Adropin exerts neuroprotection in an experimental rat model of Parkinson’s disease

Document Type : Original Article

Authors

1 Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey

2 Department of Physiology, Izmir Bakırçay University, Faculty of Medicine, İzmir, Turkey

3 Department of Physiology, Amasya University, Faculty of Medicine, Amasya, Turkey

4 Department of Medical Biochemistry, Faculty of Medicine, Antalya, Turkey

10.22038/ijbms.2025.82498.17830

Abstract

Objective(s): This study was planned to elucidate the mechanism of the protective effect of adropin in an experimental rat model of Parkinson’s Disease (PD). 
Materials and Methods: Three-month-old male Wistar rats were randomly divided into four groups: i) Control, ii) Sham, iii) PD, and iv) PD+Adropin. The performance tests were performed seven days after the 6-Hydroxydopamine hydrochloride (6-OHDA) injection into the striatum. The immunoreactivities for tyrosine hydroxylase (TH), G protein-coupled receptor 19 (GPR19), and vascular endothelial growth factor receptor 2 (VEGFR2) were detected by immunohistochemistry (IHC) in the substantia nigra (SN). Dopamine levels were measured by mass spectrometry. Glycogen synthase kinase 3β (GSK‑3β) and p‑GSK‑3β (Ser9) protein levels were evaluated by western blot analysis. 
Results: Our study demonstrated that motor performances were significantly improved by adropin treatment. Central adropin injection prevented the loss of nigral dopaminergic neurons and induced VEGFR2 expression but not GPR19 compared to the PD group. The ratio of p-GSK3β/GSK3β did not differ between groups. However, the level of dopamine in SN was increased with adropin injection in the PD+Adropin group. 
Conclusion: Our findings reveal that adropin administration has a protective effect on nigral dopaminergic neurons and acts through the VEGFR2 signaling pathway.

