RT Journal Article
SR Electronic
T1 Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 980
OP 989
DO 10.1124/mol.108.048207
VO 74
IS 4
A1 Serge Guerreiro
A1 Damien Toulorge
A1 Etienne Hirsch
A1 Marc Marien
A1 Pierre Sokoloff
A1 Patrick P. Michel
YR 2008
UL http://molpharm.aspetjournals.org/content/74/4/980.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics