ABSTRACT
Title
Adenosine A2A receptor roles in brain ischemia
Authors
A. Melani, F. Corti, M.G. Vannucchi1, D. Nosi1, M.G. Giovannini and F. Pedata
Department of Pharmacology, University of Florence, Italy;
1Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Department of Pharmacology, University of Florence, Italy;
1Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Abstract
Adenosine is a potent biological mediator, whose extracellular concentration increases dramatically following brain ischemia, reaching a concentration (in micro molar range) [1] that is able to stimulate all four adenosine receptor subtypes (A1, A2A, A2B, A3). In recent years, evidence indicates that the A2A receptor subtype is of critical importance in stroke. In the first hours after ischemia, adenosine A2A receptor antagonists reduce excitatory amino acids release in the ischemic area [2], contrasting excitotoxicity that is a precocious event during cerebral ischemia. Twenty-four hours after a permanent middle cerebral artery occlusion (MCAo), A2A receptors up-regulate on neurons and microglia of ischemic striatum and cortex [3]. The selective A2A receptor antagonist, SCH58261, sub-chronically administered, protects against ischemic brain damage, neurological deficit [4] and ischemia induced-myelin disorganization assessed by immunostaining with anti-myelin associated glycoprotein (MAG) antibody [5]. SCH58261 reduces phospho-JNK MAPK levels in oligodendrocytes into white matter fascicula of the ischemic striatum. Since phospho-JNK is involved in oligodendrocyte death [6], a phospho-JNK reduction can account for protection by A2A antagonists. Phospho-JNK MAPK is highly expressed in Olig2- and NG2-positive oligodendrocytes in the ischemic striatum, whereas low colocalization is observed in O4-positive cells. NG2 is a marker for oligodendrocyte precursor cells (OPC), while O4 is a marker for mature oligodendrocytes. Olig2 is a transcription factor that regulates phenotype specification of cells of oligodendroglia lineage [7] and is strongly expressed in OPC while mature oligodendrocytes are characterized by lower levels of Olig2 [8]. SCH58261 reduces the expression of transcription factor Olig2 in the ischemic striatum. A2A receptor antagonist in reducing activation of JNK MAPK and Olig2 transcription factor might address OPC toward a mature status.
Seven days after a transient (1 hour) MCAo, a massive cell infiltration and glial cell activation is found in the ischemic area. Phospho-JNK MAPK is still expressed into white matter fascicula of the ischemic striatum. NG2-positive OPCs are present at the border of the ischemic area and do not co localize with phospho-JNK MAPK. The absence of colocalization of phospho-JNK and NG2-positive cells indicates the vitality of OPCs and their potential to repair demyelinated tissue.
[1] Melani et al. (1999) Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage. Stroke 30,2448-54.
[2] Melani et al. (2003) The selective A2A receptor antagonist SCH58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Res 959,243-50.
[3] Trincavelli et al. (2009) Regulation of A2A adenosine receptor expression and functioning following permanent focal ischemia in rat brain. J Neurochem 104, 479–90.
[4] Melani et al. (2006) The selective A2A receptor antagonist SCH58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia. Brain Res 1073–4,470–480.
[5] Melani et al. (2009) Selective adenosine A2A receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia. Brain 132(Pt 6),1480-95.
[6] Jurewicz et al. (2006) TRAIL-induced death of human adult oligodendrocytes is mediated by JNK pathway. Glia 53, 158–66.
[7] Zhou et al. (2000) Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25,331–343.
[8] Kitada and Rowitch (2006) Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord. Glia 54,35-46.
Seven days after a transient (1 hour) MCAo, a massive cell infiltration and glial cell activation is found in the ischemic area. Phospho-JNK MAPK is still expressed into white matter fascicula of the ischemic striatum. NG2-positive OPCs are present at the border of the ischemic area and do not co localize with phospho-JNK MAPK. The absence of colocalization of phospho-JNK and NG2-positive cells indicates the vitality of OPCs and their potential to repair demyelinated tissue.
[1] Melani et al. (1999) Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage. Stroke 30,2448-54.
[2] Melani et al. (2003) The selective A2A receptor antagonist SCH58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Res 959,243-50.
[3] Trincavelli et al. (2009) Regulation of A2A adenosine receptor expression and functioning following permanent focal ischemia in rat brain. J Neurochem 104, 479–90.
[4] Melani et al. (2006) The selective A2A receptor antagonist SCH58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia. Brain Res 1073–4,470–480.
[5] Melani et al. (2009) Selective adenosine A2A receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia. Brain 132(Pt 6),1480-95.
[6] Jurewicz et al. (2006) TRAIL-induced death of human adult oligodendrocytes is mediated by JNK pathway. Glia 53, 158–66.
[7] Zhou et al. (2000) Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25,331–343.
[8] Kitada and Rowitch (2006) Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord. Glia 54,35-46.