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The Journal of Neuroscience, February 25, 2004, 24(8):1865-1872; doi:10.1523/JNEUROSCI.3309-03.2004

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Neurobiology of Disease
Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Tsuyoshi Furuya,¹ Hideki Hayakawa,¹ Masanori Yamada,² Kenji Yoshimi,² Shin Hisahara,³ Masayuki Miura,^4,5 Yoshikuni Mizuno,^1,2 and Hideki Mochizuki^1,2

¹Department of Neurology and ²Research Institute for Disease of Old Ages, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan, ³Department of Neurology, Department of Pharmacology Graduate School of Medicine, Program of Signal Transduction Medicine, Division of Brain-Neural Sciences, Neuro-molecular Pharmacology School of Medicine, Sapporo Medical University, Sapporo 060-8556, Japan, ⁴Laboratory for Cell Recovery Mechanisms, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, and ⁵Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

Key words: MPTP; Parkinson's disease; caspase-11; caspase-1; inflammation; apoptosis

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Received July 13, 2003; revised December 21, 2003; accepted December 21, 2003.

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