THE ROLE OF LINGO-1 AND MYELIN BASIC PROTEIN MRNAS IN CENTRAL REMYELINATION IN ETHIDIUM BROMIDE-INDUCED DEMYELINATION IN RATS
Objective: The study aimed to assess the possible role of quercetin, pioglitazone, metformin, and dapagliflozin in the enhancement of remyelination process after ethidium bromide (EB)-induced demyelination.
Methods: The study was conducted on 60 male Wister rats (250–300 g), randomly divided into sham-operated group and five demyelination groups (each of 10 rats) which subjected to intrapontine stereotaxic injection of EB (10 μl of 0.1% EB) to induce demyelination. Then, randomly subdivided into: EB control group: Rats were treated with normal saline, quercetin-treated group (50 mg/kg/day), pioglitazone-treated group (10 mg/kg/day), metformin-treated group (500 mg/kg/day), and dapagliflozin-treated group (10 mg/kg/day). Behavioral tests (beam balance, foot fault, rotarod, and inverted screen) were conducted for all groups as well as biochemical analysis of LINGO-1 and myelin basic protein (MBP) mRNAs and histological examination of pontine tissues.
Results: The EB control group showed deterioration of motor performance on behavioral tests. Degenerative changes were observed in pontine tissue on histological examination together with upregulation of LINGO-1 protein and downregulation of MBP level. While the treated groups after EB demyelination showed significant improvement in motor performance and decreased degenerated neurons in histological examination with upregulation of MBP level and downregulation of LINGO-1 protein level.
Conclusion: Quercetin, metformin, dapagliflozin, and pioglitazone showed neuroprotective effect and enhancement of remyelination process.
2. Pomeroy IM, Jordan EK, Frank JA, Matthews PM, Esiri MM. Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis. Mult Scler 2010;16:537-48.
3. Kremer D, Göttle P, Hartung HP, Küry P. Pushing forward: Remyelination as the new frontier in CNS diseases. Trends Neurosci 2016;39:246-63.
4. Franklin RJ, ffrench-Constant C, Edgar JM, Smith KJ. Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol 2012;8:624-34.
5. Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002;3:705-14.
6. Goudarzvand M, Javan M, Mirnajafi-Zadeh J, Mozafari S, Tiraihi T. Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell Mol Neurobiol 2010;30:289-99.
7. Blakemore WF. Ethidium bromide induced demyelination in the spinal cord of the cat. Neuropathol Appl Neurobiol 1982;8:365-75.
8. Molina MF, Sanchez-Reus I, Iglesias I, Benedi J. Quercetin, a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver. Biol Pharm Bull 2003;26:1398-402.
9. Sharma D, Ojha H, Pathak M, Singh B, Sharma N, Singh A, et al. Spectroscopic and molecular modeling studies of binding mechanism of metformin with bovine serum albumin. J Mol Struct 2016;1118:267 74.
10. Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D, et al. Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J Clin Endocrinol Metab 2004;89:5043-7.
11. Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 2006;55:120-7.
12. Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-18.
13. Bays H. Sodium glucose co-transporter Type 2 (SGLT2) inhibitors: Targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Ther 2013;4:195-220.
14. Beckmann DV, Carvalho FB, Mazzanti CM, Dos Santos RP, Andrades AO, Aiello G, et al. Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide. Life Sci 2014;103:79-87.
15. Abdalla FH, Cardoso AM, Pereira LB, Schmatz R, Gonçalves JF, Stefanello N, et al. Neuroprotective effect of quercetin in ectoenzymes and acetylcholinesterase activities in cerebral cortex synaptosomes of cadmium-exposed rats. Mol Cell Biochem 2013;381:1-8.
16. Lee HW, Hakim P, Rabu A, Sani HA. Antidiabetic effect of Gynura procumbens leaves extracts to involve modulation of hepatic carbohydrate metabolism in streptozotocin-induced diabetic rats. J Med Plants Res 2012;6:796-812.
17. Watanabe Y, Nakayama K, Taniuchi N, Horai Y, Kuriyama C, Ueta K, et al. Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese Type 2 diabetes. PLoS One 2015;10:e0116851.
18. Mishra B, Pancholi S, Deshmukh A, Panjwani D. Preclinical investigations of a novel dose regimen based on the combination of pioglitazone and Gymnema sylvestre extract. Mol Clin Pharmacol 2012;2:20-33.
19. Cetin A, Komai S, Eliava M, Seeburg PH, Osten P. Stereotaxic gene delivery in the rodent brain. Nat Protoc 2006;1:3166-73.
20. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. San Diego: Academic Press; 1998.
