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The effects of sufoxazine on various experimental amnesia models were studied using passive avoidance behavior in mice. Sufoxazine had no influence on learning and memory in intact mice. Sufoxazine, administered either immediately after CO2 exposure or 30 min prior to the acquisition trial, improved CO2 induced amnesia. It also improved both electroconvulsive shock (ECS) induced amnesia (administered immediately after the amnestic treatment) and scopolamine induced amnesia (administered immediately after the acquisition trial). The anti-depressant drugs, imipramine and desipramine had no ameliorative activity in any of these experimental amnesia models. These results suggest that sufoxazine improves amnesia experimentally induced by various methods.

The effects of long-term dosing with acetyl-L-carnitine (ALC) were examined in aged rats, and they were compared with those in young rats. ALC significantly reduced the lipofuscin deposition in the brain of aged rats. Emotional parameters such as locomotor activity and rearing behavior are lower in aged rats than in young rats, and these behaviors decreased in both age groups during the experiments. ALC diminished the decrease of these emotional behaviors, especially in rearing behavior in the aged rats. Furthermore, ALC had no effect on body weight gain. These results might reflect one of the main beneficial pharmacological mechanisms of ALC in clinical use.

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

The effect of Y-8894 on the abnormal electrocorticogram (ECoG) of alcuronium-immobilized rats, induced by destruction of the internal capsule with heat, was compared with that produced by imipramine, amantadine and Ca-hopantenate. ECoG power in the delta + theta (1-7 Hz), alpha (7.5-12.5 Hz) and beta (13-30 Hz) bands was used as an index. Delta + theta power increased following destruction of the internal capsule with heat. The increased delta + theta power (abnormal ECoG) lasted for 60 min following the injection of saline at 60 degrees C for 3 min. Y-8894 (0.1-1 mg/kg, i.v.) apparently improved the abnormal ECoG dose-dependently by significantly reducing the increased delta + theta power. Similar results were obtained with amantadine (10 mg/kg, i.v.), but its potency was weaker than that of Y-8894. Imipramine (1 mg/kg, i.v.) and Ca-hopantenate (30 mg/kg, i.v.), however, both failed to modify the abnormal ECoG. All drugs, except Ca-hopantenate, decreased the magnitudes of the alpha and beta bands. The above results suggest that Y-8894 may be effective in ameliorating cerebral dysfunction induced experimentally by the lesion of the internal capsule.

The effects of Y-8894 on experimental amnesia in rats induced by transient cerebral ischemia (600 sec) according to the method of Pulsinelli and Brierley were studied using the one trial passive avoidance response and the pole climbing discrete avoidance response. All drugs were administered to the rats immediately after recirculation. The following results were obtained: 1) In the one trial passive avoidance response test, Y-8894 (2.5, 5 and 10 mg/kg, i.p.) improved significantly the decreased latency induced by the ischemia, and it was most effective at 5 mg/kg. Calcium-hopantenate (100, 250 and 500 mg/kg, i.p.) and dihydroergotoxine (5 and 10 mg/kg, i.p.) tended to increase the latency. On the other hand, physostigmine (0.025, 0.05 and 0.1 mg/kg, i.p.), a cholinesterase inhibitor, increased the latency significantly, and it was most effective at 0.05 mg/kg. 2) The pole climbing discrete avoidance response was significantly decreased by the ischemia compared with the sham operated group, and Y-8894 (5 mg/kg, i.p.) tended to improve this decreased avoidance response. 3) Y-8894 (5 mg/kg, i.p.) facilitated recovery from the changes in glycolytic metabolism, and inhibited the accumulation of choline due to the dysfunction of the neuronal membranes induced by the ischemia. These results show that Y-8894 has beneficial effects on experimental amnesia induced by transient cerebral ischemia.

The amelioration of energy metabolic disturbance in cerebral anoxia is valuable for the treatment of various cerebral ischemic diseases and insufficiency. In this study, the effect of Y-8894 on the cerebral energy metabolism was investigated using a KCN-induced cerebral anoxia model with mice. The intravenous injection of a lethal dose of KCN (2.5 mg/kg) induced rapid and marked decreases of brain glucose, phosphocreatine and ATP contents, with a remarkable enhancement of lactate and AMP levels, indicating a severe disorder of the cerebral energy metabolism. This phenomenon was also shown by an irreversible deterioration of the energy charge potential (ECP), an index of the cerebral energy state. The treatment with Y-8894 (30 mg/kg, i.p.) remarkably ameliorated this KCN-induced energy metabolic disturbance: markedly reducing the changes in brain phosphocreatine, glucose and lactate contents, while keeping ATP, AMP and ECP at nearly their normal levels. In addition, these changes in the Y-8894 treated group recovered promptly to normal, whereas those in the control group were irreversible. In normal mice, Y-8894 induced a significant increase in the cerebral glucose content without affecting either the cerebral glycolytic metabolism or the energy state. The present findings suggest that Y-8894 has an ameliorative effect on the cerebral energy metabolic disturbance, and this effect likely plays an important role in the improvement of amnesia and other neurological deficits related to cerebral anoxia.

Iminodibenzy1 derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine (CPP) and clocapramine (CCP) have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, which also has an iminodibenzy1 nucleus, were compared with those of CPP, CCP, chlorpromazine (CPZ), haloperidol and sulpiride (SPR). Y-516 inhibited apomorphine (0.5 mg/kg s.c.)-induced hyperactivity in mice, apomorphine (1.25 mg/kg i.v.)-induced gnawing behavior in rats, methamphetamine (2 mg/kg s.c.)-induced hyperactivity in mice and methamphetamine (50 mg/kg i.ρ.)-induced mortality in grouped mice. Except for SPR,the other drugs tested also had similar inhibitory activity. Y-516 was more potent than CCP,but slightly less potent than CPZ in these tests. The antagonistic effect of Y-516 on apomorphine (0.1 mg/kg s.c.)-induced vomiting in dogs was 7 times more potent than that of CPZ. The other drugs tested also showed antagonistic activity in this test. Y-516 antagonized apomorphine (10 mg/kg s.c.)-induced hypothermia in mice. CPZ, on the other hand, potentiated this effect. When combined with methamphetamine (5 mg/kg i.p.) in rats, Y-516 did not induce mortality, but CPP and SPR did. From these results, it would appear that the central antidopaminergic activity of Y-516 differs from that of the other drugs tested.