Memantine ameliorates learning and memory disturbance and the behavioral and psychological symptoms of dementia in thiamine-deficient mice.

Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice.

Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus.

Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized.

Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice.

Deposition of amyloid-β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ degrading enzyme.

Memantine inhibits β-amyloid aggregation and disassembles preformed β-amyloid aggregates.

Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble β-amyloid (Aβ) and soluble Aβ oligomers in animal models of AD. The mechanisms by which memantine reduces Aβ levels in the brain were evaluated by determining the effect of memantine on Aβ aggregation using thioflavin T and transmission electron microscopy.

Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking.

Memantine, an uncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as medication for the treatment of Alzheimer's disease (AD). It has been reported that memantine reduces amyloid-β peptide (Aβ) levels in both neuronal cultures and in brains of animal models of AD. However, the underlying mechanism of these effects is unclear.

The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs.

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer's disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination.

A novel method for enhancement of peptide vaccination utilizing T-cell epitopes from conventional vaccines.

Peptide vaccines have two fundamental weak points, namely low antigenicity and MHC-restriction. In our previous study, we proposed the design of vaccine peptide to overcome these weakpoints. The vaccine was constructed in the following order, N-terminal, Arg-Gly-Asp (RGD), T-cell epitope peptide, di-lysine linker (KK) to B-cell epitope peptide.

Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one.

6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.

Synthesis and SAR studies of bicyclic amine series GPR119 agonists.

We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors.

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.

Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor.

In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.

Involvement of calmodulin in neuronal cell death.

A large body of evidence indicates that disturbances of Ca(2+) homeostasis may be a causative factor in the neurotoxicity following cerebral ischemia. However, the mechanisms by which Ca(2+) overload leads to neuronal cell death have not been fully elucidated. Calmodulin, a major intracellular Ca(2+)-binding protein found mainly in the central nervous system, mediates many physiological functions in response to changes in the intracellular Ca(2+) concentration, whereas Ca(2+) overload in neurons after excitotoxic insult may induce excessive activation of calmodulin signaling pathways, leading to neuronal cell death.

Effects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala-kindled seizures in rats.

Purpose: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy.

Methods: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED).

Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats.

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas).

Anticonvulsant properties of the novel nootropic agent nefiracetam in seizure models of mice and rats.

Purpose: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.

Methods: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)].

Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes.

The polyol pathway consists of two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). There is a growing body of evidence to suggest that acceleration of the polyol pathway is implicated in the pathogenesis of diabetic vascular complications. However, a functional role remains to be elucidated for SDH in the development and progression of diabetic retinopathy.

Inhibition of gastric inhibitory polypeptide signaling prevents obesity.

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance.