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Neurotoxicity Research

, Volume 16, Issue 4, pp 361–371 | Cite as

Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3

  • Yuri Cho
  • Hyo Jin Son
  • Eun-Mee Kim
  • Ji Hyun Choi
  • Sung Tae Kim
  • In Jung Ji
  • Dong Hee Choi
  • Tong H. Joh
  • Yoon Seong Kim
  • Onyou HwangEmail author
Article

Abstract

In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-α, as well as gene expression of iNOS, TNF-α, IL-1β, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.

Keywords

Doxycycline Matrix metalloproteinase-3 Parkinson’s disease Microglia Dopaminergic neurons 

Notes

Acknowledgment

This work was supported by Brain Research Center of the 21st Century Frontier Research Program of the Ministry of Science & Technology (2009K0012510) to O. Hwang.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yuri Cho
    • 1
  • Hyo Jin Son
    • 1
  • Eun-Mee Kim
    • 1
  • Ji Hyun Choi
    • 1
  • Sung Tae Kim
    • 1
  • In Jung Ji
    • 1
  • Dong Hee Choi
    • 1
  • Tong H. Joh
    • 2
  • Yoon Seong Kim
    • 2
  • Onyou Hwang
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA

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