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Caffeine and the Promise of Adenosine Antagonists in PD 
Michael A. Schwarzschild, MD, PhD (lead author)

Department Neurology, Massachusetts General Hospital, Boston Mass 

a National Parkinson Foundation Center of Excellence 

Neurology, 2002, volume 58, page 1154


Abstract
Large studies link drinking coffee and other caffeinated beverages to a
reduced risk of developing PD. Caffeine as well as more specific
antagonists of the adenosine A2A receptor have been found to decrease
neurotoxicity in a mouse model of PD. The convergence of these data
supports the possibility that caffeine may reduce the risk of developing
PD. However, a neuroprotective effect of caffeine in PD remains unproven.
Current evidence does not provide a basis for recommending caffeine
consumption to modify the risk or progression of PD. In addition to
possessing neuroprotective potential, caffeine and other A2A antagonists
have been known to reverse motor deficits in a variety of PD models. This
symptomatic benefit of blocking A2A receptors, coupled with their
restricted expression in the basal ganglia, have made A2A antagonists
targets for drug development.


Coffee, tea, and the risk for PD. 
Genetic clues are yielding insights not only into the cause of familial PD
but also into the pathways that likely contribute to typical PD. Moreover,
it is clear that in what appears to be typical PD with onset before age
50, genes play a key role. Nevertheless, recent studies of twins have
generally reinforced epidemiologic evidence against a genetic influence in
PD with onset after age 50 and have refocused research on unidentified or
underappreciated environmental risk factors for PD such as chronic
low-level exposure to heavy metals, herbicides, pesticides, and chemicals
resembling MPTP.

In addition, "negative" risk factors such as cigarette smoking raise the
possibility of protective environmental elements. Among "negative" dietary
factors, prior coffee or tea drinking has emerged as the most consistent
association with a reduced risk of PD. When first considered in the early
1990s, a reduced risk of developing PD associated with drinking coffee was
not significant. Subsequent studies have demonstrated that even after
accounting for other factors, the inverse relationship between coffee
drinking and PD is significant.

These studies investigated dose-response relationships and found that
increasing coffee consumption was associated with a decreasing likelihood
of developing PD. PD patients were 4-8 times less likely than control
subjects to have reported being heavy coffee drinkers. Fewer studies have
considered the effect of tea drinking, but these usually found a reduced
likelihood of "preventing" PD. More convincingly, 2 reports of
prospectively followed, large populations have firmly linked coffee
drinking to a reduced risk of developing PD. 8000 Japanese American men,
in the Honolulu Heart Program were followed for 30 years. Over 100 went on
to develop PD. The incidence of PD declined dose dependently with
increasing coffee drinking, with over 5 times less risk in those who drank
over 4 (6-oz) cups/day.

Confirmation of these findings is provided by a prospective study of
larger multiethnic populations: nearly 50,000 men followed for 10 years in
the Health Professionals Follow-Up Study and 90,000 women followed for 16
years in the Nurses Health Study.

Among the men, significant dose-dependent inverse relationships were
identified when coffee drinking, tea drinking, non-coffee caffeine
consumption, and total caffeine consumption were plotted against the
incidence of subsequent PD. Again, the inverse associations occurred
independently of smoking and other confounding factors. By contrast, the
rates of consuming decaffeinated coffee bore no relationship to the risk
of PD.

Interestingly, comparison of the female and male cohorts of health care
workers exposes a gender difference in caffeine's relationship to PD risk.
Just as for men, the incidence of PD appeared to decrease for women in
association with caffeine or coffee consumption at moderate levels.
However, women with high caffeine or coffee consumption rates showed the
same risk of PD as those who took in little or no caffeine or coffee. As a
result, no clear overall relationship between caffeine or coffee intake
and PD could be discerned in the women. These findings substantiated
observations by the Mayo Clinic. A potential interaction between caffeine
consumption and estrogen exposure in determining PD risk is an intriguing
hypothesis.


Caffeine: Is it a Neuroprotectant?
Despite their strength, these studies cannot answer a fundamental
question: Does caffeine help prevent PD, or does PD or its causes prevent
the habitual use of caffeine? Although this question of causality is
difficult to address in humans, animal models offer useful clues. The
possibility that caffeine protects against the dopamine degeneration in PD
is strengthened by our finding that caffeine can protect against toxicity
in a mouse model of PD. Caffeine, at doses comparable with those consumed
by humans, decreased the loss of striatal dopamine caused by MPTP.

Pharmacologic studies indicate that the CNS effects of caffeine are
mediated by its antagonistic actions at the A1 and A2A subtypes of
adenosine receptor. Adenosine A2A receptors may be relevant because their
expression in brain is restricted to the striatum. Furthermore, their
blockade is known to protect against certain types of nerve injury.
Accordingly, relatively specific A2A as well as A1-receptor antagonists
were tested for their ability to mimic caffeine's protection against MPTP.
All three of the A2A antagonists tested (but not the A1 antagonist)
significantly reduced the MPTP caused lesions. Similarly, A2A-receptor
knockout mice (which are devoid of A2A receptors) decreased MPTP caused
losses of striatal dopamine. These studies suggest that caffeine, via its
antagonistic action at the A2A receptor, is capable of protecting against
dopamine toxicity.

