Efficacy of the combination of KPR-5714, a novel transient receptor potential melastatin 8 (TRPM8) antagonist, and β-adrenoceptor agonist or anticholinergic agent on bladder dysfunction in rats with bladder overactivity.

Transient receptor potential melastatin 8 (TRPM8) channels may contribute to the pathophysiological bladder afferent hyperactivity, thus a TRPM8 antagonist would be a promising therapeutic target for the bladder hypersensitive disorders including urinary urgency in overactive bladder (OAB). We aimed to investigate a pharmacological effect of KPR-5714, a novel selective TRPM8 antagonist, on TRPM8 channels, M receptors and β-adrenoceptors using the transfected cells of each gene at first. Then, combination effects of KPR-5714 and mirabegron, a β-adrenoceptor agonist, or tolterodine tartrate, an anticholinergic agent, were studied on rhythmic bladder contractions (RBCs) in normal rats and bladder function in frequent-voiding rats.

Identification of N-acyl-N-indanyl-α-phenylglycinamides as selective TRPM8 antagonists designed to mitigate the risk of adverse effects.

Transient receptor potential melastatin 8 (TRPM8), a temperature-sensitive ion channel responsible for detecting cold, is an attractive molecular target for the treatment of pain and other disorders. We have previously discovered a selective TRPM8 antagonist, KPR-2579, which inhibited bladder afferent hyperactivity induced by acetic acid instillation into the bladder. However, additional studies have revealed potential adverse effects with KPR-2579, such as the formation of a reactive metabolite, CYP3A4 induction, and convulsions.

KPR-5714, a Novel Transient Receptor Potential Melastatin 8 Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats.

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (A-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (-[()-3,3-difluoro-4-hydroxy-1-(2-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels.

KPR-2579, a novel TRPM8 antagonist, inhibits acetic acid-induced bladder afferent hyperactivity in rats.

Aims: Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR-2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single-unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats.

Methods: Female Sprague-Dawley rats were used.

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability.

Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists.

Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure-activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist.

Synthesis and structure-activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta.

The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g.

Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing.

Accumulating evidence has demonstrated the importance of alternative splicing in various physiological processes, including the development of different diseases. CDC-like kinases (CLKs) and serine-arginine protein kinases (SRPKs) are components of the splicing machinery that are crucial for exon selection. The discovery of small molecule inhibitors against these kinases is of significant value, not only to delineate the molecular mechanisms of splicing, but also to identify potential therapeutic opportunities.

TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling.

Hedgehog (Hh) signaling is a highly conserved intercellular and intracellular communication mechanism that governs organogenesis and is dysregulated in cancers of numerous tissues, including prostate. Up-regulated expression of the Hh ligands, Sonic (Shh) and Desert (Dhh), has been reported in androgen-deprived and castration-resistant prostate cancer (CRPC). In a cohort of therapy naive, short- and long-term neoadjuvant hormone therapy-treated (NHT), and CRPC specimens, we observed elevated Dhh expression predominantly in long-term NHT specimens and elevated Shh expression predominantly in CRPC specimens.

Distribution of Spinal Sensitization Evoked by Inflammatory Pain Using Local Spinal Cord Glucose Utilization Combined with (3) H-Phorbol 12,13-Dibutyrate Binding in Rats.

Aims. Hyperalgesia following tissue injury is induced by plasticity in neurotransmission. Few investigators have considered the ascending input which activates the superficial of spinal cord.

Can the neurovascular compression volume of the trigeminal nerve on magnetic resonance cisternography predict the success of local anesthetic block after initial treatment by the carbamazepine?

Objectives: Whether NVC volume on magnetic resonance (MR) cisternography might be related to the success of local anesthetic block by tetracaine (TNB) as an additional treatment after carbamazepine (CBZ) treatments in patients with trigeminal neuralgia (TN) was evaluated.

Study Design: Detectable NVC volumes were measured from MR cisternography in 65 patients with TN treated by TNB after CBZ treatments. The correlation between the success of TNB and the NVC volume or the improvement in pain by CBZ was evaluated retrospectively.

Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model.

Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH.

A rat pain model of facial cancer.

Cancer pain is a very severe problem for patients with advanced or terminal cancer. However, the induction mechanism remains unknown. Orofacial cancer patients often report difficulties in eating and swallowing, different from patients with cancer in other regions.

Cutaneous magnetic stimulation reduces rat chronic pain via activation of the supra-spinal descending pathway.

Recent studies have demonstrated that magnetic stimulation (MS) can induce cellular responses such as Ca(2+) influx into the cultured neurons and glia, leading to increased intracellular phosphorylation. We have demonstrated previously that MS reduces rat neuropathic pain associated with the prevention of neuronal degeneration. Thus, we aimed to elucidate the actions of MS in relation to modulation of spinal neuron-glia and the descending inhibitory system in chronic pain.

Neuronal effects of neurokinin B on the rat subfornical organ.

