ARI EKMEĞİNİN ALZHEİMER SIÇAN MODELİNDE KARACİĞER 5HT2B ARACILI GLUKOZ DÜZENLEMESİ ÜZERİNE ETKİSİ

Year 2024, Volume: 25 Issue: 4, 466 - 475, 21.10.2024

Ebru Afşar , Kadirhan Doğan , Deniz Kantar Gül , Alev Duygu Kuzzu

https://doi.org/10.18229/kocatepetip.1433727

Abstract

AMAÇ: Bu çalışmada Alzheimer hastalığının (AH) sıçan mo-delinde arı ekmeğinin insülin, serotonin (5-hidroksitriptamin, 5-HT) ve leptin hormonlarında meydana getireceği değişimin glukoz regülasyonu ve kilo değişimi üzerindeki etkisinin ince-lenmesi amaçlanmıştır.GEREÇ VE YÖNTEM: Alzheimer hastalığı sıçan modeli, lateral ventriküllere intraserebroventriküler (i.c.v.) Streptozotosin (STZ) enjeksiyonu yoluyla oluşturuldu. Arı ekmeği uygulaması, STZ enjeksiyonundan sonra 3 hafta boyunca oral gavaj ile gerçek-leştirildi. Plazmada leptin, insülin, 5-HT düzeyleri ile karaciğer dokusunda leptin, insülin, 5-HT, 5HT reseptör 2B (5HT2B), glu-koz taşıyıcı 2 (GLUT2), glukoz 6-fosfataz (G6paz) düzeyleri Elisa kit ile ölçüldü. Açlık kan glukoz düzeyleri glukometre kullanıla-rak ölçüldü ve İnsülin Direnci İçin Homeostatik Model Değer-lendirmesi (HOMA-IR) düzeyleri formül kullanılarak hesaplandı. Her bir sıçanın ağırlık değişimi, başlangıç ağırlıklarının son ağır-lıklarından çıkarılmasıyla hesaplandı. BULGULAR: AH grubunda bulunan sıçanların açlık kan glukoz, plazma insülin ve HOMA-IR düzeyleri ile karaciğer 5-HT, plazma 5-HT ve leptin düzeylerinin azaldığı, karaciğer 5-HT2B ve GLUT-2 düzeyleri ile kilo kaybının arttığı görüldü. Arı ekmeği teda-visinin bu hayvanlarda karaciğer 5-HT2B, G6paz düzeyleri ve plazma leptin düzeylerini önemli ölçüde artırdığı, ayrıca plazma 5-HT, karaciğer 5-HT ve GLUT-2 düzeyleri ile kilo kaybını belirgin şekilde artırdığı görüldü. Ayrıca arı ekmeğinin plazma insülin düzeyini etkilemeden açlık kan glukoz düzeylerini azalttığı sap-tandı. SONUÇ: Bu sonuçlar, AH grubundaki sıçanların karaciğer doku-sunda glukoz metabolizmasının anti-diyabetik savunma siste-mi oluşturacak şekilde modüle edildiğini gösterdi. Arı ekmeği uygulamasının Alzheimer oluşturulmuş sıçanlarda leptin aracılı insülin duyarlılığını artırarak açlık kan glukoz düzeylerini azalt-tığı saptandı.

Keywords

Alzheimer hastalığı, Karaciğer, Arı Ek-meği, 5-HT2B, Leptin.

Ethical Statement

ID/Protokol 1619/2023.08.005

Supporting Institution

Kapadokya Üniversitesi

Project Number

KÜN.2023-BAGP-027

EFFECT OF BEE BREAD ON LIVER 5HT2B-MEDIATED GLUCOSE REGULATION IN ALZHEIMER'S RAT MODEL

Abstract

OBJECTIVE: This study aimed to examine the effect of bee bread on glucose regulation and weight change through the change of insulin, serotonin (5-hydroxytryptamine, 5-HT), and leptin hormones in the rat model of Alzheimer's disease (AD).
MATERIAL AND METHODS: Alzheimer's disease rat model created via intracerebroventricular (i.c.v.) Streptozotocin (STZ) injection into the lateral ventricles. Beebread administration was performed with daily gavage for three weeks after the STZ injection. Leptin, İnsulin, 5-HT levels in plasma and leptin, insulin, 5-HT, 5HT receptor 2B (5HT2B), glucose transporter 2 (GLUT2),glucose 6-phosphatase (G6pase) levels in liver tissue were measured with Elisa kit. Fasting blood glucose levels were measured using a glucometer, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels were calculated using the formula. Each rat's weight change was calculated by subtractingtheir initial weight from their final weight.
RESULTS: In the AD-created rats, ıt was observed that blood glucose, plasma insulin, and HOMA-IR levels, liver 5-HT, plasma 5-HT, and leptin levels decreased, liver 5-HT2B and GLUT-2, and weight loss increased. In the AD-created rats, bee bread treatment significantly increased liver 5-HT2B, liver G6pase levels,and plasma leptin levels, also markedly increased plasma 5-HT,liver 5-HT, GLUT-2, and weight loss levels, and decreased fasting blood glucose levels without affecting plasma insülin levels inthe AD group.
CONCLUSIONS: These results showed that glucose metabolism was modulated to generate an anti-diabetic defense system in the liver tissue of AD-created rats. Beebread administration reduced fasting blood glucose levels by increasing leptin-mediated insulin sensitivity in the AD-created rats.

