Blockade of microglia activation in neuroprotective in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson disease

D. C. Wu, V. Jackson-Lewis, M. Vila, K. Tieu, Peter Teismann, C. Vadseth, D. -. K. Choi, H. Ischiropoulous, S. Przedborski

Research output: Contribution to journalArticle

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Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1 and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.

Original languageEnglish
Pages (from-to)1763-1771
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number5
Publication statusPublished - 1 Mar 2002

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Microglia
Minocycline
Nitric Oxide Synthase Type II
Parkinson Disease
NADPH Oxidase
Dopaminergic Neurons
Neurotoxins
Neuroprotective Agents
Tetracycline
Interleukin-1
Neuroglia
Neurodegenerative Diseases

Keywords

  • IL-1 beta
  • iNOS
  • minocycline
  • microglia
  • MPTP
  • NADPH-oxidase
  • neurodegeneration
  • Parkinson's disease

Cite this

Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., ... Przedborski, S. (2002). Blockade of microglia activation in neuroprotective in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson disease. Journal of Neuroscience, 22(5), 1763-1771.

Blockade of microglia activation in neuroprotective in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson disease. / Wu, D. C.; Jackson-Lewis, V.; Vila, M.; Tieu, K.; Teismann, Peter; Vadseth, C.; Choi, D. -. K.; Ischiropoulous, H.; Przedborski, S.

In: Journal of Neuroscience, Vol. 22, No. 5, 01.03.2002, p. 1763-1771.

Research output: Contribution to journalArticle

Wu, DC, Jackson-Lewis, V, Vila, M, Tieu, K, Teismann, P, Vadseth, C, Choi, DK, Ischiropoulous, H & Przedborski, S 2002, 'Blockade of microglia activation in neuroprotective in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson disease' Journal of Neuroscience, vol. 22, no. 5, pp. 1763-1771.
Wu, D. C. ; Jackson-Lewis, V. ; Vila, M. ; Tieu, K. ; Teismann, Peter ; Vadseth, C. ; Choi, D. -. K. ; Ischiropoulous, H. ; Przedborski, S. / Blockade of microglia activation in neuroprotective in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson disease. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 5. pp. 1763-1771.
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AU - Jackson-Lewis, V.

AU - Vila, M.

AU - Tieu, K.

AU - Teismann, Peter

AU - Vadseth, C.

AU - Choi, D. -. K.

AU - Ischiropoulous, H.

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