A5016275553- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Histone Deacetylase Inhibitors Research
- Protein Structure and Dynamics
- Neurogenesis and neuroplasticity mechanisms
- Genomics and Chromatin Dynamics
- Cancer therapeutics and mechanisms
- DNA and Nucleic Acid Chemistry
- Treatment of Major Depression
- Neuroscience and Neuropharmacology Research
- DNA Repair Mechanisms
- Cyclopropane Reaction Mechanisms
- Enzyme Structure and Function
- Autism Spectrum Disorder Research
- 14-3-3 protein interactions
- Advanced biosensing and bioanalysis techniques
- Neurotransmitter Receptor Influence on Behavior
- Click Chemistry and Applications
- Functional Brain Connectivity Studies
- Genetics and Neurodevelopmental Disorders
- Neuroendocrine regulation and behavior
- Neuroscience and Neural Engineering
- Tryptophan and brain disorders
- Stress Responses and Cortisol
Futaba (Japan)
2008-2025
Shionogi (Japan)
2008-2024
Kyoto University
2024
Ping An (China)
2024
Shionogi (United States)
2022
Massachusetts Institute of Technology
2015-2017
The University of Tokyo
2007-2010
Tokyo University of the Arts
2008-2009
The histone deacetylase HDAC2, which negatively regulates synaptic gene expression and neuronal plasticity, is upregulated in Alzheimer's disease (AD) patients mouse models. Therapeutics targeting HDAC2 hold promise for ameliorating AD-related cognitive impairment; however, attempts to generate HDAC2-specific inhibitors have failed. Here, we take an integrative genomics approach identify proteins that mediate recruitment plasticity genes. Functional screening revealed knockdown of the...
Improvement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming key strategy in drug discovery. We applied this to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds which ethylene linker known amidine-type inhibitor 2 was replaced chiral rings. The synthesis biologic evaluation these revealed that cis-(1S,2R) isomer 6 exhibited most potent inhibitory among them. X-ray structure analysis complex its unique...
Ketamine, a rapid-acting antidepressant, has undesirable psychotomimetic effects, including dissociative effect. There is currently no effective strategy to suppress these side effects while preserving its antidepressant Here, we investigated the of D2/D3 receptor antagonist and partial agonists on ketamine in mice humans. Aripiprazole, agonist, attenuated effect, but maintaining even enhancing antidepressant-like effect forced swim test, whereas raclopride, an antagonist, suppressed both...
DTNBP1 has been recognized as a schizophrenia susceptible gene, and its protein product, dysbindin-1, is down-regulated in the brains of schizophrenic patients. However, little known about physiological role dysbindin-1 central nervous system. We hypothesized that disruption with unidentified proteins could contribute to pathogenesis symptoms schizophrenia. GST pull-down from human neuroblastoma lysates showed an association DNA-dependent kinase (DNA-PK) complex. The DNA-PK complex interacts...
The amyloid-beta (Abeta) peptide, widely known as the causative molecule of Alzheimer disease (AD), is generated by sequential cleavage amyloid precursor protein (APP) aspartyl proteases BACE1/beta-secretase and presenilin/gamma-secretase. Inhibition BACE1, therefore, a promising strategy for preventing progression AD. However, beta-secretase inhibitors (BSIs) exhibit unexpectedly low potency in cells expressing "Swedish mutant" APP (APPswe) transgenic mouse Tg2576, an AD model...
The opioid system plays crucial roles in modulating social behaviors both humans and animals. However, the pharmacological profiles of opioids regarding behavior their therapeutic potential remain unclear. Multiple pharmacological, behavioral, immunohistological c-Fos mapping approaches were used to characterize effects μ-opioid receptor agonists on investigate mechanisms naive mice autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated Fmr1-KO mice....
The amyloid-β (Aβ) peptide, widely known as the causative molecule of Alzheimer's disease (AD), is generated by sequential cleavage amyloid precursor protein (APP) aspartyl proteases BACE1/β-secretase and presenilin/γ-secretase. Inhibition BACE1, therefore, a promising strategy for preventing progression AD. However, β-secretase inhibitors (BSIs) exhibit unexpectedly low potency in cells expressing “Swedish mutant” APP (APPswe) transgenic mouse Tg2576, an AD model overexpressing APPswe....
Disease-modifying therapies, such as neuroprotective and neurorestorative interventions, are strongly desired for Alzheimer’s disease (AD) treatment. Several studies have suggested that histone deacetylase 2 (HDAC2) inhibition can exhibit disease-modifying effects in AD patients. However, whether HDAC2 shows under neuropathic conditions, amyloid β (Aβ)-elevated states, remains poorly understood. Here, we performed HDAC2-specific knockdown CA1 pyramidal cells showed increased the length of...
Prevention of the formation β-Amyloid (Aβ) peptides is a potential disease-modifying therapy for Alzheimer's disease (AD). The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors prevent production Aβ and could hence be therapeutic agents in treatment AD, especially when treating early disease. JNJ-54861911 has been described as potent oral BACE inhibitor AD spectrum. Here we report preclinical pharmacological profiles JNJ-54861911, with strong reduction CSF multiple-animal...
Recently, the importance of soluble oligomeric forms amyloid-β (Aβ-oligomers) has been recognized because some reports showed their inhibitory effects on cognitive function without inducing permanent neurological deficits by various in vivo models. However, most these studies used Aβ-oligomers prepared from synthetic peptides or conditioned medium cultured cells. The effect native spatial working memory was tested using Y-maze task wild-type mice injected with TBS (Tris-buffered...
Individuals with autism spectrum disorders (ASDs) show neurobehavioral deficits, characterized by impairments in social interactions, repetitive behaviors, as well wide sensory abnormalities. We have previously demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 (E12.5) causes autism-like behavioral abnormalities male mouse offspring. also found VPA long-lasting mechanical allodynia and spinal microglial activation. In the present study, we aimed investigate role...