Selective adenosine A(2a) receptor agonists reduce the apoptosis in an experimental model of spinal cord trauma.
Adenosine is an important regulator of inflammatory mechanisms. Functional studies indicate a protective effect of adenosine A2A receptor agonists in spinal cord injury (SCI). The basic molecular mechanisms accounting for their protective effects from spinal cord injury have to be fully elucidated. The aim of this study is to evaluate in vivo protection by two selective A2A receptor agonists, 2-[p-(2-carboxyethyl)phenylethylamino]-50-ethylcarboxamidoadenosine (CGS 21680, 100 microg/kg) and (4-[3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl)prop-2-ynyl] piperidine-1-carboxylic acid methyl ester) (ATL 313, 3 microg/kg) on the degree of apoptosis, in the experimental model of spinal cord injury. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord trauma in mice was characterised by edema, neutrophilic infiltration and apoptosis. ATL 313, administered by subcutaneously implanted osmotic minipumps after SCI, clearly reduced motor deficit for up to 19 days after operation. The selective A2A receptor agonists ATL 313 and CGS 21680 administered after SCI, reduced tissue damage, TUNEL staining, cytokine (TNF-alpha) expression, Bax, Fas-L and Caspase-3 expression, Annexin-V staining, while increasing Bcl-2 expression. In conclusion, our results demonstrate that treatment with adenosine A2A receptor agonists prevents the apoptotic process that is an important step of secondary damage after SCI.
Genovese
T
T
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Melani
A
A
Esposito
E
E
Paterniti
I
I
Mazzon
E
E
Di Paola
R
R
Bramanti
P
P
Linden
J
J
Pedata
F
F
Cuzzocrea
S
S
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; C494827:Bax protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D010627:Phenethylamines; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D011064:Poly Adenosine Diphosphate Ribose; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000241:Adenosine