RT Journal Article
SR Electronic
T1 Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1763
OP 1771
DO 10.1523/JNEUROSCI.22-05-01763.2002
VO 22
IS 5
A1 Wu, Du Chu
A1 Jackson-Lewis, Vernice
A1 Vila, Miquel
A1 Tieu, Kim
A1 Teismann, Peter
A1 Vadseth, Caryn
A1 Choi, Dong-Kug
A1 Ischiropoulos, Harry
A1 Przedborski, Serge
YR 2002
UL http://www.jneurosci.org/content/22/5/1763.abstract
AB 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-1β 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.