Yoshimasa Yamaguchi

Effects of a Novel Cognitive Enhancer, Spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on Learning Impairments Induced by Amyloid-β1–40 in the Rat

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-β (Aβ)1–40 produces oxidative stress and cholinergic dysfunction, as well as learning and memory deficits, in rats. In the present study, effects of a newly synthesized azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), were assessed in rats with learning deficits induced by Aβ1–40 or scopolamine. The i.c.v. infusion of Aβ1–40 caused impairments in spontaneous alternation behavior in a Y-maze task, spatial reference and short-term memory in a water-maze task, and retention of passive-avoidance learning. Aβ1–40-infused rats also showed reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex, and a decrease in glutathione S-transferase (GST)-like immunoreactivity in the cortex. Nicotine-stimulated acetylcholine (ACh) release in Aβ1–40-infused rats was lower than that in vehicle-infused rats. Oral administration of ZSET1446 at the dose range of 0.01 to 1 mg/kg ameliorated Aβ1–40-induced learning impairment in Y-maze, water-maze, and passive-avoidance tasks. ZSET1446 reversed the decrease of ChAT activity in the medial septum and hippocampus, GST-like immunoreactivity in the cortex, and nicotine-stimulated ACh release of Aβ1–40-treated rats to the levels of vehicle-infused control rats. Furthermore, 0.001 to 0.1 mg/kg ZSET1446 showed ameliorative effects on learning impairments caused by scopolamine in a passive-avoidance task. These results suggest that ZSET1446 may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimers disease.

A Novel Cognitive Enhancer, ZSET1446/ST101, Promotes Hippocampal Neurogenesis and Ameliorates Depressive Behavior in Olfactory Bulbectomized Mice

In the adult brain, neurogenesis persistently occurs in the subgranular zone of the hippocampal dentate gyrus (DG), and impaired neurogenesis is implicated in depressive behaviors and poor learning memory. Here, we investigated the effects of oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), a novel cognitive enhancer stimulating acetylcholine release, on adult neurogenesis in olfactory bulbectomized (OBX) mice. OBX mice showed significant decreases in the number of newborn cells in the DG by immunohistochemical analysis of 5-bromo-2-deoxyuridine incorporation. Impaired neurogenesis observed in OBX mice was significantly improved by chronic administration with ZSET1446. We confirmed that administration with mecamylamine, a nicotinic acetylcholine receptor antagonist, inhibits ZSET1446-enhanced neurogenesis in the DG. ZSET1446 administration also restored decreased phosphorylation of Akt and extracellular signal-regulated kinase in the DG of OBX mice. Consistent with restored neurogenesis, chronic but not single ZSET1446 administration promoted significant decreases in immobility in tail suspension tests and improved cognitive behaviors in OBX mice. Taken together, chronic ZSET1446 administration antagonized impaired neurogenesis seen in OBX mice, an effect closely associated with improvement of depressive behavior.

Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) Treatment Rescues Olfactory Bulbectomy-Induced Memory Impairment by Activating Ca2+/Calmodulin Kinase II and Protein Kinase C in Mouse Hippocampus

Olfactory bulbectomy (OBX) in mice elicits impaired memory and cognitive functions. Here, we found that chronic oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) (0.1–1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum by using an anti-choline acetyltransferase antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons. However, chronic treatment significantly restored OBX-induced decreases both in calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) phosphorylation without improving decreased extracellular signal-regulated kinase phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved glutamate receptor 1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired long-term potentiation (LTP) in the hippocampal CA1 region of OBX mice. Taken together, the cognition-enhancing effect of ZSET1446 is probably mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.

Potentiation of acetylcholine-mediated facilitation of inhibitory synaptic transmission by an azaindolizione derivative, ZSET1446 (ST101), in the rat hippocampus

The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM–1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either α7 or α4β2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy.

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

concerning the care receivers’ behavior and abilities to perform their activities of daily living (ADLs). Results: Data were analyzed from 40 caregiver/care receiver dyads with complete sets of data.Significant within-group improvements occurred in the treatment group caregivers in the measures of beliefs about caregiving (P1⁄40.02) and reaction to behavior (P1⁄40.001).When the outcomes were compared (Table 1), the treatment group caregivers had significantly different results (in the expected direction) from those in the control group on measures of stress and beliefs (P1⁄40.04), as well as key outcomes, response to behavior (P1⁄40.03), depression (P1⁄40.03) and burden (P1⁄40.04). Conclusions: A caregiver training intervention focused on the work of caregiving and targeted at improving the knowledge, skills and beliefs benefits caregivers in important outcome dimensions. The results suggest the benefits of providing information, linkage and role coaching to family caregivers of patients with dementia.

P4-230: A novel cognitive enhancer rescues olfactory bulbectomy-induced memory impairment through stimulation of CaMKII and PKC signalings in mouse hippocampus

Background: Impairment of the olfactory system by olfactory bulbectomy (OBX) is associated with loss of memory and cognitive functions. In the present study, we sought to address mechanisms underlying cognitionenhancing effect of ZSET1446 (ST101) in OBX mice. Methods: Therapeutic effects of ZSET1446 was identified by improved memory deficits in OBX mice, assessed by Y-maze and novel object recognition tasks, respectively. The changes in phosphorylation of CaMKII and PKC in the hippocampal CA1 region was determined by Wesern blotting. To understand how memory is improved by ZSET1446 treatment, we evaluated hippocampal LTP in the CA1 region of ZSET1446 treated and -untreated mice. Results: Here, we found that chronic oral administration of ZSET1446 (0.1-1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum using an anti-choline acetyltransferase (ChAT) antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons impaired by OBX. However, chronic treatment significantly restored OBX-induced decreases both in CaMKII and PKC phosphorylation without improving decreased ERK phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired LTP in the hippocampal CA1 region of OBX mice. Conclusions: Taken together, the cognition-enhancing effect of ZSET1446 is likely mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.