I.; Brown, J.E.; Bailey, C.J. Type 2 diabetes mellitus in older adults: clinical considerations and management. Nat. Rev. Endocrinol. 2021, 17 (9), 534–548.
4. Álvarez-Rendón, J.P.; Murillo-Maldonado, J.M.; Riesgo-Escovar, J.R. The insulin signaling pathway a century after its discovery: sexual dimorphism in insulin signaling. Gen. Comp. Endocrinol. 2023, 330, 114146.
5. Dienel, G.A. Brain glucose metabolism: integration of energetics with function. Physiol. Rev. 2019, 99 (1), 949–1045.
6. Gupta, M.; Pandey, S.; Rumman, M.; Singh, B.; Mahdi, A.A. Molecular mechanisms underlying hyperglycemia associated cognitive decline. IBRO Neurosci. Rep. 2022, 14, 57–63.
7. Marinho, L.S.R.; Ikebara, J.M.; Higa, G.S.V.; de Lima Vasconcellos, T.H.; Inês, M.; Móvio, S.H.T.; Kihara, A.H. Function of the nervous system. Handb. Neural Eng. 2024, 17.
8. Fogwe, L.A.; Reddy, V.; Mesfin, F.B. Neuroanatomy, Hippocampus. StatPearls 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482171/
9. Abraham, W.C.; Jones, O.D.; Glanzman, D.L. Is plasticity of synapses the mechanism of long-term memory storage? NPJ Sci. Learn. 2019, 4 (1), 9.
10. Chandra, S.R. Alzheimer's disease: An alternative approach. Indian J. Med. Res. 2017, 145 (6), 723–729.
11. Chokron, S.; Kovarski, K.; Dutton, G.N. Cortical Visual Impairments and Learning Disabilities. Front. Hum. Neurosci. 2021, 15, 713316.
12. Khan, M.S.; Khan, S.; Khan, N.; Khan, A.S. Dietary sources, classification, biosynthesis, and mechanism of action of flavonoids in combating oxidative stress. Role Flavonoids Chronic Metab. Dis. 2024, 67–114.
13. Muscolo, A.; Mariateresa, O.; Giulio, T.; Mariateresa, R. Oxidative stress: the role of antioxidant phytochemicals in the prevention and treatment of diseases. Int. J. Mol. Sci. 2024, 25 (6), 3264.
14. Devi, S.; Kumar, V.; Singh, S.K.; Dubey, A.K.; Kim, J.J. Flavonoids: Potential candidates for the treatment of neurodegenerative disorders. Biomedicines 2021, 9 (2), 99.
15. de Lima, E.P.; Moretti Jr, R.C.; Torres Pomini, K.; Laurindo, L.F.; Sloan, K.P.; Sloan, L.A.; Barbalho, S.M. Glycolipid Metabolic Disorders, Metainflammation, Oxidative Stress, and Cardiovascular Diseases: Unraveling Pathways. Biology 2024, 13 (7), 519.
16. Obafemi, T.O.; Akinmoladun, A.C.; Olaleye, M.T.; Agboade, S.O.; Onasanya, A.A. Antidiabetic potential of methanolic and flavonoid-rich leaf extracts of Synsepalum dulcificum in type 2 diabetic rats. J. Ayurveda Integr. Med. 2017, 8 (4), 238–246.
17. Tapas, A.R.; Sakarkar, D.M.; Kakde, R.B. Flavonoids as nutraceuticals: a review. Trop. J. Pharm. Res. 2008, 7 (3), 1089–1099.
18. John, W.G.; Scott, K.W.; Hawcroft, D. Glycated haemoglobin and glycated protein and glucose concentrations in necropsy blood samples. J. Clin. Pathol. 1988, 41 (4), 415–418.
19. Beutler, E.; Mary, K.Y. Erythrocyte glutathione reductase. Blood 1963, 21 (5), 573–585.
20. Haque, M.E.; Asanuma, M.; Higashi, Y.; Miyazaki, I.; Tanaka, K.I.; Ogawa, N. Overexpression of Cu–Zn superoxide dismutase protects neuroblastoma cells against dopamine cytotoxicity accompanied by increase in their glutathione level. Neurosci. Res. 2003, 47 (1), 31–37.
