Effect of insulin and cinnamon extract on spatial memory and gene expression of GLUT1, 3, and 4 in streptozotocin-induced Alzheimer’s model in rats

Document Type : Original Article

Authors

1 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Food Hygiene and Public Health, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

Abstract

Objective(s): Since diminished hippocampal insulin signaling leads to memory impairment, insulin resistance and hyperinsulinemia are probably associated with Alzheimer’s disease (AD). The effect of intracerebroventricular injection of insulin (Ins) and oral cinnamon extract (Cinn) on glucose transporter (GLUT) 1, 3, and 4 gene expressions in the hippocampus and spatial memory in a streptozotocin (STZ)-induced AD rat model was investigated in the present study.
Materials and Methods: Fifty-six adult male Sprague-Dawley rats (280±20 g) were allocated into eight distinct groups (n=7) of five controls (negative, Ins, Cinn, Ins+Cinn, and STZs) and three treatments (STZ+ Ins, STZ+ Cinn, and STZ+ Ins + Cinn). Single dose STZ 4  mg/kg (icv), Cinn at a dose of 200 mg/ kg (orally for 14 days), and Ins 5 mIU/5 µl (icv for 14 days) were administered in the defined groups. To evaluate the behavioral performance the animals were subjected to the Morris Water Maze (MWM) test. The level of mRNA expression of GLUTs was evaluated by the Real time-PCR method. 
Results: In the STZ+Cinn+Ins group, the performance of animals in the MWM test was improved and the over-expression of GLUTs genes in hippocampal tissue was observed. The results of Ins and Cinn synergist treatment groups revealed improvement in the behavioral tests and gene expression compared with Ins and Cinn treatment groups (P<0.001).
Conclusion: Administration of Ins and Cinn has a positive effect on the function of the AD rat model. To clarify the effect of Ins and Cinn extract on the GLUTs investigated in this study, it is essential to evaluate their influence on the protein levels. 

