SS-OCTおよびグラチクル搭載細隙灯顕微鏡によるtear meniscus評価の有用性と再現性

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Pathways Involving Beta-3 Adrenergic Receptors Modulate Cold Stress-Induced Detrusor Overactivity in Conscious Rats

ObjectiveTo investigate pathways involving beta-3 adrenergic receptors (ARs) in detrusor overactivity induced by cold stress, we determined if the beta-3 AR agonist CL316243 could modulate the cold stress-induced detrusor overactivity in normal rats. MethodsTwodays prior to cystometric investigations, the bladders of 10-week-old female Sprague-Dawley rats were cannulated. Cystometric measurements of the unanesthetized, unrestricted rats were taken to estimate baseline values at room temperature (RT, 272 degrees C) for 20min. They were then intravenously administered vehicle, 0.1, or 1.0mg/kg CL316243 (n=6 in each group). Fiveminutes after the treatments, they were gently and quickly transferred to the low temperature (LT, 42 degrees C) room for 40min where the cystometric measurements were again made. Afterward, the rats were returned to RT for final cystometric measurements. The cystometric effects of CL316243 were also measured at RT (n=6 in each group). ResultsAt RT, both low and high dose of CL316243 decreased basal and micturition pressure while the high dose (1.0mg/kg) significantly increased voiding interval and bladder capacity. During LT exposure, the high dose of CL316243 partially reduced cold stress-induced detrusor overactivity characterized by increased basal pressure and urinary frequency. The high drug dose also significantly inhibited the decreases of both voiding interval and bladder capacity compared to the vehicle- and low dose (0.1mg/kg)-treated rats. ConclusionA high dose of the beta-3 agonist CL316243 could modulate cold stress-induced detrusor overactivity. Therefore, one of the mechanisms in cold stress-induced detrusor overactivity includes a pathway involving beta-3 ARs.ArticleLUTS-LOWER URINARY TRACT SYMPTOMS.7(1):50-55(2014)journal articl

Comparison of FGF1 (aFGF) Expression between the Dorsal Motor Nucleus of Vagus and the Hypoglossal Nucleus of Rat

Neurons in the dorsal motor nucleus of the vagus (DMNV) are more severely affected by axonal injury than most other nerves, such as those of the hypoglossal nucleus. However, the mechanism underlying such a response remains unclear. In this study, we compared the expression of fibroblast growth factor 1 (FGF1), a neurotrophic factor, between the DMNV and the hypoglossal nucleus by RT-PCR and immunohistochemical analyses. RT-PCR showed that the level of FGF1 mRNA expression in the DMNV was lower than that in the hypoglossal nucleus (P<0.01). Immunohistochemistry revealed that FGF1 was localized to neurons. FGF1-positive neurons in large numbers were evenly distributed in the hypoglossal nucleus, whereas FGF1-positive neurons were located in the lateral part of the DMNV. Double immunostaining for FGF1 and choline acetyltransferase demonstrated that 22.7% and 78% of cholinergic neurons were positive for FGF1 in the DMNV and hypoglossal nucleus, respectively. A tracing study with cholera toxin B subunit (CTb) demonstrated that cholinergic neurons sending their axons from the DMNV to the superior laryngeal nerve were FGF1-negative. The results suggest that the low expression of FGF1 in the DMNV is due to severe damage of neurons in the DMNV

Combined treatment with β3-adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats

AimsThis study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the (3)-adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs). MethodsThirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 272 degrees C) for 20min. The rats were then intravenously administered vehicle, 0.1mg/kg solifenacin alone, 0.1mg/kg mirabegron alone, or the combination of 0.1mg/kg mirabegron and 0.1mg/kg solifenacin (n=8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 42 degrees C) for 40min. Finally, the rats were returned to RT. After the cystometric investigations, the (3)-ARs and M-3-MRs expressed within the urinary bladders were analyzed. ResultsJust after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M-3-MR and (3)-AR mRNA. The tissue distribution of M-3-MRs was similar to that of the (3)-ARs. ConclusionsThis study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026-1033, 2017. (c) 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.ArticleNEUROUROLOGY AND URODYNAMICS.36(4):1026-1033(2016)journal articl

Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries.

We identified drug seeds for treating Huntington's disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD