Combination of ZSET1446 (ST101) with galantamine, rivastigmine or memantine synergistically ameliorates cognitive function mediated by increase in the extracellular level of acetylcholine

Abstract

We have previously reported that ZSET1446 (ST101) ameliorates cognitive impairment induced by scopolamine, enhances object recognition memory and stimulates acetylcholine (ACh) release in the hippocampus. Moreover, concomitant administration of sub-effective doses of ZSET1446 and donepezil ameliorates cognitive impairment induced by scopolamine and increase the extracellular level of ACh in the hippocampus. In the present study, combination effect of ZSET1446 with galantamine or rivastigmine on scopolamine-induced cognitive impairment was examined in a passive avoidance task in mice. Further, combination effect of ZSET1446 with memantine on cognitive functionwas examined in the novel object recognition task. Concomitant administration of ZSET1446 (0.0001 mg/kg) with galantamine (0.1 mg/kg) or rivastigmine (1 mg/kg), at the doses that do not exert efficacy individually, significantly prolonged the step-through latency as compared with control group. These results indicate that these compounds have synergistic cognitive-ameliorating effect. On the other hand, memantine at a dose of 10 mg/kg, but not 3 mg/kg, ameliorated the cognitive performance in the object recognition test. Concomitant administration of sub-effective doses of ZSET1446 (0.001 mg/kg) and memantine (3 mg/kg) also ameliorated the cognitive performance in the novel object recognition task, indicating synergistic cognitive-enhancing effect. Moreover, oral administration of ZSET1446 (0.001 mg/kg) or galantamine (0.3 mg/kg), rivastigmine (0.3 mg/kg) or memantine (10 mg/kg) individually did not significantly increase the extracellular level of ACh in the hippocampus as compared with control. However, concomitant administration of ZSET1446 with galantamine, rivastigmine or memantine at these doses significantly increased the extracellular level of ACh as compared with control, indicating synergistic effect. These results suggest that combination of ZSET1446 with acetylcholinesterase inhibitors, such as donepezil, galantamine and rivastigmine, or NMDA receptor inhibitor, memantine, has a synergistic effect on the cognitive function via synergistic increase in the extracellular level of ACh in the hippocampus.