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Adenosine Neuromodulation and Neuroprotection

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

The adenosine moiety fulfils an important intracellular homeostatic role since it is part of molecules that play key roles in defining the status of all cells, namely energy charge (ATP), redox status (NADH), and cell division (SAH/SAM). But the signaling role of the adenosine molecule itself is restricted to a paracrine role, signaling metabolic imbalance of cells within a tissue. Apart from this general role common to most tissues in mammals, adenosine fulfils a particular role as a neuromodulator in the nervous system. This involves a predominant inhibitory effect operated by adenosine A1 receptors, which results from a combined presynaptic inhibition of the release of excitatory neurotransmitters together with a postsynaptic action leading to neuronal hyperpolarization and an ability to depress plasticity by inhibition of NMDA receptors and voltage-sensitive calcium channels. Overall, this A1 receptor-mediated inhibition is aimed at decreasing the noise of excitatory transmission in brain circuits. Adenosine can also activate facilitatory A2A receptors, which only come into play at higher frequency of nerve stimulation and are directed at selectively shutting down A1 receptor inhibition in stimulated synapses to aid implementing changes in synaptic efficiency. Therefore, the combined role of A1 and A2A receptors is designed to increase salience of information in brain circuits. Apart from this main physiological role, adenosine also plays a relevant role in controlling the demise of damage in noxious brain conditions. In fact, the inhibitory A1 receptors are able to curtail brain damage. They play a role at the onset of brain damage and function as a hurl that needs to be overcome to allow the development of brain damage. In parallel, in chronic noxious brain conditions, A2A receptors contribute for brain damage, especially when insidious damage to synapses initiates neurodegeneration. Hence, A2A receptor antagonists are now being explored as novel neuroprotective strategies to interfere with the initial processes of neurodegenerative conditions, such as Parkinson's and Alzheimer's diseases.

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Abbreviations

CCPA:

2-Chloro-N6-cyclopentyladenosine

CGS21680:

2-[p-(2-carbonyl-ethyl)-phenylethylamino]-5′-N-ethylcarboxamidoadenosine

Cl-IB-MECA:

1-[2-Chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-b-D-ribofuranuronamide

CP-68,247:

8-chloro-4-cyclohexyl-amino-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a] quinoxaline

CSC:

8-(3-chlorostyryl)caffeine

DPCPX:

1,3-dipropyl-8-cyclopentylxanthine

IB-MECA:

N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide

KF17837:

1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine

MRE3008F20:

5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine

MRS1220:

9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline

MRS1334:

1,4-Dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)methyl] ester

MRS1754:

N-(4-cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]acetamide

R-PIA:

R-N6-(phenylisopropyl)-adenosine

SCH58261:

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

ZM241385:

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

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Acknowledgements

Although I sign this manuscript alone, it is the product of daily discussion with all who worked in my lab and with all colleagues with whom I share the passion of adenosine. A special word of thanks should go to Alexandre de Mendonça and Jiang-Fan Chen for the frequency of the discussions. Finally, I should like to apologize all the colleagues not quoted in this short reference list which was based in some (few) review articles rather than the important original contributions

Authors
  1. R. A. Cunha
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 10962, 140 Old Orangeburg Road, Orangeburg, New York, USA

    Abel Lajtha (Director) (Director)

  2. Institute of Experimental Medicine, Hungarian Academy of Sciences, 43, H-1083 Budapest, Szigony, Hungary

    E. Sylvester Vizi

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Cunha, R.A. (2008). Adenosine Neuromodulation and Neuroprotection. In: Lajtha, A., Vizi, E.S. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30382-6_11

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