Seisuke Mimori

4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor.

This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase.

Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress

Neural stem cells (NSCs) play an essential role in development of the central nervous system. Endoplasmic reticulum (ER) stress induces neuronal death. After neuronal death, neurogenesis is generally enhanced to repair the damaged regions. However, it is unclear whether ER stress directly affects neurogenesis‐related processes such as neuronal differentiation and dendrite outgrowth. We evaluated whether neuronal differentiation and dendrite outgrowth were regulated by HRD1, a ubiquitin ligase that was induced under mild conditions of tunicamycin‐induced ER stress. Neurons were differentiated from mouse embryonic carcinoma P19 cells by using retinoic acid. The differentiated cells were cultured for 8 days with or without tunicamycin and HRD1 knockdown. The ER stressor led to markedly increased levels of ER stress. ER stress increased the expression levels of neuronal marker βIII‐tubulin in 8‐day‐differentiated cells. However, the neurites of dendrite marker microtubule‐associated protein‐2 (MAP‐2)‐positive cells appeared to retract in response to ER stress. Moreover, ER stress markedly reduced the dendrite length and MAP‐2 expression levels, whereas it did not affect the number of surviving mature neurons. In contrast, HRD1 knockdown abolished the changes in expression of proteins such as βIII‐tubulin and MAP‐2. These results suggested that ER stress caused aberrant neuronal differentiation from NSCs followed by the inhibition of neurite outgrowth. These events may be mediated by increased HRD1 expression.

Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid

The chemical chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater chemical chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed chemical chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinsons disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene.

Nitrogen 14 NMR and Correlations of Oxidation Potentials of Dibenzo[a,d]cycl[2.2.3]azines with the Corresponding HOMOs: Further Evidence for Peripheral Conjugate System

For the first time, 14 N NMR spectra of a novel type of heterocycles, dibenzo|a,d|cycl|2.2.3|azines were described. The chemical shifts are almost independent of substituents at position 2. The correlations of oxidation potentials with HOMO energies of dibenzo|a,d|cycl|2.2.3|azines also offer very good correlation coefficients (r 2 >0.92) regardless of calculation methods at various levels. Thus, it was concluded that the contribution of the unshared electron pairs of the central nitrogen to the peripheral conjugation in this system is almost negligible.

Increased Silent Brain Infarction Accompanied With High Prevalence of Diabetes and Dyslipidemia in Psychiatric Inpatients: A Cross-Sectional Study.

OBJECTIVE Patients with schizophrenia have increased risk of atherosclerotic diseases. It is already known that lifestyle-related disorders and the use of antipsychotics are closely related with the progression of atherosclerosis in psychiatric patients. Stroke as well as coronary heart disease play an important role in the cause of death in Asia and Japan. Thus, we studied the prevalence of cerebrovascular disease in psychiatric inpatients in Japan using brain magnetic resonance imaging (MRI). METHOD This cross-sectional study was performed from January 2012 to December 2013. Study participants were 152 hospitalized patients (61 men and 91 women) in the Department of Psychiatry at Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa City, Japan. Mean ages were 50.0 and 57.1 years old for men and women, respectively. The diagnoses (DSM-IV-TR criteria) of participants were schizophrenia (69.1%), mood disorder (18.4%), and other mental disorders (12.5%). We checked physical status, metabolic status of glucose and lipid levels, and brain MRI within 1 week of admission. RESULTS The study group showed a significantly high prevalence of diabetes and low high-density lipoprotein (HDL) cholesterolemia in both sexes (n = 61 in men, n = 91 in women, P < .05). In the study group, serum fasting plasma glucose and hemoglobin A1c levels were significantly high (n = 152, P < .05), but serum HDL cholesterol and total cholesterol were significantly low in both sexes (n = 61 in men, n = 90 in women, P < .05), and triglycerides were low in men (n = 61, P < .05). Silent brain infarction was recognized at a higher rate (n = 98, P < .05) compared with healthy controls. CONCLUSIONS Participants in this study had an increased ratio of silent brain infarction compared with Japanese healthy controls, accompanied with higher ratios of diabetes and low HDL cholesterol.

X-ray crystal structure of dibenzo〔a,d〕cycl〔2.2.3〕azines

The results of X-ray analyses of a novel type of heterocycles, 2-benzoyl- and 1,3-dimethyldibenzo[a,d]cycl[2.2.3]azines were described, which offer further evidence for the 18π peripheral conjugate nature of dibenzo-[a,d]cycl[2.2.3]azines. The molecules are essentially planer as is the parent cycl[2.2.3]azine, but less strained.

Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.

Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder

Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice. An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method. These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD.

A new methodology for functionalization at the 3-position of indoles by a combination of boron Lewis acid with nitriles.

We discovered that a reagent comprising a combination of PhBCl2 and nitriles was useful for syntheses of both 3-acylindoles and 1-(1H-indol-3-yl)alkylamine from indoles. The reaction proceeded selectively at the 3-position of indoles providing 3-acylindoles in moderate to high yields on treatment with the above reagent. Furthermore, the reaction provided the corresponding amine products in moderate to high yields after the intermediate imine was reduced by NaBH3CN. These reactions proceeded under mild conditions and are applicable to the formation of indoles functionalized at the 3-position.

Neuroprotective Effects of 4-phenylbutyric Acid and Its Derivatives: Possible Therapeutics for Neurodegenerative Diseases

The pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases involves the aggregation of denatured and misfolded nascent proteins. Consequently, many pharmacological approaches have been developed to prevent protein aggregation. 4-Phenylbutyric acid (4-PBA) is a chemical chaperone that shows potential as a candidate drug for the treatment of neurodegenerative diseases. The main actions of chemical chaperones are the amelioration of unfolded proteins and the suppression of their aggregation, which result in protective effects against endoplasmic reticulum stress-induced neuronal cell death. Furthermore, 4-PBA exhibits inhibitory activity against histone deacetylases (HDACs). However, owing to the problematically high doses of 4-PBA currently required for therapeutic efficacy, the optimization of 4-PBA is crucial for its effective medicinal application. In the present review, we summarize the recent advances in research on the basic actions of 4-PBA and its derivatives. We also discuss whether these compounds could be viable therapeutic agents against neurodegenerative diseases.