Keywords

Main Subjects

References

1. Nguyen TT, Ta QTH, Nguyen TKO, Nguyen TTD, Giau VV. Type 3 diabetes and its role implications in Alzheimer’s disease. Int J Mol Sci 2020; 21:1-16.
2. Pitt J, Wilcox KC, Tortelli V, Diniz LP, Oliveira MS, Dobbins C, et al. Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aβ oligomers. Mol Biol Cell 2017; 28:2623-2636.
3. Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting insulin-degrading enzyme in insulin clearance. Int J Mol Sci 2021; 22:1-21.
4. Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer’s disease: Current knowledge. Fron Neurosci 2015; 9:1-13.
5. Chen Z, Zhong C.  Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies.  Prog Neurobiol 2013; 108:21-43.
6. Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472:1299-1343.
7. Wang L, Liu W, Fan Y, Liu T, Yu C. Effect of rosiglitazone on amyloid precursor protein processing and Aβ clearance in streptozotocin-induced rat model of Alzheimer’s disease. Iran J Basic Med Sci 2017; 20:474-480.
8. Shingo AS, Kanabayashi T, Kito S, Murase T.  Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res 2013; 241:105-111.
9. Mullins RJ, Diehl TC, Chia CW, Kapogiannis D. Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer’s disease. Front Aging Neurosci 2017; 9:1-16.
10. Shahmohamady P, Eidi A, Mortazavi P, Panahi N, Minai-Tehrani D. Effect of sinapic acid on memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pol J Pathol 2018; 69:266-277.
11. Hajinejad M, Ghaddaripouri M, Dabzadeh M, Forouzanfar F, Sahab-Negah S. Natural cinnamaldehyde and its derivatives ameliorate neuroinflammatory pathways in neurodegenerative diseases. Biomed Res Int 2020; 2020:1-9.
12. Błaszczyk N, Rosiak A, Kałużna-Czaplińska J. The potential role of cinnamon in human health. Forests 2021; 12:1-17.
13. Momtaz S, Hassani S, Khan F, Ziaee M, Abdollahi M. Cinnamon, a promising prospect towards Alzheimer’s disease. Pharmacol Res 2018; 130:241-258.
14. Hafizur RM, Hameed A, Shukrana M, Raza SA, Chishti S, Kabir N, et al. Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro. Phytomedicine 2015; 22:297-300.
15. Hemmati AA, Alboghobeish S, Ahangarpour A. Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice. Korean J Physiol Pharmacol
2018; 22:257-267.
16. Do J, Kim N, Jeon SH, Gee MS, Ju YJ, Kim JH. Trans-cinnamaldehyde alleviates amyloid-beta pathogenesis via the SIRT1-PGC1α-PPARγ pathway in 5XFAD transgenic mice. Int J Mol Sci 2020; 21:1-13.
17. Madhavadas S, Subramanian S. Cognition enhancing effect of the aqueous extract of Cinnamomum zeylanicum on non-transgenic Alzheimer’s disease rat model: Biochemical, histological, and behavioural studies. Nutr Neurosci 2017; 20:526-537.
18. Balali Dehkordi S, Sajedianfard J, Owji AA. The effect of intra-cerebroventricular injection of insulin on the levels of monoamines on the raphe magnus nucleus of non-diabetic and short-term diabetic rats in the formalin test. Iran J Basic Med Sci 2019; 22:915-921.
19. Malik J, Munjal K, Deshmukh R. Attenuating effect of standardized lyophilized Cinnamomum zeylanicum bark extract against streptozotocin-induced experimental dementia of Alzheimer’s type. J Basic Clin Physiol Pharmacol 2015; 26:275-285.
20. Vorhees CV, Williams MT. Assessing Spatial Learning and Memory in Rodents. ILAR J 2014; 55:310-332.
21. Maurer R, Derivaz V. Rats in a transparent morris water maze use elemental and configural geometry of landmarks as well as distance to the pool wall. Spatial Cognition and Computation 2000; 2:135-156.
22. Guo Z, Chen Y, Mao Y-F, Zheng T, Jiang Y, Yan Y, et al. Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model. Sci Rep 2017; 7:45971.
23. Kyrtata N, Emsley HC, Sparasci O, Parkes LM, Dickie BR. A systematic review of glucose transport alterations in alzheimer’s disease. Front Neurosci 2021; 15:1-15.
24. Leloup C, Arluison M, Kassis N, Lepetit N, Cartier N, Ferré P, et al. Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Brain Res Mol Brain Res 1996; 38:45-53.
25. Hölscher C. Insulin signaling impairment in the brain as a risk factor in alzheimer’s disease. Front Aging Neurosci 2019; 11:1-11.
26. Iqbal K, Grundke-Iqbal I. Metabolic/signal transduction hypothesis of Alzheimer’s disease and other tauopathies. Acta Neuropathol 2005; 109:25-31.
27. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 2004; 101:3100-3105.
28. Gonçalves RA, Wijesekara N, Fraser PE, De Felice FG. The link between tau and insulin signaling: Implications for Alzheimer’s disease and other tauopathies. Front Cell Neurosci 2019; 13:17-17.
29. Kulas JA, Franklin WF, Smith NA, Manocha GD, Puig KL, Nagamoto-Combs K, et al. Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues. Am J Physiol Endocrinol Metab 2019; 316:E106-E120.
30. Chua L-M, Lim M-L, Chong P-R, Hu ZP, Cheung NS, Wong B-S. Impaired neuronal insulin signaling precedes Aβ 42 Accumulation in female AβPPsw/PS1ΔE9 mice. J Alzheimers Dis 2012; 29:783-791.
31. Pearson-Leary J, McNay EC. Intrahippocampal administration of amyloid-β 1-42 oligomers acutely impairs spatial working memory, insulin signaling, and hippocampal metabolism. J Alzheimers Dis 2012; 30:413-422.
32. Belfiore A, Malaguarnera R, Vella V, Lawrence MC, Sciacca L, Frasca F, et al. Insulin receptor isoforms in physiology and disease: an updated view. Endocr Rev 2017; 38:379-431.
33. Suzanne M, Tong M. Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 2014; 88:548-559.
34. Steen E, Terry BM, J Rivera E, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis 2005; 7:63-80.
35.  LSS, Fernandes CS, Vieira MNN, De Felice FG. Insulin resistance in Alzheimer’s disease. Front Neurosci 2018; 12:1-11.
36. Weinstein G, Davis-Plourde KL, Conner S, Himali JJ, Beiser AS, Lee A, et al. Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts. PLoS One 2019; 14:e0212293.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 6
June 2023
Pages 680-687

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