21. Pandey, R.K.; Maranville, J.W.; Chetima, M.M. Tropical wheat response to irrigation and nitrogen in a Sahelian environment. II. Biomass accumulation, nitrogen uptake and water extraction. Eur. J. Agron. 2001, 15 (2), 107–118.
22. Kakkar, P.; Das, B.; Viswanathan, P.N. A modified spectrophotometric assay of superoxide dismutase. Indian J. Biochem. Biophys. 1984, 21 (2), 130–132.
23. Varshney, R.; Kale, R.K. Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int. J. Radiat. Biol. 1990, 58 (5), 733–743.
24. Levine, R.L.; Garland, D.; Oliver, C.N.; Amici, A.; Climent, I.; Lenz, A.G.; Stadtman, E.R. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990, 186, 464–478.
25. Ellman, G.L.; Courtney, K.D.; Andres Jr, V.; Featherstone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961, 7 (2), 88–95.
26. Svoboda, P.; Mosinger, B. Catecholamines and the brain microsomal Na, K-adenosinetriphosphatase-I. Protection against lipoperoxidative damage. Biochem. Pharmacol. 1981, 30 (5), 427–432.
27. Day, M.J.; Bilzer, T.; Mansell, J.; Wilcock, B.; Hall, E.J.; Jergens, A.; Washabau, R. Histopathological standards for the diagnosis of gastrointestinal inflammation in endoscopic biopsy samples from the dog and cat: a report from the World Small Animal Veterinary Association Gastrointestinal Standardization Group. J. Comp. Pathol. 2008, 138, S1–S43.
28. Horton, W.B.; Barrett, E.J. Microvascular dysfunction in diabetes mellitus and cardiometabolic disease. Endocr. Rev. 2021, 42 (1), 29–55.
29. Blázquez, E.; Hurtado-Carneiro, V.; LeBaut-Ayuso, Y.; Velázquez, E.; García-García, L.; Gómez-Oliver, F.; Pozo, M.Á. Significance of brain glucose hypometabolism, altered insulin signal transduction, and insulin resistance in several neurological diseases. Front. Endocrinol. 2022, 13, 873301.
30. Magistretti, P.J.; Allaman, I. Brain energy and metabolism. Neurosci. 21st Century 2022, 2197–2227.
31. Cacciatore, M.; Grasso, E.A.; Tripodi, R.; Chiarelli, F. Impact of glucose metabolism on the developing brain. Front. Endocrinol. 2022, 13, 1047545.
32. Speisky, H.; Shahidi, F.; Costa de Camargo, A.; Fuentes, J. Revisiting the oxidation of flavonoids: Loss, conservation or enhancement of their antioxidant properties. Antioxidants 2022, 11 (1), 133.
33. Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022, 383, 132531.
34. Papachristoforou, E.; Lambadiari, V.; Maratou, E.; Makrilakis, K. Association of glycemic indices (hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress and diabetic complications. J. Diabetes Res. 2020, 2020 (1), 7489795.
35. Lana, J.V.; Rios, A.; Takeyama, R.; Santos, N.; Pires, L.; Santos, G.S.; Lana, J.F. Nebulized Glutathione as a Key Antioxidant for the Treatment of Oxidative Stress in Neurodegenerative Conditions. Nutrients 2024, 16 (15), 2476.
36. Dumanović, J.; Nepovimova, E.; Natić, M.; Kuča, K.; Jaćević, V. The significance of reactive oxygen species and antioxidant defense system in plants: A concise overview. Front. Plant Sci. 2021, 11, 552969.
37. Colombo, G.; Reggiani, F.; Angelini, C.; Finazzi, S.; Astori, E.; Garavaglia, M.L.; Dalle-Donne, I. Plasma protein carbonyls as biomarkers of oxidative stress in chronic kidney disease, dialysis, and transplantation. Oxid. Med. Cell. Longev. 2020, 2020 (1), 2975256.
38. Bellavite, P. Neuroprotective potentials of flavonoids: Experimental studies and mechanisms of action. Antioxidants 2023, 12 (2), 280.
39. Salem, H. R., S Hanna, G., H Hassan, M., El-kotb, S., Rashad, S., Yassien, R. I., and Amer, G. S. Combined metformin and insulin therapy improves neurocognitive dysfunction in type 2 diabetic rat model via anti-inflammatory and antioxidant mechanisms. Physiol. Pharmacol. 2024, 28(2), 141-156.