Protection against ischemia-induced neuronal damage by the alpha 2-adrenoceptor antagonist idazoxan: influence of time of administration and possible mechanisms of action.
The protective effect of the alpha 2-receptor antagonist idazoxan against neuronal damage in the neocortex and in the hippocampal CA1 region was studied in rats exposed to 10 min of incomplete forebrain ischemia. When administered i.v. immediately after ischemia (0.1 mg/kg) and subsequently for 6 h (10 micrograms/kg/min), idazoxan significantly reduced neuronal damage in the hippocampus (from 84 to 26%) and in the vulnerable parts of the neocortex (from 15 to 1%). The bolus dose alone provided no significant protection. When idazoxan administration was delayed for 30 min, no significant protection was noticed in the neocortex, and the effect in the hippocampus was ambiguous. A transient elevation of plasma corticosterone levels was induced during ischemia. Idazoxan administration for 2 h did not affect postischemic changes in corticosterone levels compared with saline infusion. Idazoxan (10(-7)-10(-4) M) did not influence the in vitro binding to glutamate receptors in brain slices. Thus, the protective effect of idazoxan cannot be explained by suppression of the plasma corticosteroid levels or via an antagonistic effect on glutamate receptors. Idazoxan apparently protects neurons when given during the first hours of postischemic reperfusion, while histopathological necrosis of neurons becomes visible 48-72 h after ischemia. Detrimental processes causing delayed neuronal death occur in the early postischemic phase and can be influenced by adrenoceptor ligands. Idazoxan may protect by several mechanisms but probably exerts its protective postischemic effect mainly through an increased noradrenergic neuronal activity and an elevation of extracellular noradrenaline (NA) levels in the brain. The favorable effects of NA may either be due to inhibition of excitotoxic neurotransmission or activation of survival-promoting and trophic processes.
Gustafson
I
I
Laboratory for Experimental Brain Research, University of Lund, Sweden.
Westerberg
E
E
Wieloch
T
T
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D004146:Dioxanes / Q000494:pharmacology*; D019329:Idazoxan; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D003345:Corticosterone; D019329:Idazoxan