Neuroprotective Effects of Caffeine in Sleep Deprivation - Caffeine: Chemistry, Analysis, Function and Effects - page 295

NREM sleep, during which the brain is less active and is thereby better able to
enter into a recovery phase (Porkka-Heiskanen et al 2003). During this phase,
glycogen stores are replenished and adenosine is continuously metabolized by
the enzyme adenosine deaminase leading to conditions that favor wakefulness
(Huang et al 2011).

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16.5.1 Adenosine Pharmacology
The pharmacological behavior of adenosine is complex as the activation of its
various receptor subtypes can produce different downstream effects. More
specifically, adenosine binds and activates a group of purinergic G-protein
coupled adenosine receptor subtypes A 1 ,A 2A ,A 2B and A 3 . Adenosine binding
to A 1 receptors present in wake promoting areas such as the basal forebrain
promotes sleep. Activation of A 1 receptors inhibits the enzyme adenylate
cyclase, which then suppresses the influx of calcium ions into the presynaptic
terminals. Under normal physiological conditions, this calcium influx
promotes the release of neurotransmitters, thus with decreased calcium there
is smaller amounts of neurotransmitters secretion by many neurons resulting in
an overall inhibitory effect.
In the areas of the brain containing neurons that promote sleep such as the
midbrain reticular formation and basal forebrain, adenosine injection
produces a sleep-promoting effect. At first glance, this finding would seem
paradoxical, however, this effect can be explained by the fact that there are
different adenosine receptor subtypes, which can enhance or decrease
adenylate cyclase levels along with subsequent neuronal activity. For example,
activation of A 2 adenosine receptors in the preoptic nucleus leads to increased
activity of sleep promoting neurons (Dunwiddie and Masino 2001). This
allows for one particular molecule to diversify its effects on the already
complex system of sleep-wake regulation.

16.5.2 Caffeine Pharmacology
In general, caffeine produces long-term cerebral hypoperfusion while at the same
time producing its alerting effect via nonselective blockade of adenosine A 1 and
A 2a receptors in the basal forebrain and midbrain reticular formation (Fredholm
1995). However, the pharmacological effects of caffeine reach beyond that of
sleep-wake regulation. Specifically, caffeine, independent of its stimulant effects,
modulates adenosine pharmacology to induce beneficial changes in molecular
signaling cascades that mediate synaptic plasticity. In fact, studies have shown
that caffeine has a neuroprotective action against cognitive decline in
neurodegenerative disorders such as Alzheimer's disease (Dall'Igna et al 2007).
Normally, adenosine disrupts the underlying processes of learning and
memory at the synaptic level whereas caffeine seems to reverse many of
adenosine effects on sleep propensity and even learning and memory by
blocking adenosine receptor signaling (Alhaider et al 2010a; 2011). One of the