Possible therapeutic effect of T-794, a novel reversible inhibitor of monoamine oxidase-A, on post-stroke emotional disturbances, assessed in animal models of depression

Abstract

Emotional disturbances, such as lack of motivation or depression, are common after stroke. The drugs mainly used to treat these syndromes in Japan are the cerebral metabolic enhancers whose biochemical and pharmacological profiles are similar to those of antidepressant drugs. In order to examine the possible therapeutic effect of T-794 [(5R)-3-(6-(cyclopropylmethoxy) 2- naphthalenyl)-5-(methoxymethyl) 2-oxazolidone], a new reversible inhibitor of monoamine oxidase (MAO) type A, on those emotional disturbances, its antidepressant activity was compared with those of major cerebral metabolic enhancers in rodents with or without treatment of cerebral ischemia. Oral administration of T-794 potently prevented reserpine-induced ptosis (ED50=4.41 mg/kg), akinesia (ED50 = 3.29 mg/kg), and hypothermia (minimum effective dose = 3 mg/kg) in mice. It was at least 3.7, 13.0, and 3.3 times more potent than cerebral metabolic enhancers tested (indeloxazine, bifemelane, amantadine and idebenone) in antagonism of the ptosis, the akinesia, and the hypothermia, respectively. Effect of T-794 was also examined in the behavioral despair test in rats subjected to forebrain ischemia. The ischemia was induced by a combination of bilateral common carotid artery occlusion (15 min) and systemic hypotension (sodium nitroprusside 5 mg/kg, s.c.). From 13 d after the surgery, drugs were orally administered twice daily 7 times, and following the last administration rats were assessed for their behavior. T-794 reduced the duration of immobility in the behavioral despair test at 30 mg/kg without affecting spontaneous motor activity, whereas indeloxazine showed no significant effect. Antidepressant- like activity of T-794 was suggested in rodents with as well as those without cerebral ischemia. The results suggest that T-794 may make an important contribution to the treatment of emotional disturbances following stroke.