The Role and Regulation of Adenosine in the Central Nervous System

Abstract

Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.

The adenosine kinase hypothesis of epileptogenesis

“…Adenosine is an ubiquitous modulator of synaptic transmission and neuronal activity, exerting most of its functions via activation of the high-affinity inhibitory adenosine A 1 and excitatory A 2A receptors, while the low-affinity or low-abundance A 2B and A 3 receptors provide an additional layer of modulatory receptor crosstalk (Dunwiddie and Masino, 2001;Fredholm et al, 2005a;Fredholm et al, 2005b;Fredholm et al, 2001). Different affinities of these receptors for adenosine and highly specific spatial distribution patterns within the brain allow a high degree of complexity in the effects of adenosine and modulation of the action of other neurotransmitters or modulators (Cunha-Reis et al, 2007;Sebastiao and Ribeiro, 2000).…”

“…In contrast to A 1 receptors, A 2A receptors are coupled to stimulatory G s or G olf proteins (Dunwiddie and Masino, 2001) and both inhibitory as well as excitatory responses mediated via A 2A receptors have been described in discrete brain areas (Fredholm et al, 2001). Inhibitors of the A 2A R have profound neuroprotective functions (Cunha, 2005) and the capability to prevent apoptosis (Silva et al, 2007).…”

“…Due to the widespread systemic distribution of adenosine receptors pharmacological approaches to antiepileptic therapy are limited by widespread systemic side effects including suppression of cardiovascular functions (Dunwiddie and Masino, 2001;Monopoli et al, 1994). While A 1 receptor-selective antagonists exacerbate convulsions indicating that endogenous adenosine modulates epileptiform activity via the A 1 receptor (Etherington and Frenguelli, 2004), A 1 selective agents such as 2-chloro-N 6 -cyclopentyladenosine (CCPA) have previously been used to suppress seizures in various models of epilepsy (Huber et al, 2002;Monopoli et al, 1994).…”

“…These findings nicely demonstrate that A 2A R stimulation promotes astrogliosis. Thus, it is compelling to conclude that under conditions of brain injury, hypoxia, or inflammation, which all cause both upregulation of A 2A Rs (Cunha, 2005) as well as acute increase in adenosine (Dunwiddie and Masino, 2001), an adenosine-based mechanism contributes to astrogliosis. This notion is further supported by findings that stimulation of A 1 Rs, which are downregulated during epileptogenesis (Ekonomou et al, 2000;Rebola et al, 2003;Rebola et al, 2005), leads to a reduction of astrocyte proliferation (Rathbone et al, 1991).…”

Adenosine dysfunction in astrogliosis: cause for seizure generation?

“…A 1 Rs, coupled to inhibitory G proteins, display high abundance in seizure-susceptible brain regions such as hippocampus. Consequently, A 1 R agonists are powerful anticonvulsants (Dunwiddie, 1999), effective even in pharmacoresistant epilepsy (Gouder et al, 2003), however associated with prominent cardiovascular and sedative side effects (Dunwiddie and Worth, 1982;Dunwiddie and Masino, 2001;Güttinger et al, 2005). As demonstrated in A 1 R knockout mice, activation of the receptor is necessary to prevent the spread of seizures and seizure-associated cell death; following either kainic acid or traumatic brain injury (Kochanek et al, 2006) induced status epilepticus (SE) all A 1 R knockout animals died within 5 days.…”