Keywords

Alzheimer, Liver, Bee Bread, 5-HT2B, Leptin

Project Number

KÜN.2023-BAGP-027

References

• 1. Rice DM, Buchsbaum MS, Starr A, et al. Abnormal EEG slow activity in left temporal areas in senile dementia of the Alzheimer type. J Gerontol. 1990;45(4):145-51.
• 2. Park S, Kim DS, Kang S, et al. The combination of luteolin and l-theanine improved Alzheimer's disease-like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-beta-infused rats. Nutr Res. 2018;60:116-31.
• 3. Bassendine MF, Taylor-Robinson SD, Fertleman M, et al. Is Alzheimer's Disease a Liver Disease of the Brain? J Alzheimers Dis. 2020;75(1):1-14.
• 4. Nguyen TT, Ta QTH, Nguyen TKO, et al. Type 3 Diabetes and Its Role Implications in Alzheimer's Disease. Int J Mol Sci. 2020;21(9):3165.
• 5. Acun AD, Kantar D, Er H, ve ark. Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters. Mol Neurobiol. 2023; 60(7):4030-48.
• 6. Himmerich H, Treasure J. Psychopharmacological advances in eating disorders. Expert Rev Clin Pharmacol. 2018;11(1):95-108.
• 7. Nonogaki K. The Regulatory Role of the Central and Peripheral Serotonin Network on Feeding Signals in Metabolic Diseases. Int J Mol Sci. 2022;23(3):1600.
• 8. Donovan MH, Tecott LH. Serotonin and the regulation of mammalian energy balance. Front Neurosci. 2013;7:36.
• 9. Choi W, Moon JH, Kim H. Serotonergic regulation of energy metabolism in peripheral tissues. J Endocrinol. 2020;245(1):1-10.
• 10. D'Souza A M, Neumann UH, Glavas MM, et al. The glucoregulatory actions of leptin. Mol Metab. 2017;6(9):1052-65.
• 11. McGuire MJ, Ishii M. Leptin Dysfunction and Alzheimer's Disease: Evidence from Cellular, Animal, and Human Studies. Cell Mol Neurobiol. 2016;36(2):203-17.
• 12. Muck-Seler D, Presecki P, Mimica N, et al. Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle, and late phase of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1226-31.
• 13. Doganyigit Z, Yakan B, Soylu M, ve ark. Histological, immunohistochemical and biochemical effects of bee bread on stomach tissue of obese rats. Bratisl Lek Listy. 2020;121(7):504-11.
• 14. Bakour M, El Menyiy N, El Ghouizi A, et al. Hypoglycemic, the hypolipidemic and hepato-protective effect of bee bread in streptozotocin-induced diabetic rats. Avicenna J Phytomed. 2021;11(4):343-52.
• 15. Moreira-Silva D, Vizin RCL, Martins TMS, et al. Intracerebral Injection of Streptozotocin to Model Alzheimer Disease in Rats. Bio Protoc. 2019;9(20):3397.
• 16. Kolaylı S, Keskin M. Natural bee products and their apitherapeutic applications. Studies in Natural Products Chemistry 2020; 66: 175-96.
• 17. Bayram NE, Gercek YC, Çelik S, et al.. Phenolic and Free Amino Acid Profiles of Bee Bread and Bee Pollen with the Same Botanical Origin-Similarities and Differences. Arab. J. Chem. 2021;14:103004.
• 18. Yang S, Chen Z, Cao M, et al. Pioglitazone ameliorates Abeta42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3beta activation. Mol Med Rep. 2017;15(5):2588-94.
• 19. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.
• 20. Kshirsagar V, Thingore C, Juvekar A. Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder. Metab Brain Dis. 2021;36(1):67-83.
• 21. Banks WA, Jaspan JB, Kastin AJ. Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides. 1997;18(10):1577-84.
• 22. Griffith CM, Eid T, Rose GM, et al. Evidence for altered insulin receptor signaling in Alzheimer's disease. Neuropharmacology. 2018;136:202-15.
• 23. Rivera EJ, Goldin A, Fulmer N, et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8(3):247-68.
• 24. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333-46.
• 25. González-González JG, Violante-Cumpa JR, Zambrano-Lucio M, et al. HOMA-IR as a predictor of Health Outcomes in Patients with Metabolic Risk Factors: A Systematic Review and Meta-analysis. High Blood Press Car. 2022;29(6):547-64.
