It is well established that in the CNS, endogenous
adenosine plays a pivotal role in neurodegeneration. A low, nanomolar concentration of
adenosine is normally present in the extracellular fluid, but it increases dramatically during enhanced nerve activity,
hypoxia or
ischemia. In these pathological conditions, adenosinergic transmission-potentiating agents, which elevate
adenosine level by either inhibiting its degradation (
adenosine deaminase and
kinase inhibitors) or preventing its transport, offer protection against ischemic or excitotoxic neuronal damage. The directly acting
adenosine A1 receptor agonists are known to mediate neuroprotection, mostly by the blockade of Ca2+ influx, which results in the inhibition of
glutamate release and reduction of its excitatory effects at a postsynaptic level. More recent data have shown that antagonists of
adenosine A2A receptors markedly reduce cerebral ischemic damage in animal models of focal and global
ischemia. Moreover, these compounds attenuate the neuronal loss induced by
excitatory amino acids (EAA). A
neuroprotective effect of
adenosine A2A receptor antagonists was also shown in animal models of
Parkinson's disease (
MPTP, 6-OHDA,
methamphetamine). Hence, it might be suggested that
adenosine A2A receptor antagonists may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events, since they not only reverse motor impairment but can act as neuroprotective compunds by promoting cell survival.