Effect of vitamin D supplementation on CREB-TrkB-BDNF pathway in the hippocampus of diabetic rats

Document Type: Original Article

Authors

1 Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran

3 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

4 Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran

5 Department of Biochemistry, Nutrition and Genetics, Medical School, Alborz University of Medical Sciences, Karaj, Iran

6 Dietary supplements and probiotics Research Center, Alborz University of Medical Sciences, Karaj, Iran

7 Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

8 Department of Biochemistry and Nutrition, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

Abstract

Objective(s): Cyclic AMP (adenosine monophosphate) response element-binding protein (CREB) and Brain-derived neurotrophic factor (BDNF) are reported to broadly involve in learning capacity and memory. BDNF exerts its functions via tropomyosin receptor kinase B (TrkB). BDNF transcription is regulated by stimulating CREB phosphorylation. The CREB-TrkB-BDNF pathway is reported to be affected by diabetes, which may contribute to its cognitive deficits. This study was conducted to investigate the effect of vitamin D supplementation on the hippocampal fraction of this pathway in an animal model of type-1 diabetes mellitus (T1DM).
Materials and Methods: Thirty-six adult male Sprague-Dawley rats were randomly divided into 4 groups as follows: Group 1: normal healthy rats (n=8); group 2: normal healthy rats receiving sesame oil supplementation as placebo (n=8); Group 3: diabetic rats receiving sesame oil (n=10); and Group 4: diabetic rats treated with 4300 IU/kg/week vitamin D dissolved in sesame oil (n=10). Diabetes was induced by intraperitoneal (IP) injection of streptozotocin. Blood and hippocampal samples were acquired at the end of the experiment. RNA was extracted from the hippocampus, and real-time PCR (polymerase chain reaction) was performed for BDNF and TrkB gene expression.
Results: Administration of vitamin D (4300 IU/kg/week) in a T1DM animal model increased CREB phosphorylation in the hippocampus, but the serum and hippocampal BDNF levels and TrkB and BDNF gene expression did not change significantly.
Conclusion: Vitamin D increased hippocampal CREB phosphorylation in a T1DM animal model. Our findings showed that vitamin D might be protective against central nervous system complications in diabetes. However, future studies are warranted.

