title: Estrogen prevents neuroprotection by caffeine in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
abstract: Epidemiological studies have strongly linked caffeine consumption with a reduced risk of developing Parkinson's disease (PD) in men. Interestingly, in women, this inverse association is present only in those who have not taken postmenopausal estrogens, suggesting an interaction between the influences of estrogen and caffeine use on the risk of PD. To explore a possible biological basis for this interaction, we systematically investigated how the neuroprotective effect of caffeine is influenced by gender, ovariectomy (OVX), and then exogenous estrogen in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. (1) Caffeine treatment produced a dose-dependent attenuation of MPTP-induced striatal dopamine loss in both young and retired breeder (RB) male, but not female, mice. (2) In female mice (both young and RB), caffeine was less potent or altogether ineffective as a neuroprotectant after sham surgery compared to OVX or after OVX plus estrogen replacement compared to OVX plus placebo treatment. (3) Estrogen treatment also prevented the protection of caffeine against dopamine loss in young male mice. (4) Consistent with the putative protective effect of estrogen, female and OVX plus estrogen mice were relatively resistant to MPTP toxicity compared to male and OVX plus placebo mice, respectively. (5) There was no overall difference in brain levels of caffeine and its metabolites between OVX plus placebo and OVX plus estrogen mice. Together, these results suggest that estrogen can occlude and thereby prevent the neuroprotective effect of caffeine in a model of PD neurodegeneration, supporting a biological basis for the interaction between estrogen and caffeine in modifying the risk of PD.
authors.affiliation: Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. xu@helix.mgh.harvard.edu
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.forename: Yuehang
authors.initials: Y
authors.lastname: Xu
authors.forename: Deborah
authors.initials: D
authors.lastname: Brown-Jermyn
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.forename: Alberto
authors.initials: A
authors.lastname: Ascherio
authors.forename: Dean E
authors.initials: DE
authors.lastname: Dluzen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000367:Age Factors; D000818:Animals; D002110:Caffeine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004298:Dopamine / Q000032:analysis; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D010052:Ovariectomy; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: D004343:Drug Implants; D018696:Neuroprotective Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D002110:Caffeine; D004958:Estradiol; D019388:Cytochrome P-450 CYP1A2; D004298:Dopamine