Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Abstract

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

The adenosine kinase hypothesis of epileptogenesis

“…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). Thus, adenosine controls many brain functions in physiological and pathophysiological conditions (Fredholm et al, 2005a;Fredholm et al, 2005b) and has potent anticonvulsant (Boison, 2005;Dragunow, 1986;Dunwiddie, 1999) and neuroprotective (Cunha, 2005;Dragunow and Faull, 1988;Ribeiro, 2005) properties. Due to these properties of adenosine, an adenosinebased pharmacopoeia has been established for a variety of conditions (Jacobson and Gao, 2006) including the development of adenosine-based cell therapies for the treatment of focal epilepsies (Boison, 2007a;2007b).…”

“…These inhibit adenylyl cyclase, activate inwardly rectifying K + channels, inhibit Ca 2+ channels and activate phospholipase C. As a net result, the release of various neurotransmitters, in particular glutamate is inhibited by presynaptic A 1 receptors. Consequently, adenosine and A 1 -selective receptor agonists are effective in seizure suppression (Boison, 2007a) and neuroprotection (Cunha, 2005). In addition to these synaptic effects, A 1 receptors are believed to provide beneficial extra synaptic effects, which are based on a decrease in brain metabolism (Haberg et al, 2000) and the control of astrocyte function (van Calker and Biber, 2005).…”

“…Inhibitors of the A 2A R have profound neuroprotective functions (Cunha, 2005) and the capability to prevent apoptosis (Silva et al, 2007). In addition to regulating neuronal vulnerability, these receptors play a key role in modulating the action of other neurotransmitters and neuromodulators (Sebastiao and Ribeiro, 2000).…”

“…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).…”

A population of immature cerebellar parallel fibre synapses are insensitive to adenosine but are inhibited by hypoxia

“…Adenosine accumulates during hypoxia and ischemia and has a neuroprotective role (Goldberg et al 1988;Von Lubitz et al 1988;Cunha 2005) reducing the brains energy requirements during periods of metabolic stress. The actions of adenosine are well characterised, it acts via multiple cell surface G-protein coupled receptors: A 1 , A 2A , A 2B and A 3 (Fredholm et al 2000).…”