Irisin protect the Dopaminergic neurons of the Substantia nigra in the rat model of Parkinson’s disease

Document Type : Original Article


1 Research Center of Nervous System Stem Cells, Department of Anatomy, Semnan University of Medical Sciences, Semnan , Iran

2 Department of Anatomy, AJA University of Medical Sciences, Tehran, Iran


Objective(s): Exercise ameliorates the quality of life and reduces the risk of neurological derangements such as Alzheimer’s (AD) and Parkinson’s disease (PD). Irisin is a product of the physical activity and is a circulating hormone that regulates the energy metabolism in the body. In the nervous system, Irisin influences neurogenesis and neural differentiation in mice. We previously demonstrated that co-treatment of bone marrow stem cells (BMSCs) with a neurotrophic factor reduce Parkinson’s symptoms. Our goal in this project was to evaluate whether Irisin with BMSCs can protect the dopaminergic (DA) neurons in PD.
Materials and Methods: 35 adult male Wistar rat weighing (200-250 g) were chosen. They were separated into five experimental groups (n=7). To create a Parkinson’s model, intranasal (IN) administration of the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was used. The BMSCs (2×106) and Irisin (50 nm/ml) was used for 7 days for treatment after creation of the PD model. After completion of the tests (4 weeks), their brains were used for the TUNEL and immunohistochemical (IHC) assays.
Results: One of the important results of this study was that the Irisin induce BMSCs transport into the injured area of the brain. Co-treatment of the Irisin with BMSCs increased tyrosine hydroxylase-positive neurons (TH+) in substantia nigra (SN) and striatum of the PD mice brain. In this group, the number of TUNEL-positive cells significantly decreased. Behavioral symptoms were better in the combination group and Irisin simultaneously.
Conclusion: Co- treatment of Irisin with BMSCs protects the DA neurons from degeneration and apoptotic process after MPTP injection.


Main Subjects

1. Safari M, Jafari B, Zarbakhsh S, Sameni H, Vafaei AA, Mohammadi NK, et al. G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson’s disease. Iran J Basic Med Sci 2016;19:1318-1324.
2. Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med 1988; 318:876-880.
3. Olanow CW, Obeso JA, Stocchi F. Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Nat Clin Pract Neurol 2006; 2:382-392.
4. Yang M, Donaldson AE, Jiang Y, Iacovitti L. Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol. 2003; 23:851-864
5. Kim HJ. Stem cell potential in Parkinson’s disease and molecular factors for the generation of dopamine neurons. Biochim Biophys Acta 2011; 1812:1-11.
6. Bjorklund LM, Sánchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 2002; 99:2344-2349.
7. Lee HS, Huang GT, Chiang H, Chiou LL, Chen MH, Hsieh CH, et al. Multipotential mesenchymal stem cells from femoral bone marrow near the site of osteonecrosis. Stem Cells 2003;21:190-199.
8. Badban L, Safari M, Sameni HR, Bandegi AR, Vafaei AA, Rashidy-Pour A, et al. Protective effects of water extract of propolis on dopaminergic neurons, brain derived neurotrophic factor and stress oxidative factors in the rat model of Parkinson’s disease. Int J Pharmacol 2015; 11:300-308.
9. Novelle MG, Contreras C, Romero-Pico A, Lopez M, Dieguez C. Irisin, two years later. Int j endocrinol 2013; 2013:746281.
10. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol 2007; 103:1093-1098.
11. Erickson HP. Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? Adipocyte 2013; 2:289-293.
12. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 11:463-468
13. Dun SL, Lyu RM, Chen YH, Chang JK, Luo JJ, Dun NJ. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience 2013; 240:155-162.
14. Hashemi MS, Ghaedi K, Salamian A, Karbalaie K, Emadi-Baygi M, Tanhaei S, et al. Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells. Neuroscience 2013; 231:296-304.
15. Wrann CD. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast 2015; 1:55-61.
16. Russo-Neustadt A, Beard RC, Cotman CW. Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 1999; 21:679-682.
17. Greenberg ME, Xu B, Lu B, Hempstead BL. New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 2009; 29:12764-12767.
18. Moon HS, Dincer F, Mantzoros CS. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism 2013; 62:1131-1136.
19. Hastings TG. The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson’s disease. J Bioenerg Biomembr 2009; 41:469-472.
20. Prediger RD, Batista LC, Medeiros R, Pandolfo P, Florio JC, Takahashi RN. The risk is in the air: Intranasal administration of MPTP to rats reproducing clinical features of Parkinson’s disease. Exp Neurol 2006; 202:391-403.
21. Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis 2013; 1:19-33.
22. Zhang W, He H, Song H, Zhao J, Li T, Wu L, et al. Neuroprotective effects of salidroside in the MPTP mouse model of Parkinson’s disease: Involvement of the PI3K/Akt/GSK3β Pathway. Parkinsons Dis 2016; 2016:9450137.
23. Jadidi M, Biat SM, Sameni HR, Safari M, Vafaei AA, Ghahari L. Mesenchymal stem cells that located in the electromagnetic fields improves rat model of Parkinson’s disease. Iran J Basic Med Sci 2016; 19:741-748.
24. Zarbakhsh S, Goudarzi N, Shirmohammadi M, Safari M. Histological study of bone marrow and umbilical cord stromal cell transplantation in regenerating rat peripheral nerve. Cell journal 2016; 17:668-677.
25. Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 1997; 77:1037-1048.
26. Grygiel-Górniak B, Puszczewicz M. A review on irisin, a new protagonist that mediates muscle-adipose-bone-neuron connectivity. Eur Rev Med Pharmacol Sci 2017; 21:4687-4693.
27. Yan QS, Feng MJ, Yan SE. Different expression of brain-derived neurotrophic factor in the nucleus accumbens of alcohol-preferring (P) and -nonpreferring (NP) rats. Brain Res 2005; 1035:215-218.
28. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease.  Nat Rev Immunol 2011; 11: 607-615.
29. Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Neurol Clin 2006; 24:585-599.
30. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 2013; 18:649-659.
31. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci 2006; 110:167-173.
32. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998; 37:1553-1561.
33. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012; 16:706-722.
34. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127:397-408.
35. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 2006; 116:615-622.
36. Ma D, Li S, Lucas EK, Cowell RM, Lin JD. Neuronal inactivation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protects mice from diet-induced obesity and leads to degenerative lesions. J Biol Chem 2010; 285:39087-39095.
37. Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 2004; 119:121-135.
38. Puddifoot C, Martel MA, Soriano FX, Camacho A, Vidal-Puig A, Wyllie DJ, et al. PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity. J Neurosci 2012; 32:6995-7000.