# Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Caffeine

   The research papers quoted here are but a small sample of a large body of literature pointing towards the neuroprotection from PD by caffeine and its metabolites.

## Background

Caffeine is a white, crystalline, xanthine alkaloid with the formula C$_8$H$_{10}$N$_4$O$_2$. It occurs naturally in coffee beans, tea leaves, and a number of seeds and fruit. In nature it functions as a pesticide, but in human nutrition serves as a neurological stimulant, being taken mostly in the form of ground, roasted coffee, tea infusions, soft drinks and energy drinks. It is one of a class of compounds known as purines which, in humans, are metabolised by the kidneys into uric acid which functions beneficially as an antioxidant and is excreted in urine. Over-expression of uric acid can result in the formation of urate crystals which are deposited by gravity in the lower limbs leading to the painful condition known as gout.

## Research

2000
Ross et al conducted a survey of 8,004 Japanese/ American men aged 45 to 68 years over a 30 year period. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849921/?tool=pmcentrez There were 102 cases of P.D. Statistical analysis showed that the risk of contracting PD decreased proportionately to the amount of coffee in the diet from 10.4 per 10,000 in non-coffee drinkers to 1.9 per 10,000 among those who drank 28 oz, or more per day. The same ratios held for men who imbibed caffeine from other sources. They also found that:-
   Other nutrients in coffee, including niacin, were unrelated to PD incidence. The relationship between caffeine and PD was unaltered by intake of milk and sugar.
2001
Ascherto et al ,studied two cohorts comprising 47,351 men and 88,565 women who were free of Parkinson's disease stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), they documented a total of 288 incident cases of Parkinson's disease. An inverse association was also observed with consumption of coffee.
Chen et al measured the effects of caffeine consumption on animal PD models. They concluded:-
   These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.
2002
Xu et al,studied the effects of caffeine upon Parkinsonian mice. Their conclusions stated:-
   Acute pretreatment with caffeine attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites, and this attenuation was identical in mice pretreated chronically with caffeine or with saline. Thus, in contrast to the locomotor stimulant effect of caffeine, its neuroprotectant effect did not show tolerance to prior caffeine exposure. These data raise the possibility that caffeine may induce neuroprotection and locomotion by distinct mechanisms.
2003
Aschierto et al studied the influence of female hormones upon the neuroprotective effects of caffeine upon PD. They concluded:-
   These results suggest that caffeine reduces the risk of PD among women who do not use postmenopausal hormones, but increases risk among hormone users. Clinical trials of caffeine or estrogens in women should avoid the combined use of these agents.
Tan et al examined the relationship between coffee and tea drinking, cigarette smoking, and other environmental factors and risk of PD among ethnic Chinese. 200 case controlled pairs matched for age, gender, and race were recorded.
The resultant statistical analysis demonstrated that the amount of coffee drunk, the amount of tea drunk, the number of cigarettes smoked, the history of heavy metal and toxin exposure, and the history of heart disease were all factors which had a bearing on the onset of PD. One unit of coffee and tea (3 cups/day for 10 years) would lead to a 22% and 28% risk reduction of PD. One unit of cigarette smoke (3 packs/day for 10 years) reduced the risk of PD by 62%.
2004
Joghataie et al sought to assess the effect of administering caffeine to Parkinsonian rats. They concluded:-
   The results demonstrated that caffeine administration for 1 month could attenuate the rotational behavior in lesioned rats and protect the neurons of SNC against 6-OHDA toxicity.
2006
Aguiar et al carried out further studies of the effects of caffeine on parkinsonian rats.
   In conclusion, our data demonstrated beneficial effects of caffeine in this model of PD, suggesting the potential use of A2A antagonists as a novel treatment for this neurodegenerative disease.
Xu et al [9]sought to explain previously observed gender differences on the neuroprotective effects of caffeine upon PD. They studied the effects of caffeine on Parkinsonian mice coupled with the presence of oestrogen. They found that:-
   These results suggest that oestrogen can occlude and thereby prevent the neuroprotective effect of caffeine in a model of PD neurodegeneration.
2008
Sääksjärvi et al studied a cohort of 6,710 men and women, aged 50-79 years and free from Parkinson's disease at the baseline. At baseline, enquiries were made about coffee consumption in a self-administered questionnaire. They reported:-
   After adjustments for age, sex, marital status, education, community density, alcohol consumption, leisure-time physical activity, smoking, body mass index, hypertension and serum cholesterol, the relative risk for subjects drinking 10 or more cups of coffee per day compared with non-drinkers was 0.26. The results support the hypothesis that coffee consumption reduces the risk of Parkinson's disease, but protective effect of coffee may vary by exposure to other factors.
2010
Costa et al reviewed the evidence from 22 previous epidemiological studies and concluded-
   This study confirms an inverse association between caffeine intake and the risk of PD, which can hardly by explained by bias or uncontrolled confounding.
Kachroo et al[12]tested the effects of caffeine against PD models induced by the use of the pesticides Paraquat and Maneb. The conclusions were:-
   Caffeine at 20mg/kg significantly reduced TH+ neuron loss (to 85% of the respective control). The results demonstrate the neuroprotective potential of caffeine in a chronic pesticide exposure model of model of PD.
Trin et al found that coffee and tobacco, but not caffeine or nicotine, are neuroprotective in fly PD models, and that decaffeinated coffee and nicotine-free tobacco are as neuroprotective as their caffeine and nicotine-containing counterparts and also that the neuroprotective effects of decaffeinated coffee and nicotine-free tobacco are also evident in Drosophila models of Alzheimer's disease and polyglutamine disease.
They also report that the neuroprotective effects of decaffeinated coffee and nicotine-free tobacco require the cytoprotective transcription factor Nrf2 and that a known Nrf2 activator in coffee, cafestol, is also able to confer neuroprotection in fly models of PD. They sum up these findings as:-
   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.
Xu et all examined the time window of caffeine's neuroprotection as well as the effects of caffeine's metabolites (theophylline and paraxanthine) in the MPTP mouse model of PD. Their findings were:-
   In the first experiment, caffeine pre-treatment (30 mg/kg ip) significantly attenuated MPTP-induced striatal dopamine depletion when it was given 10 min, 30 min, 1 h, or 2 h but not 6 h before MPTP (40 mg/kg ip) treatment. Meanwhile, caffeine post-treatment also significantly attenuated striatal dopamine loss when it was given 10 min, 30 min, 1 h or 2 h but not 4 h, 8 h or 24 h after MPTP injection. In the second experiment, both theophylline (10 or 20 mg/kg) and paraxanthine (10 or 30 mg/kg) administration (10 min before MPTP) significantly attenuated MPTP-induced dopamine depletion in mice, as did caffeine (10 mg/kg) treatment.
   Thus the metabolites of caffeine also provide neuroprotective effects in this mouse model of PD. The data suggest that if caffeine protects against putative toxin-induced dopaminergic neuron injury in humans, then precise temporal pairing between caffeine and toxin exposures may not be critical because the duration of neuroprotection by caffeine may be extended by protective effects of its major metabolites.
2011
Tanaka et al carried out a study of 249 PD cases and 368 controls to see whether the previously recorded neuroprotective benefits of drinking coffee were repeated for Japanese and Chinese teas. (also caffeine-rich). Their results concluded:-
   A clear inverse dose-response relationship between total caffeine intake and PD risk was observed. We confirmed that the intake of coffee and caffeine reduced the risk of PD. Furthermore, this is the first study to show a significant inverse relationship between the intake of Japanese and Chinese teas and the risk of PD.
2012
Previous epidemiological research has shown that the intake of caffeine reduces the risk of contracting PD. Postuma et al set out to establish whether caffeine might be beneficial to people with PD.
A cohort of 61 PD patients was assembled and and given additional caffeine intake or a placebo for 6 weeks. The rest were given placebos. Measurements were taken at the start and end of the experiment of mobility, sleep markers, fatigue, depression, and quality of life. The result was that the mobility of patients on enhanced caffeine improved: other factors were unaffected.
There is scope for a continuation of this work to establish the duration of th benefits conferred and the effect on uric acid levels.