21. Lekic T, Tang J, Zhang JH. A rat model of pontine hemorrhage. Acta Neurochir Suppl 2008;105:135-7.
22. Jeffery ND, Blakemore WF. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 1997;120 (Pt 1):27-37.
23. Kondziella W. A new method for the measurement of muscle relaxation in white mice. Arch Int Pharmacodyn Ther 1964;152:277-84.
24. Hernandez TD, Schallert T. Seizures and recovery from experimental brain damage. Exp Neurol 1988;102:318-24.
25. Deacon RM. Measuring the strength of mice. J Vis Exp 2013;76:2610.
26. Latronico T, Branà MT, Gramegna P, Fasano A, Di Bari G, Liuzzi GM, et al. Inhibition of myelin-cleaving poteolytic activities by interferon beta in rat astrocyte cultures. Comparative analysis between gelatinases and calpain-II. PLoS One 2013;8:e49656.
27. Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, et al. LINGO-1 is a component of the nogo-66 receptor/p75 signaling complex. Nat Neurosci 2004;7:221-8.
28. Cao J, Wang J, Dwyer JB, Gautier NM, Wang S, Leslie FM, et al. Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences. Transl Psychiatry 2013;3:e247.
29. Zhao L, Guo Y, Ji X, Zhang M. The neuroprotective effect of picroside II via regulating the expression of myelin basic protein after cerebral ischemia injury in rats. BMC Neurosci 2014;15:25.
30. Crawford AH, Chambers C, Franklin RJ. Remyelination: The true regeneration of the central nervous system. J Comp Pathol 2013;149:242-54.
31. Graça DL, Blakemore WF. Delayed remyelination in rat spinal cord following ethidium bromide injection. Neuropathol Appl Neurobiol 1986;12:593-605.
32. Bondan EF, Lallo MA, Orsini H, Bentubo HL, Yazbek A, Macrini DJ, et al. Evaluation of locomotor activity after a local induction of toxic demyelination in the brainstem of Wistar rats. Arq Neuropsiquiatr 2006;64:496-503.
33. Mi S, Sandrock A, Miller RH. LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol 2008;40:1971-8.
34. Salem NA, Assaf N, Ismail MF, Khadrawy YA, Samy M. Ozone therapy in ethidium bromide-induced demyelination in rats: Possible protective effect. Cell Mol Neurobiol 2016;36:943-54.
35. Benjamins JA, Morell P. Proteins of myelin and their metabolism. Neurochem Res 1978;3:137-74.
36. Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 2001;81:871-927.
37. Priyanga KS, Vijayalakshmi K, Selvaraj R. Behavioral studies of Wistar rats in rotenone induced model of Parkinson’s disease. Int J Pharm Pharm Sci 2017;9:159-64.
38. Qu X, Qi D, Dong F, Wang B, Guo R, Luo M, et al. Quercetin improves hypoxia-ischemia induced cognitive deficits via promoting remyelination in neonatal rat. Brain Res 2014;1553:31-40.
39. Fancy SP, Chan JR, Baranzini SE, Franklin RJ, Rowitch DH. Myelin regeneration: A recapitulation of development? Annu Rev Neurosci 2011;34:21-43.
40. Chakraborty S, Torgal SS. Effect of metformin and simvastatin in diazepam-and sodium nitrite-induced anterograde amnesia in male swiss albino mice. Int J Pharm Pharm Sci 2018;11:18-22.
41. Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 2006;55:496-505.
42. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16:1001 8.
43. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S, et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 2009;182:8005-14.
44. Paintlia AS, Paintlia MK, Mohan S, Singh AK, Singh I. AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am J Pathol 2013;183:526-41.
45. Millar P, Pathak N, Parthsarathy V, Bjourson AJ, O’Kane M, Pathak V, et al. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. J Endocrinol 2017;234:255-67.
46. Abdelsameea AA, Kabil SL. Mitigation of cisplatin-induced peripheral neuropathy by canagliflozin in rats. Naunyn Schmiedebergs Arch Pharmacol 2018;391:945-52.
47. Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT 2 inhibition with dapagliflozin reduces the activation of the nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with Type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther 2017;31:119-32.
48. Klotz L, Schmidt M, Giese T, Sastre M, Knolle P, Klockgether T, et al. Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients. J Immunol 2005;175:4948-55.
49. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications – a review. Nutr J 2014;13:17.
50. Kanakasabai S, Pestereva E, Chearwae W, Gupta SK, Ansari S, Bright JJ, et al. PPAR? agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes. PLoS One 2012;7:e50500.
51. De Nuccio C, Bernardo A, De Simone R, Mancuso E, Magnaghi V, Visentin S, et al. Peroxisome proliferator-activated receptor ? agonists accelerate oligodendrocyte maturation and influence mitochondrial functions and oscillatory ca(2+) waves. J Neuropathol Exp Neurol 2011;70:900-12.
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