How A2A-receptor blockade might protect dopamine neurons is unknown. The
A2A-receptors in the striatum are not on the dopamine cells that begin in
the substantia nigra suggesting their modulation of dopamine neuron
toxicity is indirect. They are confined to a group of medium spiny neurons
that also express D2-dopamine and enkephalin receptors. These neurons may
influence dopamine toxicity through a feedback circuit running back to the
dopamine neurons of the substantia nigra.

Specifically, the A2A-receptor striatal neurons project to the globus
pallidus, where A2A-receptor stimulation increases the release GABA (a
chemical transmitter). This increases the blockade of pallidal neurons.
The pallidal cells are inhibitory and project to the subthalamic nucleus.
Thus stimulation of A2A-receptors can lead to unblocking inhibition or
stimulation of the subthalamic nucleus. Because the subthalamic nucleus
sends a glutamine projection to the substantia nigra its increased
activity may contribute to over-excitement and injury of nigral dopamine
neurons. (Deep brain stimulation of the subthalamic nucleus decreases its
over-activity. This may account for its beneficial effects in PD).

The simplest alternative to caffeine impeding the development of PD is
that PD may impede the development of a caffeine habit. Subtle disorders
of smell, sleep, and mood have been proposed as early features of PD. And
that may lead to reduced caffeine intake. However, this possibility can be
dismissed since the inverse correlations between coffee or caffeine are
strongest when based on dietary intake assessed more than a decade before
diagnosis of PD. Follow-up surveys of coffee and caffeine habits did not
show a strengthening of the correlation, which would have been expected if
PD symptoms were contributing to the reduced caffeine consumption.

In addition to caffeine consumption, cigarette smoking is the only other
environmental exposure that has been clearly and consistently linked to a
reduced risk of developing PD. Like caffeine, nicotine has been found, at
least under certain conditions, to decrease dopamine neuron toxicity in
models of PD. And based on experimental evidence, one may propose that
smoking and coffee drinking are associated with a reduced risk of
developing PD because both caffeine and a component of cigarette smoke
independently confer protection against dopamine toxicity. The fact that
smoking and caffeine consumption are both addictive habits may be a
coincidence. The coincidence, however, seems striking if one considers
that alcohol consumption, particularly when heavy or excessive, has also
been independently linked to a reduced risk of PD.

Thus, a broader unifying hypothesis emerges from this pattern of reduced
consumption of addictive substances among those who have an increased risk
of developing PD: Something about individuals that make them less likely
to develop addictive behaviors may make them more likely to develop PD.
Addiction, reward behaviors, and PD all share a common chemical
denominator: Dopamine in the nigra and other brain regions is central to
PD and addiction biology.

Adenosine Antagonists: A Novel Therapy for PD?
In the early 1970s, several studies in animal models of PD characterized
the motor-stimulant properties of caffeine. These led to two clinical
trials to test for a symptomatic benefit of caffeine in combination with
levodopa or dopamine agonists. No clinical improvement was seen.

In the early 1980s, accumulating evidence attributed caffeine's actions in
brain to adenosine receptor antagonism. Caffeine's actions are complex
owing in part to the multiplicity of adenosine receptor subtypes (A1, A2A,
A2A, and A3), each having a unique distribution in different brain
regions. A1 and A2A receptors are present in brain at particularly high
densities. Whereas A1 receptors are distributed widely throughout the
brain, the expression of A2A receptors is restricted to the dopamine-rich
striatum and olfactory tubercle.

Over the last decade, steady refinements in adenosine receptor
pharmacology and the development of receptor knockout models have led to
the conclusion that caffeine's motor-stimulant properties can he
attributed to its blockade of the A2A adenosine receptor. Recently, the
role for A2A receptors has been confirmed by a transgenic mouse model.

Evidence supports an antagonistic interaction between the A2A and D2
receptors co-localized on striatal output neurons. These neurons modulate
motor function through the so-called "indirect" pathway within the basal
ganglia. The A2A receptor, based on its modulation of dopaminergic motor
function and its selective expression in neurons mediating that function,
has emerged as a target for the development of novel anti-PD agents.

Chorea and dyskinesias are major motor complications of chronic
intermittent treatment with levodopa. We have found evidence that the A2A
receptor also plays an important role in establishing the maladaptive
response to levodopa treatment, raising the possibility that A2A
antagonists may offer an additional benefit of decreasing the development
of dyskinesias in PD. And unlike caffeine, whose motor effects often show
tolerance with repeated exposure, the motor benefit of A2A antagonist
persist.

This article was modified by Dr. Abe Lieberman to make it more readable
for lay people.
Caffeine stimulates adenosine receptors in the striatum. This modulates
the actions of dopamine. This may be part of the reason why caffeine is
neuroprotective. The adenosine receptor antagonists are more specific for
the adenosine receptors than caffeine. They may have a role in blocking
the development of dyskinesia. They may have a role in slowing the
progression of PD.

Interesting,  Phyllis

 
   

 

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