Effects of tempol, a membrane-permeable radical scavenger, in a gerbil model of brain injury.
There is evidence that the excessive generation of reactive-oxygen radicals contributes to the brain injury associated with transient, cerebral ischemia. This study investigates the effects of tempol, a small, water-soluble molecule, that crosses biological membranes, on the brain injury caused by bilateral occlusion and reperfusion of both common carotid arteries in the gerbil (BCO). Treatment of gerbils with tempol (30 mg/kg i.p. at 30 min prior to reperfusion and at 1 and 6 h after the onset of reperfusion) reduced the formation of post-ischemic brain oedema. Tempol also attenuated the increase in the cerebral levels of malondialdehyde (MDA) and the hippocampal levels of myeloperoxidase (MPO) caused by cerebral ischemia and reperfusion. The immunohistochemical analysis of the hippocampal region of brains subjected to ischemia-reperfusion exhibited positive staining for nitrotyrosine (an indicator of the generation of peroxynitrite) and poly(ADP-ribose) synthetase (PARS) (an indicator of the activation of this nuclear enzyme secondary to single strand breaks in DNA). In gerbils subjected to BCO, which were treated with tempol, the degree of staining for nitrotyrosine and PARS was markedly reduced. Tempol increased survival and reduced the hyperactivity (secondary to the ischemia-induced neurodegeneration) caused by cerebral ischemia and reperfusion. The loss of neurons from the pyramidal layer of the CA1 region caused by ischemia and reperfusion was also attenuated by treatment of gerbils with tempol. This is the first evidence that the membrane-permeable, radical scavenger tempol reduces the cerebral injury caused by transient, cerebral ischemia in vivo.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria, Gazzi, 98100 Messina, Italy. salvator@www.unime.it
McDonald
M C
MC
Mazzon
E
E
Siriwardena
D
D
Costantino
G
G
Fulia
F
F
Cucinotta
G
G
Gitto
E
E
Cordaro
S
S
Barberi
I
I
De Sarro
A
A
Caputi
A P
AP
Thiemermann
C
C
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000517:prevention & control; D002536:Cerebral Arteries; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013113:Spin Labels; D016019:Survival Analysis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D009566:Nitrates; D009573:Nitrites; D013113:Spin Labels; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; C001803:tempol