Combination Effects of ZSET1446/ST101 With Memantine on Cognitive Function and Extracellular Acetylcholine in the Hippocampus

Abstract

Abstract. In the novel object recognition task, ZSET1446 (also coded as ST101) enhanced object recognition memory in mice and ameliorated cognitive impairment caused by scopolamine in rats. The enhancement induced by ZSET1446 in mice was abolished by injection of mechamylamine, a nonselective antagonist of nicotinic acetylcholine (ACh) receptors, or dihydro-berythroidine, a selective antagonist against the a4 subunit of nicotinic ACh receptors. These results suggest that the procognitive effect of ZSET146 is probably mediated by stimulation of nicotinic receptors. Memantine was also effective in these tests and concomitant administration of subeffective doses of ZSET1446 and memantine significantly ameliorated the cognitive performance in the novel object recognition task in both mice and rats. Moreover, oral administration of ZSET1446 or memantine increased the extracellular level of ACh in the hippocampus as compared with the control. Further, concomitant administration of subeffective doses of ZSET1446 and memantine significantly increased the extracellular level of ACh as compared with the group of ZSET1446 or memantine alone. These results suggest that these two compounds have a synergistic effect on the cognitive function possibly by synergistic increase in the extracellular level of ACh in the hippocampus, and that the combination therapy of these compounds might be effective in clinical settings.

Effects of Memantine on the Spontaneous Firing Frequency of Hippocampal CA1 Pyramidal Neurons in Intact and Alzheimer Rat Model: An Electrophysiological Study

“…Moreover, in the radial maze test, the acute intraperitoneal injection of 0.3 and 0.56 mg/kg of memantine 20 minutes prior to the acquisition reduced the error and improved memory in the memory recall test (18 hours after the last acquisition session) ( Wise & Lichtman, 2007 ). It seems that memantine affects memory enhancement in these cases through the imbalance between GABAergic and glutamatergic functions and higher levels of extracellular acetylcholine ( Drever et al, 2007 ; Ihalainen et al, 2011 ; Povysheva & Johnson, 2016 ; Shearman et al, 2006 ; Yamaguchi et al, 2013 ). Also, the differences in the effective amount of memantine are related to the treatment method (oral and intraperitoneal), the duration of treatment (acute and chronic), and the treatment time (before training, immediately after training, and before recalling).…”

Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease: Rationale and Current Status

“…Interestingly, a recent study suggests that coapplication of ZSET1446 and the NMDA receptor antagonist memantine has a positive effect on cognitive functions in mice and rats. An increase in the extracellular levels of ACh in the hippocampus was observed upon application of this compound [149,150]. It was also demonstrated that a7 AChR has a permissive role in NMDA receptor action in the primate prefrontal cortex, strengthening cognitive functions, thus suggesting a promising combination therapy of these two compounds in clinical settings [151].…”

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

“…ST-101 (ZSET-1446; Sonexa Therapeutics, San Diego, CA under license from Zenyaku Kogyo, Tokyo) is in Phase II clinical trials for AD since February 2009 and for the treatment of essential tremor since May 2011 (for the structure, see [7]). Combination effects of ZSET1446/ST101 with memantine on cognitive function and extracellular acetylcholine in the hippocampus of rats were described [45]. It was recognized that ST-101 targeted T-type voltage-gated calcium channels in mediating improved cognition in the CNS [46] (Thomson Reuters Pharma, update of October 8, 2013).…”