The subfornical organ is an essential central nucleus for angiotensin II-induced body fluid regulation. Similar to angiotensin II, centrally injected neurokinin B (NKB) may induce cardiovascular responses by the subfornical organ; however, it does not induce water intake. To clarify this inconsistency, we investigated the neuronal effects of NKB on subfornical organ neurons in slice preparations along with its behavioral effects in vivo.

Distinct mechanisms underlie the regulation of body fluid balance by neurokinin B and angiotensin II in the rat brain.

Although central injections of either neurokinin B (NKB) or angiotensin II (ANGII) induce a pressor response, they show different involvements in fluid intake behaviors. The aim of the present study was to elucidate the mechanisms by which these two peptides regulate body fluid balance in rats. We demonstrate that intracerebroventricular injections of NKB (1nmol) and ANGII (0.

Relationship between the curative effects of carbamazepine administration and the neurovascular compression volume of the trigeminal nerve measured using magnetic resonance cisternography.

Objectives: To elucidate the relationship between the extent of pain and neurovascular compression (NVC) volume, measured by magnetic resonance (MR) cisternography, in patients with trigeminal neuralgia. In addition, we aimed to evaluate the relationship between NVC volume and the efficacy of carbamazepine administration in patients with trigeminal neuralgia.

Methods: MR cisternography was performed on 214 patients with clinical signs and symptoms that suggested trigeminal neuralgia retrospectively.

The importance of clinical features and computed tomographic findings in numb chin syndrome: a report of two cases.

Background: Dentists need to be aware of the relationship between malignancies and paresthesia or complete loss of sensation in a jaw segment. In particular, dentists should be aware of numb chin syndrome (NCS) and its clinical manifestations, as well as the limitations of using panoramic radiographs to detect the causative malignancy.

Case Description: The authors report two cases of paresthesia in the mental region.

Behavioral characteristics and c-Fos expression in the medullary dorsal horn in a rat model for orofacial cancer pain.

It is well known that patients with orofacial cancer suffer from cancer-induced pain which produces feeding difficulties. To understand the mechanisms of pain associated with orofacial cancer, we have recently created a model for rat orofacial cancer by inoculation with Walker carcinosarcoma 256B-cells into the vibrissal pads. The present study used both behavioral and immunohistochemical techniques to investigate changes in pain-related and ingestive behavior, along with c-Fos expression in the medullary dorsal horn which is a site for processing orofacial pain.

Effect of WAVE2 phosphorylation on activation of the Arp2/3 complex.

Members of the family of WASP-family Verprolin homologous proteins (WAVEs) activate the Arp2/3 complex to induce actin polymerization. The WAVE family comprises three proteins, namely, WAVE1, WAVE2 and WAVE3. Among them, WAVE2 is crucial for activation of the Arp2/3 complex for the formation of branched actin filaments in lamellipodia.

Utility of magnetic resonance cisternography using three-dimensional fast asymmetric spin-echo sequences with multiplanar reconstruction: the evaluation of sites of neurovascular compression of the trigeminal nerve.

Objective: To evaluate the utility of magnetic resonance (MR) cisternography using 3-dimensional (3D) fast asymmetric spin-echo (FASE) sequences with multiplanar reconstruction (MPR) for detection of the sites of neurovascular compression (NVC) in patients with trigeminal neuralgia.

Study Design: Both MR cisternography with 3D-FASE sequences and MR angiography (MRA) were performed on 150 patients with clinical signs and symptoms that suggested trigeminal neuralgia. Results from the original MR cisternography with 3D-FASE sequences, the original MRA, and 4 reformatted images were used for interpretation.

Epigenetic modulation of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma.

Purpose: Histone deacetylase (HDAC) inhibitors have been shown to reverse epigenetic repression of certain genes, including retinoic acid receptor beta2 (RARbeta2). In this study, we examined whether RARbeta2 expression is repressed in human renal cell carcinoma (RCC) and whether the HDAC inhibitor MS-275 may revert its epigenetic repression.

Experimental Design: Six human tumor RCC cell lines were analyzed for RARbeta2 gene expression and for methylation and acetylation status at the promoter level.

In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells.

Background: In retinoid resistant epithelial tumors, the lack of retinoic acid receptor beta2 (RARbeta2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARbeta2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARbeta2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARbeta2 re-activation with anti-tumor activity.

Methods: We selected the RARbeta2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARbeta2 promoter (pGL2-RARbeta2-PC3).

Intrathecal adenosine A1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat.

The analgesia effects of intrathecal adenosine A1 receptor agonist, R-PIA, on the hyperalgesia and CSF-glutamate release after formalin injection into the rat paw were evaluated. R-PIA significantly and dose-dependently attenuated increases in flinching behavior, and this attenuating effect was reversed by the adenosine A1 receptor antagonist, aminophylline. Morphine blocked flinchs, however MK-801 partially abolished.