Molecular Neurobiology

, Volume 55, Issue 8, pp 6572–6588 | Cite as

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson’s Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects

  • Mariama S. Azmy
  • Esther T. MenzeEmail author
  • Reem N. El-Naga
  • Mariane G. Tadros


All current treatments of Parkinson’s disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40 μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40 μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.


Filgrastim Parkinson’s disease Neuroinflammation Apoptosis BDNF Motor function 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Pringsheim T, Jette N, Frolkis A, Steeves TD (2014) The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 29(13):1583–1590. CrossRefPubMedGoogle Scholar
  2. 2.
    Barzilai A, Melamed E (2003) Molecular mechanisms of selective dopaminergic neuronal death in Parkinson’s disease. Trends Mol Med 9(3):126–132. CrossRefPubMedGoogle Scholar
  3. 3.
    Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376. CrossRefPubMedGoogle Scholar
  4. 4.
    Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86(1):109–127. CrossRefPubMedGoogle Scholar
  5. 5.
    Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, Mas N, Hofeneder D et al (2015) The onset of nonmotor symptoms in Parkinson’s disease (the ONSET PD study). Mov Disord 30(2):229–237.
  6. 6.
    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106(6):518–526. CrossRefPubMedGoogle Scholar
  7. 7.
    Subramaniam SR, Federoff HJ (2017) Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease. Front Aging Neurosci 9:176. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381. CrossRefGoogle Scholar
  9. 9.
    Alam Q, Alam MZ, Mushtaq G, Damanhouri GA, Rasool M, Kamal MA, Haque A (2016) Inflammatory process in Alzheimer’s and Parkinson’s diseases: central role of cytokines. Curr Pharm Des 22(5):541–548. CrossRefPubMedGoogle Scholar
  10. 10.
    Montgomery SL, Bowers WJ (2012) Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J NeuroImmune Pharmacol 7(1):42–59. CrossRefPubMedGoogle Scholar
  11. 11.
    Lev N, Melamed E, Offen D (2003) Apoptosis and Parkinson’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 27(2):245–250. CrossRefGoogle Scholar
  12. 12.
    Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M et al (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12(1):25–31Google Scholar
  13. 13.
    Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H et al (2000) Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci U S A 97(6):2875–2880.
  14. 14.
    Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137(2):120–123. CrossRefPubMedGoogle Scholar
  15. 15.
    Baquet ZC, Bickford PC, Jones KR (2005) Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci 25(26):6251–6259. CrossRefPubMedGoogle Scholar
  16. 16.
    Howells DW, Porritt MJ, Wong JY, Batchelor PE, Kalnins R, Hughes AJ, Donnan GA (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166(1):127–135. CrossRefPubMedGoogle Scholar
  17. 17.
    Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (1999) Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett 270(1):45–48. CrossRefPubMedGoogle Scholar
  18. 18.
    Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301–1306. CrossRefPubMedGoogle Scholar
  19. 19.
    Michel HE, Tadros MG, Esmat A, Khalifa AE, Abdel-Tawab AM (2016) Tetramethylpyrazine ameliorates rotenone-induced Parkinson’s disease in rats: involvement of its anti-inflammatory and anti-apoptotic actions. Mol Neurobiol 54(7):4866–4878. CrossRefPubMedGoogle Scholar
  20. 20.
    Thakur P, Nehru B (2013) Anti-inflammatory properties rather than anti-oxidant capability is the major mechanism of neuroprotection by sodium salicylate in a chronic rotenone model of Parkinson’s disease. Neuroscience 231:420–431. CrossRefPubMedGoogle Scholar
  21. 21.
    Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. BioEssays 24(4):308–318. CrossRefPubMedGoogle Scholar
  22. 22.
    Khurana N, Gajbhiye A (2013) Ameliorative effect of Sida cordifolia in rotenone-induced oxidative stress model of Parkinson’s disease. Neurotoxicology 39:57–64. CrossRefPubMedGoogle Scholar
  23. 23.
    Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T et al (2003) Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 23(34):10756–10764Google Scholar
  24. 24.
    Ulusoy GK, Celik T, Kayir H, Gürsoy M, Isik AT, Uzbay TI (2011) Effects of pioglitazone and retinoic acid in a rotenone model of Parkinson’s disease. Brain Res Bull 85(6):380–384. CrossRefPubMedGoogle Scholar
  25. 25.
    Gao HM, Liu B, Hong JS (2003) Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 23(15):6181–6187CrossRefPubMedGoogle Scholar
  26. 26.
    Gao HM, Hong JS, Zhang W, Liu B (2002) Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22(3):782–790CrossRefPubMedGoogle Scholar
  27. 27.