Keywords


1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers  2015; 1:15019.
2. Control CfD, Prevention. National diabetes statistics report, 2017. Atlanta, GA: Centers for Disease Control and Prevention 2017.
3. Rathmann W, Giani G. Global Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030: Response to Wild et al. Diabetes care 2004; 27:2568-2569.
4. Chan GC, Tang SC. Diabetic nephropathy: landmark clinical trials and tribulations. Nephrol Dial Transplant. 2015; 31:359-368.
5. Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015; 6: 1246-1258.
6. Kumar TP, Antony S, Gireesh G, George N, Paulose C. Curcumin modulates dopaminergic receptor, CREB and phospholipase C gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats. J Biomed Sci  2010; 17:43.
7. Gonzalez CD, Lee M-S, Marchetti P, Pietropaolo M, Towns R, Vaccaro MI, et al. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 2011; 7:2-11.
8. Kitamura T. The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol 2013; 9:615-623.
9. Jiang T, Wang X-q, Ding C, Du X-l. Genistein attenuates isoflurane-induced neurotoxicity and improves impaired spatial learning and memory by regulating cAMP/CREB and BDNF-TrkB-PI3K/Akt signaling. Korean J Physiol Pharmacol 2017; 21:579-589.
10. Janardhanan A, Sadanand A, Vanisree AJ. Nardostachys jatamansi targets BDNF-TrkB to alleviate ketamine-Induced Schizophrenia-Like symptoms in rats. Neuropsychobiology 2016; 74:104-114.
11. Ravichandran V, Kim M, Han S, Cha Y. Stachys sieboldii extract Supplementation Attenuates Memory Deficits by Modulating BDNF-CREB and Its Downstream Molecules, in Animal Models of Memory Impairment. Nutrients 2018; 10:917.
12. Qi G, Mi Y, Wang Y, Li R, Huang S, Li X, et al. Neuroprotective action of tea polyphenols on oxidative stress-induced apoptosis through the activation of the TrkB/CREB/BDNF pathway and Keap1/Nrf2 signaling pathway in SH-SY5Y cells and mice brain. Food Funct 2017; 8:4421-4432.
13. Ye Y-L, Zhong K, Liu D-D, Xu J, Pan B-B, Li X, et al. Huanglian-Jie-du-tang extract ameliorates depression-like behaviors through BDNF-TrkB-CREB pathway in rats with chronic unpredictable stress. Evid Based Complement Alternat Med 2017; 7903918.
14. Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, Gray NA, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003; 53:707-742.
15. Reusch JE, Watson PA, Pugazhenthi S. Disruption of CREB regulated of gene expression in diabetes. Adv Mol Cell Endocrinol 2006; 5:211-231.
16. Dalle S, Quoyer J, Varin E, Costes S. Roles and regulation of the transcription factor CREB in pancreatic beta -cells. Curr Mol Pharmacol 2011; 4:187-195.
17. Begum N, Ragolia L. High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38 MAPK activation. Am J Physiol Cell Physiol 2000; 278:C81-C91.
18. Conejo R, de Alvaro C, Benito M, Cuadrado A, Lorenzo M. Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway. Oncogene 2002; 21:3739-3753.
19. Kalwat MA, Huang Z, McGlynn K, Cobb M. BDNF/TrkB signaling in pancreatic islet beta cells. BioRxiv 2018: 400010.
20. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and β cell dysfunction. Am J Clin Nutr 2004; 79:820-825.
21. Ahmed HH, El Dayem SMA, Foda FMA, Mohamed HA. Significance of vitamin D in combination with calcium in modulation of depression in the experimental model. Der Pharma Chemica 2015, 7:128-147
22. Latimer CS, Brewer LD, Searcy JL, Chen K-C, Popović J, Kraner SD, et al. Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 2014; 111:E4359-E4366.
23. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C T method. Nat Protoc 2008; 3:1101-1108.
24. Cholerton B, Baker LD, Montine TJ, Craft S. Type 2 diabetes, cognition, and dementia in older adults: toward a precision health approach. Diabetes Spectr 2016; 29:210-219.
25. Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 2013; 37:1346-1362.
26. Nitta A, Murai R, Suzuki N, Ito H, Nomoto H, Katoh G, et al. Diabetic neuropathies in brain are induced by deficiency of BDNF. Neurotoxicol Teratol 2002; 24:695-701.
27. Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 2013; 37:1346-1362.
28. Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology 2013; 227:93-100.
29. Bathina S, Das UN. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis 2018; 17:168-178.
30. Xiang Q, Zhang J, Li C-Y, Wang Y, Zeng M-J, Cai Z-X, et al. Insulin resistance-induced hyperglycemia decreased the activation of Akt/CREB in hippocampus neurons: molecular evidence for mechanism of diabetes-induced cognitive dysfunction. Neuropeptides 2015; 54:9-15.
31. Alvarez-Nölting R, Arnal E, Barcia JM, Miranda M, Romero FJ. Protection by DHA of early hippocampal changes in diabetes: possible role of CREB and NF-κB. Neurochemical research 2012; 37:105-115.
32. Rubin M. vitamin D and Diabetic Neuropathy. Internal Medicine Alert 2015; 37.
33. McCann JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? FASEB J 2008; 22:982-1001.
34. Franco-Robles E, Campos-Cervantes A, Murillo-Ortiz BO, Segovia J, López-Briones S, Vergara P, et al. Effects of curcumin on brain-derived neurotrophic factor levels and oxidative damage in obesity and diabetes. Appl Physiol Nutr Metab 2013; 39:211-218.
35. Farhangi MA, Mesgari-Abbasi M, Nameni G, Hajiluian G, Shahabi P. The effects of vitamin D administration on brain inflammatory markers in high fat diet induced obese rats. BMC Neurosci 2017; 18:81-88.
36. Hajiluian G, Nameni G, Shahabi P, Mesgari-Abbasi M, Sadigh-Eteghad S, Farhangi MA. Vitamin D administration, cognitive function, BBB permeability and neuroinflammatory factors in high-fat diet-induced obese rats. Int J Obes 2017; 41:639-644.
37. Babaei P, Shirkouhi SG, Hosseini R, Tehrani BS. Vitamin D is associated with metabotropic but not neurotrophic effects of exercise in ovariectomized rats. Diabetol Metab Syndr 2017; 9:91-98.
38. Shirazi HA, Rasouli J, Ciric B, Rostami A, Zhang G-X. 1, 25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol 2015; 98:240-245.
39. Smith MP, Fletcher-Turner A, Yurek DM, Cass WA. Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res 2006; 31:533-539.
40. Tetich M, Dziedzicka-Wasylewska M, Kuśmider M, Kutner A, Leśkiewicz M, Jaworska-Feil L, et al. Effects of PRI-2191—a low-calcemic analog of 1, 25-dihydroxyvitamin D3 on the seizure-induced changes in brain gene expression and immune system activity in the rat. Brain Res 2005; 1039: 1-13.
41. Neveu I, Naveilhan P, Baudet C, Brachet P, Metsis M. 1, 25-dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes. Neuroreport 1994; 6: 124-126.
42. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat 2005; 29:21-30.
43. Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, et al. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology 2012; 79:1397-1405.
44. Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 2006; 58:115-134.
45. Berdanier CD, Moustaid-Moussa N. Nutrient-gene interactions in health and disease: CRC Press; 2001.
46. Davis E, Keating B, Byrne G, Russell M, Jones T. Impact of improved glycaemic control on rates of hypoglycemia in insulin dependent diabetes mellitus. Arch Dis Child 1998; 78:111-115.