## Further Reading

2007
Gao,Xiang; Chen, Honglei; Fung, Tresa T.; Logroscino, Giancarlo; Schwarzchild, Michael A.; Hu, FrankB. And Ascherio, Alberto Full Text Am. J. Clin. Nutr. 86 (5): 1486 – 1494.
Prospective study of dietary pattern and risk of Parkinson disease.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225168/?tool=pmcentrez
2010
Tan, Louis C.; Koh, Woon-Puay; Yuan, Jian-Min; Wang, Renwei; Au, Wing-Lok; Tan, June H,; Tan. Eng-King and Yu, Mimi C. Full Text Am. J. Epidemiol. 167 (5): 553–560.
Differential Effects of Black versus Green Tea on Risk of Parkinson's Disease in the Singapore Chinese Health Study
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737529/?tool=pmcentrez
Morelli, Micaela: Anna R Carta, Anna R,; Kachroo, Anil and Schwarzschild, Michael A. Full Text Prog. Brain Res. 183: 183–208.
Pathophysiological roles for purines: adenosine, caffeine and urate.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102301/?tool=pmcentrez
Today
   Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease Caffeine.
   This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.
Pubmed (abstracts)
Pubmed_Central (Full_Text)
Google_Scholar

## Related pages

Therapy > Neuroprotection
Sub Pages:
    Neuroprotective agents
    Substances with possible neuroprotective properties:
    Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--