ANTIHYPOXIC AND ANTIISCHEMIC ACTIONS OF INDELOXAZINE HYDROCHLORIDE AND ITS OPTICAL ISOMERS - POSSIBLE INVOLVEMENT OF CEREBRAL ENERGY-METABOLISM

We evaluated the anti-hypoxic and anti-ischemic actions of indeloxazin e hydrochloride {(+/-)-2-[(inden-7-yloxy)methyl] morpholine hydrochlor ide, YM-08054} in comparison with its optical isomers and several sele ctive monoamine uptake inhibitors in mice. The effects of indeloxazine on both cerebral energy metabolism in normal mice and local cerebral glucose utilization in normal rats were also studied. Indeloxazine and its (-)-isomer, with both serotonin and norepinephrine uptake inhibit ory actions, and its (+)-isomer, with a serotonin uptake inhibitory ac tion, prolonged the survival time of mice subjected to nitrogen gas an d the gasping duration in decapitated mice. Indeloxazine and its (+)-i somer were approximately 3- times more potent than the (-)-isomer with regard to their anti-hypoxic and anti-ischemic activities. Selective norepinephrine uptake inhibitors such as maprotiline and viloxazine, a nd selective serotonin uptake inhibitors such as citalopram, alaprocla te and zimeldine, did not show anti-hypoxic properties. On the other h and, amantadine, a selective dopamine uptake inhibitor, and amitriptyl ine, a tricyclic antidepressant with anticholinergic properties, signi ficantly shortened the survival time in hypoxic mice. In biochemical s tudies, increases in brain ATP and glucose levels without affecting la ctate level in mice and an elevation in local cerebral glucose utiliza tion in 10 brain regions involving the frontal cortex in rats were obs erved after administration of indeloxazine. These results suggest that indeloxazine and its optical isomers possess anti-hypoxic and anti-is chemic actions distinct from those of typical monoamine uptake inhibit ors, and that these effects of indeloxazine may be due, at least in pa rt, to a facilitation of cerebral energy metabolism.