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. 2017 Mar 20;23(4):272–290. doi: 10.1111/cns.12684

Table 3.

Summary of the human epidemiological studies and the in vitro and in vivo animal studies investigating the effect of caffeine on Parkinson's disease (PD)

Parkinson's disease (PD)—human epidemiological studies
Reference Participants Duration Main results Conclusion
Postuma et al., 2012 61 PD patients
Placebo: n=31 (19 M, 12 F)
Caffeine: n=30 (25 M, 5 F)
65‐68 y
6 wk
1st three wk: 100 mg caffeine, 2×/d
2nd three wk: 200 mg caffeine, 2×/d
Improved the total UPDRS (unified Parkinson's disease rating scale) by 4.7 points
Improved the motor manifestation by 3.2 points
Caffeine treatment in PD patients has potential motor benefits
Ross et al., 2000 8004
American Japanese men
53 y
27 y Caffeine >421 mg of caffeine: 5× ↓ risk of developing PD vs nondrinkers, 2.6× ↓ risk vs 124‐208 mg/d, 3.8× ↓ risk vs 209‐287 mg/d, and 2× ↓ risk vs 288‐420 mg/d. Caffeine has an inverse association with the risk of developing PD.
Liu et al., 2012 318 260 participants
187 499 women
130 761 men
61 y
9‐11 y Coffee at >5 cups/d: ↓ risk of PD in men (OR=0.70, CI=0.47‐1.04) and women (OR=0.74, CI=0.42‐1.29) vs nonusers
Women on hormone therapy: ↓ risk of PD development upon caffeine consumption
129‐511 mg/d OR=0.66 (CI=0.42‐1.05) vs intakes <17.4 mg/d
511‐590 mg/d OR=0.64 (CI=0.39‐1.04) vs intakes <17.4 mg/d
>590 mg/d OR=0.53 (CI=0.28‐0.98) vs intakes <17.4 mg/d
Caffeine has an inverse association with the risk of developing PD.
Qi et al., 2014 492 722 participants for caffeine
Women and men
901 764 participants for coffee
Women and men
For every 200 mg/d increment of caffeine, risk of PD ↓ by 17%
Coffee at ~ three cups/d (volume not identified): ↓ risk of PD (RR=0.72, CI=0.65‐0.81)
Coffee at two cups/d: 26% ↓ risk of PD vs nonusers
Coffee consumption (3 cups/d) ↓ PD risk in men (RR=0.68, CI=0.59‐0.78) and women (RR=0.76, CI=0.63‐0.93) vs nonusers
Coffee and caffeine consumption have inverse associations with the risk of developing PD.
Palacios et al., 2012 63 590 women
69 y
48 532 men
71 y
8 y Men—caffeine at 120 mg/d: ↓ risk of PD by 38% (RR=0.62, CI=0.40‐0.95) vs 9.2 mg/d
Men—caffeine at ≥274 mg/d (≥2 cups coffee/d) ↓ risk of PD by ~50% (RR=0.54, CI=0.37‐0.80) vs 9.2 mg/d
Men—caffeine at 478 mg/d ↓ risk of PD (RR=0.43, CI=0.26‐0.71) vs 9.2 mg/d
Women—caffeine at 435 mg/d (3.2 cups coffee/d) ↓ risk of PD by 40% (RR=0.61, CI=0.34‐1.09) vs 5.6 mg/d.
Caffeine has a protective effect against the risk of developing PD.
Hu et al., 2007 15 042 women
64.0 y
14 293 men
62.2 y
12.9 y In men, 0, 1‐4 cups, and >5 cups of coffee (100 mL/cup) had a hazard ratio of 1.00, 0.55 (CI=0.26‐1.15) and 0.41 (CI=0.19‐0.88), respectively, of PD
In women, 0, 1‐4 cups and >5 cups of coffee (100 mL/cup) had a hazard ratio of 1.00, 0.50 (CI=0.22‐1.12) and 0.39 (CI=0.17‐0.89), respectively, for PD.
Coffee drinking is associated with lower risk of developing PD
Ascherio et al., 2003 77 713 women
30‐55 y
18 y Postmenopausal hormone users + ~1/2 a cup of coffee/d (68 mg/d of caffeine): ↓ 34% risk of PD
Postmenopausal hormone users + five cups of coffee/d (688 mg/d of caffeine): ↑ 55% risk among
