Neurochemical Research

, Volume 35, Issue 10, pp 1546–1556 | Cite as

Neuroprotection of Pramipexole in UPS Impairment Induced Animal Model of Parkinson’s Disease

ORIGINAL PAPER
First Online:
Accepted:

Abstract

Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson’s disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin–proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD.

Keywords

Parkinson’s disease Pramipexole Lactacystin UPS Autophagy 

Abbreviations

AD

Alzheimer’s disease

ALP

Autophagy lysosome pathway

BDNF

Brain-derived neurotrophic factor

DA

Dopamine

DAB

3, 3-diaminobenzidine tetrachloride

DOPAC

4-dihydroxy-phenylacetic acid

DPBS

Dulbecco’s phosphate buffered saline

GDNF

Glial cell line-derived neurotrophic factor

GFAP

Glial fibrillary acidic protein

HD

Huntington’s disease

HVA

Homovanillic acid

LC3–II

Light chain3–II

MFB

Medial forebrain bundle

mTOR

Mammalian target of rapamycin

PBS

Phosphate-buffered saline

PD

Parkinson’s disease

ppx

Pramipexole

sn

Substantia nigra

TH

Tyrosine hydroxylase

UPS

Ubiquitin proteasome system

This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This work is supported by Research Grant from Boehringer Ingelheim Pharma GmbH & Co. KG Research Grant, and Diana Helis Henry Medical Research Foundation We also thank the High Resolution Electron Microscopy Facility, University of Texas MD Anderson for their help in electronic microscope examination.

References

  1. 1.
    Snyder H, Wolozin B (2004) Pathological proteins in Parkinson’s disease: focus on the proteasome. J Mol Neurosci 24:425–442CrossRefPubMedGoogle Scholar
  2. 2.
    Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Ann Rev Neurosci 28:57–87CrossRefPubMedGoogle Scholar
  3. 3.
    Le W, Chen S, Jankovic J (2009) Etiopathogenesis of Parkinson disease: a new beginning? Neuroscientist 15:28–35Google Scholar
  4. 4.
    Barone P (2003) Clinical strategies to prevent and delay motor complications. Neurology 61:S12–S16PubMedGoogle Scholar
  5. 5.
    Jankovic J (2006) An update on the treatment of Parkinson’s disease. Mt Sinai J Med 73:682–689PubMedGoogle Scholar
  6. 6.
    Clarke CE, Guttman M (2002) Dopamine agonist monotherapy in Parkinson’s disease. Lancet 360:1767–1769CrossRefPubMedGoogle Scholar
  7. 7.
    Shannon KM, Bennett JP Jr, Friedman JH (1997) Efficacy of pramipexole a novel dopamine agonist, in mild to moderate Parkinson’s disease. The pramipexole study group. Neurology 49:724–728PubMedGoogle Scholar
  8. 8.
    Albrecht S, Buerger E (2009) Potential neuroprotection mechanisms in PD: focus on dopamineagonist pramipexole. Curr Med Res Opin 25:2977–2987CrossRefPubMedGoogle Scholar
  9. 9.
    Le WD, Jankovic J (2001) Are dopamine receptor agonists neuroprotective in Parkinson’s disease? Drugs Aging 18:389–396CrossRefPubMedGoogle Scholar
  10. 10.
    Zou LL, Xu J, Jankovic J, He Y, Appel SH, Le W (2000) Pramipexole inhibits lipid peroxidation and reduces injury in the substantia nigra induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in C57BL/6 mice. Neurosci Lett 281:167–170CrossRefPubMedGoogle Scholar
  11. 11.
    Cassarino DS, Fall CP, Smith TS, Bennett JP Jr (1998) Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion. J Neurochem 71:295–301CrossRefPubMedGoogle Scholar
  12. 12.
    Joyce JN, Millan MJ (2007) Dopamine D3 receptor agonists for protection and repair in Parkinson’s disease. Curr Opin Pharmacol 7:100–105CrossRefPubMedGoogle Scholar
  13. 13.
    Olanow CW, Kordower JH (2009) Modeling Parkinson’s disease. Ann Neurol 66:432–435CrossRefPubMedGoogle Scholar
  14. 14.
    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 3:1301–1306CrossRefPubMedGoogle Scholar
  15. 15.
    Höglinger GU, Oertel WH, Hirsch EC (2006) The rotenone model of parkinsonism–the five years inspection. J Neural Transm Suppl 70:269–272CrossRefPubMedGoogle Scholar
  16. 16.
    Sun F, Kanthasamy A, Anantharam V, Kanthasamy AG (2007) Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson’s disease. Pharmacol Ther 114:327–344CrossRefPubMedGoogle Scholar
  17. 17.
    Cook C, Petrucelli L (2009) A critical evaluation of the ubiquitin-proteasome system in Parkinson’s disease. Biochem Biophys Acta 1792:664–675PubMedGoogle Scholar
  18. 18.
    Bennett EJ, Bence NF, Jayakumar R, Kopito RR (2005) Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17:351–365CrossRefPubMedGoogle Scholar
  19. 19.
    McNaught KS, Olanow CW (2006) Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol Aging 27:530–545CrossRefPubMedGoogle Scholar
  20. 20.
    Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang X, Xie WJ, Qu S, Pan T, Wang X, Le W (2005) Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochem Biophys Res Commun 333:544–549CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu W, Xie WJ, Pan TH, Jankovic J, Li J, Youdim MB, Le W (2007) Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. FASEB J 21:3835–3844CrossRefPubMedGoogle Scholar
  23. 23.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721CrossRefPubMedGoogle Scholar
  24. 24.
    Martinez-Vicente M, Cuervo AM (2007) Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 6:352–361CrossRefPubMedGoogle Scholar
  25. 25.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884CrossRefPubMedGoogle Scholar
  26. 26.
    Glaser JR, Glaser EM (2000) Stereology, morphometry, and mapping: the whole is greater than the sum of its parts. J Chem Neuroanat 20:115–126CrossRefPubMedGoogle Scholar
  27. 27.
    Du F, Li R, Huang Y, Li X, Le W (2005) Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons. Eur J Neurosci 22:2422–2430CrossRefPubMedGoogle Scholar
  28. 28.
    Zemke D, Azhar S, Majid A (2007) The mTOR pathway as a potential target for the development of therapies against neurological disease. Drug News Perspect 20:495–499CrossRefPubMedGoogle Scholar
  29. 29.
    Pan TH, Kondo S, Zhu W, Xie W, Jankovic J, Le W (2008) Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 32:16–25CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of NeurologyBaylor College of MedicineHoustonUSA
  2. 2.Department of NeurosurgeryQilu Hospital of Shandong UniversityJinanChina
  3. 3.Department of CardiologyQilu Hospital of Shandong UniversityJinanChina

Personalised recommendations