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. 2005 Mar 17;1(2):111–134. doi: 10.1007/s11302-005-0649-1

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

Rodrigo A Cunha 1,2,✉
PMCID: PMC2096528  PMID: 18404497

Abstract

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A1 receptors (A1Rs) and the less abundant, but widespread, facilitatory A2ARs. It is commonly assumed that A1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A1R 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 A1Rs in chronic noxious situations. In contrast, A2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A2AR 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 A2AR blockade compared to A1R activation does not mean that A1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A1Rs 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.

Key words: A1 receptors, A2A receptors, adenosine, adenosine kinase, brain, neuroprotection

Abbreviations

Aβ

β-amyloid peptide

A1Rs

A1 receptors

A2ARs

A2A receptors

CGS 21680

2-[4-(2-P-carboxyethyl)phenylamino]-5′-N-ethylcarboxamidoadenosine

CGS 15943

9-chloro-2-(2-furyl)(1,2,4)triazolo(1,5-c)quinazolin-5-amine

CPA

N6-cyclopenthyladenosine

CSC

8-(3-chlorostyryl)caffeine

DMPX

3,7-dimethyl-1-propargylxanthine

DPCPX

1,3-dipropyl-8-cyclopentyladenosine

KW6002

(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

SCH 58261

7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e(-1,2,4-triazolo(1,5-c(pyrimidine

ZM 241385

4-(2-{7-amino-2(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol

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