JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on September 20, 2002
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow All Versions of this Article:
277/39/36040    most recent
M206830200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, J.-F.
Right arrow Articles by Schwarzschild, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, J.-F.
Right arrow Articles by Schwarzschild, M. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Papers In Press, published online ahead of print July 18, 2002
J. Biol. Chem, 10.1074/jbc.M206830200
Submitted on July 9, 2002
Revised on July 18, 2002
Accepted on July 18, 2002

8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of MAO inhibition and A2A receptor antagonism

Jiang-Fan Chen, Salome Steyn, Roland Staal, Jacobus P. Petzer, Kui Xu, Cornelis J. Van der Schyf, Kay Castagnoli, Patricia K. Sonsalla, Neal Castagnoli Jr, and Michael A. Schwarzschild

Neurology, Massachusetts General Hospital, Charlestown, MA 02129

Corresponding Author: chenjf{at}bu.edu, michaels@helix.mgh.harvard.edu

Caffeine and more specific antagonists of the adenosine A2A receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson’s disease (PD). Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A2A antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP+, we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP+ and of MPP+, suggesting that CSC blocks the conversion of MPTP to MPDP+ in vivo. In assessing the direct effects of CSC and A2A receptors on MAO activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a Ki value of 100 nM whereas caffeine and another relatively specific A2A antagonist produced little or no inhibition. The A2A receptor-independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A2A receptor knockout (A2A KO) and wild-type mice, and was confirmed by demonstrating potent inhibition of A2A KO-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
A. Kachroo, L. R. Orlando, D. K. Grandy, J.-F. Chen, A. B. Young, and M. A. Schwarzschild
Interactions between Metabotropic Glutamate 5 and Adenosine A2A Receptors in Normal and Parkinsonian Mice
J. Neurosci., November 9, 2005; 25(45): 10414 - 10419.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. Hubalek, C. Binda, A. Khalil, M. Li, A. Mattevi, N. Castagnoli, and D. E. Edmondson
Demonstration of Isoleucine 199 as a Structural Determinant for the Selective Inhibition of Human Monoamine Oxidase B by Specific Reversible Inhibitors
J. Biol. Chem., April 22, 2005; 280(16): 15761 - 15766.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
B. B. Fredholm and P. Svenningsson
Adenosine-dopamine interactions: Development of a concept and some comments on therapeutic possibilities
Neurology, December 9, 2003; 61(90116): S5 - 9.
[Abstract] [Full Text]

Home page
 NeurologyHome page
P. Jenner
A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD
Neurology, December 9, 2003; 61(90116): S32 - 38.
[Abstract] [Full Text]

Home page
 NeurologyHome page
F. Pedata, A. M. Pugliese, A. Melani, and M. Gianfriddo
Introduction: A2A receptors in neuroprotection of dopaminergic neurons
Neurology, December 9, 2003; 61(90116): S49 - 50.
[Full Text]

Home page
 NeurologyHome page
M. A. Schwarzschild, K. Xu, E. Oztas, J. P. Petzer, K. Castagnoli, N. Castagnoli Jr., and J.-F. Chen
Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson's disease
Neurology, December 9, 2003; 61(90116): S55 - 61.
[Abstract] [Full Text]

Home page
 NeurologyHome page
N. Castagnoli Jr., J. P. Petzer, S. Steyn, K. Castagnoli, J.-F. Chen, M. A. Schwarzschild, and C. J. Van der Schyf
Monoamine oxidase B inhibition and neuroprotection: Studies on selective adenosine A2A receptor antagonists
Neurology, December 9, 2003; 61(90116): S62 - 68.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.