Effects of the spin trap-alpha-phenyl-N-tert-butyl nitrone (PBN) in transient forebrain ischaemia in the rat.
The free radical spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) has previously been shown markedly to reduce infarct size in permanent or transient focal ischaemia in rats. The mechanisms of action have not been clearly defined, but data obtained in focal ischaemia suggest microvessels or mitochondria as targets. Since microvascular dysfunction and/or mitochondrial failure are probably not the immediate causes of delayed neuronal damage following forebrain ischaemia in rats, we induced 15 min of two-vessel occlusion ischaemia in anaesthetized rats, and assessed brain damage by histopathological techniques 7 days later. Animals were treated either before (30 min) or after ischaemia (30 min or 6 h) with PBN or its vehicle. Other animals received a more soluble PBN analogue (2'-sulfonyl PBN), and received the drug 30 min prior to 12 or 15 min of ischaemia. PBN reduced neuronal necrosis in the neocortex when given 30 min post-treatment, but not when given before or 6 h after ischaemia, and it failed to reduce damage to the CA 1 sector of the hippocampus, or the caudoputamen. The sulphonyl derivative of PBN failed to reduce damage in any region. The results provide important hints as to the action of PBN. It is tentatively concluded that the nitrones ameliorate either the microvascular dysfunction or the mitochondrial failure, which could be the crucial events leading to infarction in focal ischaemia, but that they have only a weak effect on the mechanisms that yield selective neuronal necrosis in transient ischaemia of brief duration.
Pahlmark
K
K
Laboratory for Experimental Brain Research, Experimental Research Centre, University of Lund, Sweden.
Siesjö
B K
BK
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides; D005849:Gerbillinae; D008297:Male; D009589:Nitrogen Oxides / Q000494:pharmacology*; D016548:Prosencephalon / Q000098:blood supply / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D012995:Solubility; D013113:Spin Labels
D001786:Blood Glucose; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone