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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Chao Li, Wenjie Xie, Joseph Janokovic & Weidong Le

  2. Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Road, Jinan, China

    Chao Li & Xingang Li

  3. Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

    Yuan Guo

Authors
  1. Chao Li
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  2. Yuan Guo
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  3. Wenjie Xie
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  4. Xingang Li
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  6. Weidong Le
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Correspondence to Xingang Li or Weidong Le.

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Chao Li and Yuan Guo contributed equally to this work.

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Li, C., Guo, Y., Xie, W. et al. Neuroprotection of Pramipexole in UPS Impairment Induced Animal Model of Parkinson’s Disease. Neurochem Res 35, 1546–1556 (2010). https://doi.org/10.1007/s11064-010-0214-3

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