Neurochemical Research

, Volume 35, Issue 10, pp 1546–1556

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

ORIGINAL PAPER

DOI: 10.1007/s11064-010-0214-3

Cite this article as:
Li, C., Guo, Y., Xie, W. et al. Neurochem Res (2010) 35: 1546. doi:10.1007/s11064-010-0214-3

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 diseasePramipexoleLactacystinUPSAutophagy

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

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