    Kandil EA, Abdelkader NF, El-Sayeh BM, Saleh S (2016) Imipramine and amitriptyline ameliorate the rotenone model of Parkinson’s disease in rats. Neuroscience 332:26–37. CrossRefPubMedGoogle Scholar
  28. 28.
    Samantaray S, Knaryan VH, Guyton MK, Matzelle DD, Ray SK, Banik NL (2007) The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. Neuroscience 146(2):741–755. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sapkota K, Kim S, Park SE, Kim SJ (2011) Detoxified extract of Rhus verniciflua stokes inhibits rotenone-induced apoptosis in human dopaminergic cells, SH-SY5Y. Cell Mol Neurobiol 31(2):213–223. CrossRefPubMedGoogle Scholar
  30. 30.
    Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation. Exp Neurol 179(1):9–16. CrossRefPubMedGoogle Scholar
  31. 31.
    DeMaagd G, Philip A (2015) Part 2: Introduction to the pharmacotherapy of Parkinson’s disease, with a focus on the use of dopaminergic agents. Pharmacy and Therapeutics 40(9):590–600PubMedPubMedCentralGoogle Scholar
  32. 32.
    Oertel WH, Quinn NP (1997) Parkinson’s disease: drug therapy. Baillieres Clin Neurol 6(1):89–108PubMedGoogle Scholar
  33. 33.
    Strecker K, Schwarz J (2008) Parkinson’s disease: emerging pharmacotherapy. Expert Opin Emerg Drugs 13(4):573–591. CrossRefPubMedGoogle Scholar
  34. 34.
    Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH et al (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115(8):2083–2098.
  35. 35.
    Meuer K, Pitzer C, Teismann P, Krüger C, Göricke B, Laage R, Lingor P, Peters K et al (2006) Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson’s disease. J Neurochem 97(3):675–686.
  36. 36.
    Pollari E, Savchenko E, Jaronen M, Kanninen K, Malm T, Wojciechowski S, Ahtoniemi T, Goldsteins G et al (2011) Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 8(1):74.
  37. 37.
    Chao PK, Lu KT, Lee YL, Chen JC, Wang HL, Yang YL, Cheng MY, Liao MF et al (2012) Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury. PLoS One 7(8):e43680.
  38. 38.
    Li L, McBride DW, Doycheva D, Dixon BJ, Krafft PR, Zhang JH, Tang J (2015) G-CSF attenuates neuroinflammation and stabilizes the blood-brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats. Exp Neurol 272:135–144. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Song S, Kong X, Acosta S, Sava V, Borlongan C, Sanchez-Ramos J (2016) Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. J Neurosci Res 94(5):409–423. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y et al (2006) Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 26(3):402–413.
  41. 41.
    Zavala F, Abad S, Ezine S, Taupin V, Masson A, Bach JF (2002) G-CSF therapy of ongoing experimental allergic encephalomyelitis via chemokine- and cytokine-based immune deviation. J Immunol 168(4):2011–2019. CrossRefPubMedGoogle Scholar
  42. 42.
    Crawford J (2003) Safety and efficacy of pegfilgrastim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy 23(8 Pt 2):15S–19S. CrossRefPubMedGoogle Scholar
  43. 43.
    Mahdy HM, Tadros MG, Mohamed MR, Karim AM, Khalifa AE (2011) The effect of Ginkgo biloba extract on 3-nitropropionic acid-induced neurotoxicity in rats. Neurochem Int 59(6):770–778. CrossRefPubMedGoogle Scholar
  44. 44.
    Bishnoi M, Chopra K, Kulkarni SK (2006) Involvement of adenosinergic receptor system in an animal model of tardive dyskinesia and associated behavioral, biochemical, and neurochemical changes. Eur J Pharmacol 552(1–3):55–66. CrossRefPubMedGoogle Scholar
  45. 45.
    Price DA, Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, Strong R, Lutz B et al (2009) WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur J Neurosci 29(11):2177–2186.
  46. 46.
    Costall B, Naylor RJ (1974) On catalepsy and catatonia and the predictability of the catalepsy test for neuroleptic activity. Psychopharmacologia 34(3):233–241. CrossRefPubMedGoogle Scholar
  47. 47.
    Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) 3-nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18(4):492–498. CrossRefPubMedGoogle Scholar
  48. 48.
    Bancroft JD, Stevens A, Turner DR (1996) Theory and practice of histological techniques, 4th edn. Churchil Livingstone, New YorkGoogle Scholar
  49. 49.
    Bancroft JD, Gamble M (2002) Theory and practice of histological techniques, 5th edn. Churchil Livingstone, EdinburghGoogle Scholar
  50. 50.
    Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A, Ottolenghi S, Pandolfi PP et al (2004) Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131(15):3805–3819.
  51. 51.
    Yuan GJ, Zhou XR, Gong ZJ, Zhang P, Sun XM, Zheng SH (2006) Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury. World J Gastroenterol 12(15):2375–2381. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34(2):279–290. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gibson CL, Bath PM, Murphy SP (2005) G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25(4):431–439. CrossRefPubMedGoogle Scholar
  54. 54.
    Schäbitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Schölzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34(3):745–751. CrossRefPubMedGoogle Scholar
  55. 55.
    Prakash A, Medhi B, Chopra K (2013) Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer’s disease. Pharmacol Biochem Behav 110:46–57. CrossRefPubMedGoogle Scholar
  56. 56.
    Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 163(1):55–72. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Duning T, Schiffbauer H, Warnecke T, Mohammadi S, Floel A, Kolpatzik K, Kugel H, Schneider A et al (2011) G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial. PLoS One 6(3):e17770.
  58. 58.
    Cao XQ, Arai H, Ren YR, Oizumi H, Zhang N, Seike S, Furuya T, Yasuda T et al (2006) Recombinant human granulocyte colony-stimulating factor protects against MPTP-induced dopaminergic cell death in mice by altering Bcl-2/Bax expression levels. J Neurochem 99(3):861–867.
  59. 59.
    Alam M, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136(1):317–324. CrossRefPubMedGoogle Scholar
  60. 60.
    Frank T, Klinker F, Falkenburger BH, Laage R, Lühder F, Göricke B, Schneider A, Neurath H et al (2012) Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson’s disease. Brain 135(Pt 6):1914–1925.
  61. 61.
    Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501. CrossRefPubMedGoogle Scholar
  62. 62.
    Cookson MR, van der Brug M (2008) Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp Neurol 209(1):5–11. CrossRefPubMedGoogle Scholar
  63. 63.
    Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, Cerny R, Gelman B et al (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 104(6):1504–1525.
  64. 64.
    Rocha NP, de Miranda AS, Teixeira AL (2015) Insights into neuroinflammation in Parkinson’s disease: from biomarkers to anti-inflammatory-based therapies. Biomed Res Int 2015:628192–628112. PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7(4):354–365. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Collins LM, Toulouse A, Connor TJ, Nolan YM (2012) Contributions of central and systemic inflammation to the pathophysiology of Parkinson’s disease. Neuropharmacology 62(7):2154–2168. CrossRefPubMedGoogle Scholar
  67. 67.
    Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20(16):6309–6316CrossRefPubMedGoogle Scholar
  68. 68.
    Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52(6):1830–1836. CrossRefPubMedGoogle Scholar
  69. 69.
    Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36(3):348–355. CrossRefPubMedGoogle Scholar
  70. 70.
    Lee JS, Yang CC, Kuo YM, Sze CI, Hsu JY, Huang YH, Tzeng SF, Tsai CL et al (2012) Delayed granulocyte colony-stimulating factor treatment promotes functional recovery in rats with severe contusive spinal cord injury. Spine (Phila Pa 1976) 37(1):10–17.
  71. 71.
    Gall CM, Gold SJ, Isackson PJ, Seroogy KB (1992) Brain-derived neurotrophic factor and neurotrophin-3 mRNAs are expressed in ventral midbrain regions containing dopaminergic neurons. Mol Cell Neurosci 3(1):56–63. CrossRefPubMedGoogle Scholar
  72. 72.
    Altar CA, DiStefano PS (1998) Neurotrophin trafficking by anterograde transport. Trends Neurosci 21(10):433–437. CrossRefPubMedGoogle Scholar
  73. 73.
    Anusha C, Sumathi T, Joseph LD (2017) Protective role of apigenin on rotenone induced rat model of Parkinson’s disease: suppression of neuroinflammation and oxidative stress mediated apoptosis. Chem Biol Interact 269:67–79. CrossRefPubMedGoogle Scholar
  74. 74.
    Perier C, Bové J, Vila M (2012) Mitochondria and programmed cell death in Parkinson’s disease: apoptosis and beyond. Antioxid Redox Signal 16(9):883–895. CrossRefPubMedGoogle Scholar
  75. 75.
    Hartmann A, Michel PP, Troadec JD, Mouatt-Prigent A, Faucheux BA, Ruberg M, Agid Y, Hirsch EC (2001) Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson’s disease? J Neurochem 76(6):1785–1793. CrossRefPubMedGoogle Scholar
  76. 76.
    Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (2000) Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J Neural Transm (Vienna) 107(3):335–341. CrossRefGoogle Scholar
  77. 77.
    Tatton NA (2000) Increased caspase-3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson’s disease. Exp Neurol 166(1):29–43. CrossRefPubMedGoogle Scholar
  78. 78.
    Nagatsu T (2002) Parkinson’s disease: changes in apoptosis related factors suggesting possible gene therapy. J Neural Transm (Vienna) 109(5–6):731–745. CrossRefGoogle Scholar
  79. 79.
    Chen Y, Zhang DQ, Liao Z, Wang B, Gong S, Wang C, Zhang MZ, Wang GH et al (2015) Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiplerodent models of Parkinson’s disease. Mol Neurodegener 10(1):4.
  80. 80.
    Lieberthal W, Menza SA, Levine JS (1998) Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Phys 274(2 Pt 2):F315–F327Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyAin Shams UniversityCairoEgypt

Personalised recommendations