• 26. Sampath Kumar A, Maiya AG, Shastry BA, et al. Exercise and insulin resistance in type 2 diabetes mellitus: A systematic review and meta-analysis. Ann Phys Rehabil Med. 2019;62(2):98-103.
• 27. Bondar A, Shabelnikova O. Clinical features and complication rates in type 2 diabetes mellitus clusters on five variables: glycated hemoglobin, age at diagnosis, body mass index, HOMA-IR, HOMA-B. Probl Endokrinol (Mosk). 2023;11;69(5):84-92.
• 28. Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer's disease and decline in cognitive function. Arch Neurol. 2004;61(5):661-6.
• 29. Paulose CS, Dakshinamurti K. Effect of pyridoxine deficiency in young rats on high-affinity serotonin and dopamine receptors. J Neurosci Res. 1985;14(2):263-70.
• 30. Chakraborty S, Lennon JC, Malkaram SA, et al. Serotonergic system, cognition, and BPSD in Alzheimer's disease. Neurosci Lett. 2019;704:36-44.
• 31. Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020;472(9):1273-1298.
• 32. Gibbs ME, Hutchinson D, Hertz L. Astrocytic involvement in learning and memory consolidation. Neurosci Biobehav Rev. 2008;32(5):927-44.
• 33. Tajeddinn W, Fereshtehnejad SM, Seed Ahmed M, et al. Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers. J Alzheimers Dis. 2016;53(2):621-30.
• 34. Kaluzna-Czaplinska J, Gatarek P, Chirumbolo S, et al. How important is tryptophan in human health? Crit Rev Food Sci Nutr. 2019;59(1):72-88.
• 35. Wyler SC, Lord CC, Lee S, et al. Serotonergic Control of Metabolic Homeostasis. Front Cell Neurosci. 2017;11:277.
• 36. Tubio RI, Perez-Maceira J, Aldegunde M. Homeostasis of glucose in the rainbow trout (Oncorhynchus mykiss Walbaum): the role of serotonin. J Exp Biol. 2010;213(11):1813-21.
• 37. Perez-Maceira JJ, Mancebo MJ, Aldegunde M. Serotonin-induced brain glycogenolysis in rainbow trout (Oncorhynchus mykiss). J Exp Biol. 2012;215(17):2969-79.
• 38. Lee CY, Yau SM, Liau CS, et al. Serotonergic regulation of blood glucose levels in the crayfish, Site of action and receptor characterization. J Exp Zool. 2000;286(6):596-605.
• 39. Denroche HC, Levi J, Wideman RD, et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes. 2011;60(5):1414-23.
• 40. Fujikawa T, Chuang JC, Sakata I, et al. Leptin therapy improves insulin-deficient type 1 diabetes by CNS- dependent mechanisms in mice. Proc Natl Acad Sci U S A. 2010;107(40):17391-6.
• 41. Maioli S, Lodeiro M, Merino-Serrais P, et al. Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease. Aging Cell. 2015;14(1):122-9.
• 42. Ishii M, Wang G, Racchumi G, et al. Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons. J Neurosci. 2014;34(27):9096-106.
• 43. Fewlass DC, Noboa K, Pi-Sunyer FX, et al. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004;18(15):1870-8.
• 44. Greco M, Chiefari E, Montalcini T, et al. Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals. Mediators Inflamm. 2014;2014:750860.
• 45. Marwarha G, Dasari B, Prabhakara JPR, et al. β-Amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway. Journal of Neurochemistry. 2010;115(2):373-84.
• 46. Balaha M, De Filippis B, Cataldi A, et al. CAPE and Neuroprotection: A Review. Biomolecules. 2021;11(2):176.
• 47. Nisa N, Rasmita B, Arati C, et al. Repurposing of phyto-ligand molecules from the honey bee products for Alzheimer's disease as novel inhibitors of BACE-1: small molecule bioinformatics strategies as amyloid-based therapy. Environ Sci Pollut R. 2023;30(17):51143-69.
• 48. Shahinozzaman M, Taira N, Ishii T, et al. Anti-Inflammatory, Anti-Diabetic, and Anti-Alzheimer's Effects of Prenylated Flavonoids from Okinawa Propolis: An Investigation by Experimental and Computational Studies. Molecules. 2018;23(10): 2479.