Use of postmenopausal hormone therapy was associated with a lower risk of PD in women with low caffeine intake, but it was associated with higher risk of PD in women with high caffeine intake.
Parkinson's disease—in vitro and in vivo animal studies
Reference Subjects Treatment Main results Conclusion
Bagga et al., 2015 PD mice
n=10 control
n=7 caffeine
n=10 MPTP
n=8 MPTP and caffeine
Males
4 mo
0.9 mg of caffeine
8 d of caffeine administration 30 min prior to MPTP treatment
Caffeine: ↓ neuron damage in the striatum
Caffeine: ↑ motor function (60.6% improvement in grip strength)
Pretreatment with caffeine provides partial neuroprotection against severe striatal degeneration in PD.
Sonsalla et al., 2012 Sprague Dawley rats
n=5 per group
Males
Age not identified
Oral caffeine (1 g/L in drinking water—equivalent to 60‐80 mg/kg/d in humans and plasma concentrations at ~22 μmol/L) Caffeine: ↓ loss of nigral dopamine cell bodies
Caffeine at 1 wk or 3 wk: ↓ the loss of nigral cells by 94% and 69%, respectively
Caffeine: ↓ microglia activation in the substantia nigra
Caffeine protects against the loss of nigral dopamine neurons in a chronic progressive rat model of PD.
Chen et al., 2001 C57BL6 mice
n=13 MPTP
n=5 saline
Male
9 mo
Caffeine administered 10 min before MPTP administration
(5, 10, 20, and 30 mg/kg)
Caffeine (10 mg/kg): residual dopamine was 40% of control vs 15% of control
Caffeine (20 mg/kg): reversed MPTP‐induced dopamine depletion
Caffeine at higher dosage caused excessive systemic toxicity.
There is a potential neural basis for the neuroprotection effects of caffeine in PD.
Xu et al., 2006 C57BL6 mice
n=3‐7 saline treatment
n=4‐15 MPTP
Females and males
Young: 10 wk
Old: 6‐9 mo
10, 20, 40 mg/kg of caffeine treatment
Caffeine administration 10 min before MPTP administration
Caffeine: ↓ MPTP‐induced dopamine loss (38% of the control dopamine levels) in a dose‐dependent manner in young male mice, with maximal effects achieved at 10 mg/kg (78% of the control dopamine levels with caffeine).
In old male mice, MPTP‐induced dopamine loss (3% of control without caffeine) ↓ by caffeine pretreatment in a dose‐dependent manner, with 10 mg/kg of caffeine offering the most neuroprotective effect (~30% of control with caffeine).
In female mice, caffeine ↓ toxicity only at 40 mg/kg. In ovariectomized mice treated with placebo (striatal dopamine 27% of control), caffeine at 5, 10, 20 mg/kg was neuroprotective.
In ovariectomized mice treated with estrogen (striatal dopamine 39% of control), caffeine was neuroprotective only at higher doses (40 mg/kg).
In males treated with estrogen, estrogen was neuroprotective, but caffeine in these mice did not attenuate their striatal dopamine loss.
Estrogen can prevent the neuroprotective effects of caffeine in a model of PD mice.
Nakaso et al., 2008 Human dopaminergic neuroblastoma cell lines Caffeine concentrations (10 and 100 μmol/L) Caffeine ↓cell death and ↓the number of apoptotic nuclei from 13.1% to 9.7% under MPP+‐exposed conditions
Caffeine (10 and 100 μmol/L) ↓ caspase 3 in a dose‐dependent manner (21% and 23%, respectively), ↑ Akt phosphorylation (1.96‐fold and 2.96‐fold, respectively).
Inhibiting PI3K/Akt pathway abolished caffeine's effects.
The neuroprotective effects of caffeine involve the PI3K/AKT pathway