Decaffeinated Coffee and Nicotine-Free Tobacco Provide Neuroprotection in Drosophila Models of Parkinson's Disease through an NRF2-Dependent Mechanism

Abstract

Epidemiological studies have revealed a significantly reduced risk of Parkinson's disease (PD) among coffee and tobacco users, although it is unclear whether these correlations reflect neuroprotective/symptomatic effects of these agents or preexisting differences in the brains of tobacco and coffee users. Here, we report that coffee and tobacco, but not caffeine or nicotine, are neuroprotective in fly PD models. We further report that decaffeinated coffee and nicotine-free tobacco are as neuroprotective as their caffeine and nicotine-containing counterparts and that the neuroprotective effects of decaffeinated coffee and nicotine-free tobacco are also evident in Drosophila models of Alzheimer's disease and polyglutamine disease. Finally, we report that the neuroprotective effects of decaffeinated coffee and nicotinefree tobacco require the cytoprotective transcription factor Nrf2 and that a known Nrf2 activator in coffee, cafestol, is also able to confer neuroprotection in our fly models of PD. Our findings indicate that coffee and tobacco contain Nrf2-activating compounds that may account for the reduced risk of PD among coffee and tobacco users. These compounds represent attractive candidates for therapeutic intervention in PD and perhaps other neurodegenerative diseases.

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…Our results indicate that caffeine is not the primary protective compound in aqueous coffee extracts, in agreement with the Drosophila studies examining the protective effects of coffee in PD models (Trinh et al 2010). We cannot exclude the possibility that the protective effects of coffee are due to changes in the E. coli food source used in these experiments, but this seems highly unlikely given the effects of coffee extracts in other systems, such as flies, Figure 5.-SKN-1 is required for coffee extract protection against Ab 42 -induced paralysis.…”

“…Similarly, chemical or genetic activation of the Nrf2 pathway is protective in multiple Drosophila models of PD (Trinh et al 2008). Of perhaps greatest relevance to our C. elegans studies, coffee and tobacco extracts have recently been shown to be protective in Drosophila neurodegeneration models, and this protection is Nrf2 dependent (Trinh et al 2010). Our demonstration that coffee exposure protects against GFPTdegron, a model toxic aggregating protein not associated with a specific disease, further supports the generality of protection by Nrf2 activation.…”

“…Multiple components of coffee have been shown to induce Nrf2 activation, including cafestol and kahweol (Higgins et al 2008), and cafestol is protective in the Drosophila PD models (Trinh et al 2010). A number of natural polyphenols, including hydroxytyrosol (Martin et al 2010), quercetin (Kimura et al 2009), and epigallocatechin-3-gallate (Na et al 2008), have also been shown to activate the Nrf2 pathway.…”

“…Coffee extract preparation: We employed an aqueous extraction protocol originally developed in the Pallanck lab (Trinh et al 2010). Coffee beans (Starbucks House Blend, caffeinated or decaffeinated) were ground for 3 min in a standard coffee grinder, and then an 18.4% (w/v) slurry of grounds in deionized water was boiled for 30 min before removing grounds with a French press.…”

“…Caffeine concentrations were based on the caffeine concentration reported for Starbucks caffeinated drip coffee or from direct mass spectroscopy measurements of decaffeinated coffee extracts (Trinh et al 2010). Plates were spotted with Escherichia coli strain OP50 or, for feeding RNAi, strain HT115 transformed with a skn-1 dsRNA-expressing plasmid or vector-only control (Kamath et al 2003).…”