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Research ArticleArticle

Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels

Serge Guerreiro, Damien Toulorge, Etienne Hirsch, Marc Marien, Pierre Sokoloff and Patrick P. Michel
Molecular Pharmacology October 2008, 74 (4) 980-989; DOI: https://doi.org/10.1124/mol.108.048207
Serge Guerreiro
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Damien Toulorge
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Etienne Hirsch
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Marc Marien
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Pierre Sokoloff
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Patrick P. Michel
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Abstract

Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.

Footnotes

  • S.G. and D.T. contributed equally to this work.

  • ABBREVIATIONS: DA, dopamine (dopaminergic); PD, Parkinson's disease; PX, paraxanthine; GDNF, glial cell line-derived neurotrophic factor; Ca2+cyt, free cytosolic calcium; RyR, ryanodine receptor; MPP+, 1-methyl-4-phenylpyridinium; MX, methylxanthine; PSB36, 1-butyl-8-(hexahydro-2, 5-methanopentalen-3a(1H)-yl)-3, 7-dihydro-3-(3-hydroxy-propyl)-1H-purine-2, 6-dione; SCH 58261, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4, 3-epsilon]-1, 2, 4-triazolo[1, 5-c]pyrimidine; MRS1334, 1, 4-dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3, 5-pyridinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)-methyl]ester; NMDA, N-methyl-d-aspartate; MK-801, 5H-dibenzo[a,d]cyclohepten-5, 10-imine (dizocilpine maleate); TH, tyrosine hydroxylase; DIV, day in vitro; PBS, phosphate-buffered saline; MAP, microtubule-associated protein; GBR-12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine.

    • Received April 24, 2008.
    • Accepted July 11, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (4)
Molecular Pharmacology
Vol. 74, Issue 4
1 Oct 2008
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Research ArticleArticle

Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels

Serge Guerreiro, Damien Toulorge, Etienne Hirsch, Marc Marien, Pierre Sokoloff and Patrick P. Michel
Molecular Pharmacology October 1, 2008, 74 (4) 980-989; DOI: https://doi.org/10.1124/mol.108.048207

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Research ArticleArticle

Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels

Serge Guerreiro, Damien Toulorge, Etienne Hirsch, Marc Marien, Pierre Sokoloff and Patrick P. Michel
Molecular Pharmacology October 1, 2008, 74 (4) 980-989; DOI: https://doi.org/10.1124/mol.108.048207
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