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.