Keywords

Main Subjects

References

1. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): A review of publications since the decade of the brain. Clinics (Sao Paulo) 2017; 72: 649-651.
2. Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: A tale of two circuits? Brain 2012; 135: 3206-3226.
3. Frisardi V, Santamato A, Cheeran B. Parkinson’s disease: New insights into pathophysiology and rehabilitative approaches. Parkinsons Dis 2016; 2016: 3121727-3121729.
4. Blednov YA, Borghese CM, Dugan MP, Pradhan S, Thodati TM, Kichili NR, et al. Apremilast regulates acute effects of ethanol and other GABAergic drugs via protein kinase A-dependent signaling. Neuropharmacology 2020; 178: 108220-105250.
5. Lau LT, Yu AC. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 2001; 18: 351-359.
6. Ferrari CC, Pott Godoy MC, Tarelli R, Chertoff M, Depino AM, Pitossi FJ. Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra. Neurobiol Dis 2006; 24: 183-193.
7. Poot M, van’t Slot R, Leupert R, Beyer V, Passarge E, Haaf T. Three de novo losses and one insertion within a pericentric inversion of chromosome 6 in a patient with complete absence of expressive speech and reduced pain perception. Eur J Med Genet 2009; 52: 27-30.
8. Aydin S, Kuloglu T, Aydin S, Eren MN, Yilmaz M, Kalayci M, et al. Expression of adropin in rat brain, cerebellum, kidneys, heart, liver, and pancreas in streptozotocin-induced diabetes. Mol Cell Biochem 2013; 380: 73-81.
9. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, et al. Adropin is a novel regulator of endothelial function. Circulation 2010; 122: S185-192.
10. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, et al. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab 2008; 8: 468-481.
11. Stein LM, Yosten GL, Samson WK. Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19. Am J Physiol Regul Integr Comp Physiol 2016; 310: R476-480.
12. Hoffmeister-Ullerich SA, Susens U, Schaller HC. The orphan G-protein-coupled receptor GPR19 is expressed predominantly in neuronal cells during mouse embryogenesis. Cell Tissue Res 2004; 318: 459-463.
13. O’Dowd BF, Nguyen T, Lynch KR, Kolakowski LF, Jr Thompson M, Cheng R, et al. A novel gene codes for a putative G protein-coupled receptor with an abundant expression in brain. FEBS Lett 1996; 394: 325-329.
14. Hossain MS, Mineno K, Katafuchi T. Neuronal orphan G-protein coupled receptor proteins mediate plasmalogens-induced activation of ERK and Akt signaling. PLoS One 2016; 11: e0150846.
15. Cui W, Li W, Zhao Y, Mak S, Gao Y, Luo J, et al. Preventing H(2)O(2)-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone. Brain Res 2011; 1394: 14-23.
16. Hao T, Rockwell P. Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress. Free Radic Biol Med 2013; 63: 421-431.
17. Cole A. GSK3 as a Sensor Determining Cell Fate in the Brain. Front Mol Neurosci 2012; 5: 1-10.
18. Liu X, Yao Z. Chronic over-nutrition and dysregulation of GSK3 in diseases. Nutr Metab 2016; 13: 49-67.
19. Jaworski T, Banach-Kasper E, Gralec K. GSK-3β at the Intersection of Neuronal Plasticity and Neurodegeneration. Neural plasticity 2019; 2019: 4209475-4209475.
20. Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C, et al. Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med 2014; 52: 751-758.
21. Li L, Xie W, Zheng XL, Yin WD, Tang CK. A novel peptide adropin in cardiovascular diseases. Clin Chim Acta 2016; 453: 107-113.
22. Zhao LP, You T, Chan SP, Chen JC, Xu WT. Adropin is associated with hyperhomocysteine and coronary atherosclerosis. Exp Ther Med 2016; 11: 1065-1070.
23. Wong CM, Wang Y, Lee JT, Huang Z, Wu D, Xu A, et al. Adropin is a brain membrane-bound protein regulating physical activity via the NB-3/Notch signaling pathway in mice. J Biol Chem 2014; 289: 25976-25986.
24. Guzelad O, Ozkan A, Parlak H, Sinen O, Afsar E, Ogut E, et al. Protective mechanism of Syringic acid in an experimental model of Parkinson’s disease. Metab Brain Dis 2021; 36: 1003-1014.
25. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates: Hard Cover Edition. 6th Edition - November 2, 2006.
26. Bulbul M, Sinen O, Ozkan A, Aslan MA, Agar A. Central neuropeptide-S treatment improves neurofunctions of 6-OHDA-induced Parkinsonian rats. Exp Neurol 2019; 317: 78-86.
27. Yildirim FB, Ozsoy O, Tanriover G, Kaya Y, Ogut E, Gemici B, et al. Mechanism of the beneficial effect of melatonin in experimental Parkinson’s disease. Neurochem Int 2014; 79: 1-11.
28. Ozkan A, Parlak H, Tanriover G, Dilmac S, Ulker SN, Birsen I, et al. The protective mechanism of docosahexaenoic acid in mouse model of Parkinson: The role of hemeoxygenase. Neurochem Int 2016; 101: 110-119.
29. Abada YS, Nguyen HP, Schreiber R, Ellenbroek B. Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for Huntington disease. PLoS One 2013; 8: e68584-68597.
30. Lopez S, Turle-Lorenzo N, Acher F, De Leonibus E, Mele A, Amalric M. Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson’s disease. J Neurosci 2007; 27: 6701-6711.
31. 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: 248-254.
32. Gonzalez RR, Fernandez RF, Vidal JL, Frenich AG, Perez ML. Development and validation of an ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS) method for the simultaneous determination of neurotransmitters in rat brain samples. J Neurosci Methods 2011; 198: 187-194.
33. Sinen O, Bulbul M, Derin N, Ozkan A, Akcay G, Aslan MA, et al. The effect of chronic neuropeptide-S treatment on non-motor parameters in experimental model of Parkinson’s disease. Int J Neurosci 2021;131: 765-774.
34. Wen S, Aki T, Unuma K, Uemura K. Chemically induced models of Parkinson’s disease: History and perspectives for the involvement of ferroptosis. Front Cell Neurosci 2020; 14: 581191-581207.
35. Javoy F, Sotelo C, Herbet A, Agid Y. Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Res 1976; 102: 201-215.
36. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65: 135-172.
37. Glinka YY, Youdim MB. Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 1995; 292: 329-332.
38. Ozkan A, Aslan MA, Sinen O, Munzuroglu M, Derin N, Parlak H, et al. Effects of adropin on learning and memory in rats tested in the Morris water maze. Hippocampus 2022; 32: 253-263.
39. Srinivasan J, Schmidt WJ. The effect of the alpha2-adrenoreceptor antagonist idazoxan against 6-hydroxydopamine-induced Parkinsonism in rats: Multiple facets of action? Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 629-638.
40. Rodriguez Diaz M, Abdala P, Barroso-Chinea P, Obeso J, Gonzalez-Hernandez T. Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson’s disease. Behav Brain Res 2001; 122: 79-92.
41. Sato K, Yamashita T, Shirai R, Shibata K, Okano T, Yamaguchi M, et al. Adropin contributes to anti-atherosclerosis by suppressing monocyte-endothelial cell adhesion and smooth muscle cell proliferation. Int J Mol Sci 2018; 19: 1293-1309.
42. Thapa D, Stoner MW, Zhang M, Xie B, Manning JR, Guimaraes D, et al. Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. Redox Biol 2018; 18: 25-32.
43. Yasuhara T, Shingo T, Muraoka K, Kameda M, Agari T, Wen Ji Y, et al. Neurorescue effects of VEGF on a rat model of Parkinson’s disease. Brain Res 2005; 1053: 10-18.
44. Herran E, Ruiz-Ortega JA, Aristieta A, Igartua M, Requejo C, Lafuente JV, et al. In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson’s disease. Eur J Pharm Biopharm 2013; 85: 1183-1190.
45. Yue X, Hariri DJ, Caballero B, Zhang S, Bartlett MJ, Kaut O, et al. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease. Neuroscience 2014; 258: 385-400.
46. Dellinger MT, Brekken RA. Phosphorylation of Akt and ERK1/2 is required for VEGF-A/VEGFR2-induced proliferation and migration of lymphatic endothelium. PLoS One 2011; 6: e28947-28956.
47. Golpich M, Amini E, Hemmati F, Ibrahim NM, Rahmani B, Mohamed Z, et al. Glycogen synthase kinase-3 beta (GSK-3beta) signaling: Implications for Parkinson’s disease. Pharmacol Res 2015; 97: 16-26.
48. Doble BW, Woodgett JR. GSK-3: Tricks of the trade for a multi-tasking kinase. J Cell Sci 2003; 116: 1175-1186.
49. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 2004; 29: 95-102.
50. Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 1993; 296: 15-19.
51. Jensen J, Brennesvik EO, Lai YC, Shepherd PR. GSK-3beta regulation in skeletal muscles by adrenaline and insulin: evidence that PKA and PKB regulate different pools of GSK-3. Cell Signal 2007; 19: 204-210.
52. Hsu WJ, Wildburger NC, Haidacher SJ, Nenov MN, Folorunso O, Singh AK, et al. PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer’s disease. Exp Neurol 2017; 295: 1-17.
53. Scala F, Nenov MN, Crofton EJ, Singh AK, Folorunso O, Zhang Y, et al. Environmental enrichment and social isolation mediate neuroplasticity of medium spiny neurons through the GSK3 pathway. Cell Rep 2018; 23: 555-567.
54. Stertz L, Di Re J, Pei G, Fries GR, Mendez E, Li S, et al. Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients. Neuropsychopharmacology 2021; 46: 673-682.
55. Huang Y, Sun L, Zhu S, Xu L, Liu S, Yuan C, et al. Neuroprotection against Parkinson’s disease through the activation of Akt/GSK3β signaling pathway by tovophyllin A. Front Neurosci 2020; 14: 723-733.
56. Xie CL, Lin JY, Wang MH, Zhang Y, Zhang SF, Wang XJ, et al. Inhibition of glycogen synthase kinase-3beta (GSK-3beta) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats. Sci Rep 2016; 6: 23527-23536.
57. Cai P, Ye J, Zhu J, Liu D, Chen D, Wei X, et al. Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effect of bFGF in the 6-OHDA-induced Parkinson’s disease model. Aging Dis 2016; 7: 336-449.
58. Zhang Y, Huang N, Chen M, Jin H, Nie J, Shi J, et al. Procyanidin protects against 6-hydroxydopamine-induced dopaminergic neuron damage via the regulation of the PI3K/Akt signalling pathway. Biomed Pharmacother 2019; 114: 108789-108798.
59. Parlak H, Ozkan A, Sinen O, Bulbul M, Aslan MA, Agar A. Adropin increases with swimming exercise and exerts a protective effect on the brain of aged rats. Exp Gerontol 2022; 169: 111972.
60. Altamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, et al. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 2019; 98: 37-48.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 6
June 2025
Pages 790-798

Files

Share

How to cite

Statistics