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Abstract Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia. Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711

We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion. Keywords: T-type calcium channel, Middle cerebral artery occlusion, Ischemia-reperfusion

We studied the pronociceptive role of proteinase-activated receptor-2 (PAR2) in mouse bladder. In female mice, intravesical infusion of the PAR2-activating peptide, SLIGRL-amide (SL), caused delayed mechanical hypersensitivity in the lower abdomen, namely ‘referred hyperalgesia’, 6–24 h after the administration. The PAR2-triggered referred hyperalgesia was prevented by indomethacin or a selective TRPV1 blocker, and restored by a T-type Ca2+ channel blocker. In human urothelial T24 cells, SL caused delayed prostaglandin E2 production and COX-2 upregulation. Our data suggest that luminal PAR2 stimulation in the bladder causes prostanoid-dependent referred hyperalgesia in mice, which involves the activation of TRPV1 and T-type Ca2+ channels.

Nuclear HMGB1 that contains 3 cysteine residues is acetylated and secreted to the extracellular space, promoting inflammation via multiple molecules such as RAGE and TLR4. We thus evaluated and characterized the redox state-dependent effects of peripheral HMGB1 on nociception. Intraplantar (i.pl.) administration of bovine thymus-derived HMGB1 (bt-HMGB1), all-thiol HMGB1 (at-HMGB1) or disulfide HMGB1 (ds-HMGB1) caused long-lasting mechanical hyperalgesia in mice. The hyperalgesia following i.pl. bt-HMGB1 or at-HMGB1 was attenuated by RAGE inhibitors, while the ds-HMGB1-induced hyperalgesia was abolished by a TLR4 antagonist. Thus, nociceptive processing by peripheral HMGB1 is considered dependent on its redox states.

This paper presents the effect of frictional force between colloidal particles and a solid substrate on the formation of particle monolayer by a numerical simulation. Discrete Element Method is employed to simulate the dynamics of colloidal particles trapped in liquid film. Forces such as capillary immersion force, van der Waals force and frictional force are included in the simulation model. Isotropic ordering factor and non-dimensional boundary length are introduced to quantify the structures of colloidal particles. In the case where the diameter of colloidal particles ranges from 100nm to 1000nm, the monolayer structures depend strongly on the frictional constant between a particle and a solid substrate. On the other hand, in the case where diameter is about 10nm, large domains of hexagonal close-packed structures are formed because of the Brownian force.† This report was originally printed in J. Soc. Powder Technology, Japan, 41, 465-472 (2004) in Japanese, before being translated into English by KONA Editorial Committee with the permission of the editorial committee of the Soc. Powder Technology, Japan.

Abstract.: We evaluated the effect of buprenorphine, a mixed agonist for μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors, in neuropathic rats, using the paw pressure test. Buprenorphine, administered i.p. at 50, but not 20, μg/kg, exhibited naloxone-reversible analgesic activity in naïve rats. In contrast, buprenorphine at 0.5 – 20 μg/kg produced a naloxone-sensitive antihyperalgesic effect in the L5 spinal nerve–injured neuropathic rats. Intrathecal injection of [N-Phe1]nociceptin(1-13)NH2, a NOP-receptor antagonist, reversed the effect of buprenorphine in neuropathic rats, but not in naïve rats. Together, buprenorphine suppresses neuropathic hyperalgesia by activating NOP and opioid receptors, suggesting its therapeutic usefulness in treatment of neuropathic pain. Keywords:: buprenorphine, nociceptin/orphanin FQ peptide receptor, neuropathic pain

We examined if TRPA1, like TRPV1, contributes to pancreatic nociceptor excitation following proteinase-activated receptor-2 (PAR2) stimulation and to pancreatitis-related pain in mice. A PAR2-activating peptide, infused into the pancreatic duct, caused spinal Fos expression, which was prevented by AP18, a TRPA1 inhibitor. Repeated administration of cerulein caused referred hyperalgesia accompanying pancreatitis, which was reversed by SB366791, a TRPV1 inhibitor, but not AP18. AP18, administered in combination with a subeffective dose of SB366791, significantly suppressed the referred hyperalgesia. Our findings suggest that TRPA1, like TRPV1, mediates PAR2-triggered pancreatic nociception and that TRPA1 in collaboration with TRPV1 latently contributes to pancreatitis-related pain. Keywords:: transient receptor potential ankyrin-1 (TRPA1), proteinase-activated receptor-2 (PAR2), pancreatic pain

The one-pot synthesis of a Cu(II) complex with partially oxidized tetrathiafulvalene (TTF) moieties in its capping MT-Hsae-TTF ligands, [CuII(MT-sae-TTF)2] [CuICl2] was realized by the simultaneous occurrence of Cu(II) complexation and CuIICl2 mediated oxidation of TTF moieties. The crystal structure was composed of one-dimensional columns formed by partially oxidized TTF moieties and thus the cation radical salt showed relatively high electrical conductivity. Tight binding band structure calculations indicated the existence of a Peierls gap due to the tetramerization of the TTF moieties in the one-dimensional stacking column at room temperature, which is consistent with the semiconducting behavior of this salt.

An experiment and a time series analysis have been made on the flow in a rectangular natural convection loop. It was found that the flow reversal occurs in a certain range of the heat flux and Reynolds number, which depends on the cooling water temperature. Based on time series temperature data of the system, an attractor in a state space has been reconstructed. Geometrical structures and orbital instability for this attractor were evaluated by the recurrence plot analysis and a nonlinear prediction by the method of local linear approximation. A nonlinear prediction was applied to the turbulence time series. As a result, a recurrence plot of the predicted time series obtained from the turbulence data has characteristics similar to those of the measured of the unstable flow. This fact suggests that, even when an apparent turbulent flow is observed, a transition to the unstable flow may occur. In order to confirm this conjecture, we have performed another experiment with the addition of a disturbance to the loop. The experimental results are consistent with the chaos analysis. We have successfully shown the validity of the nonlinear prediction and its recurrence plot as a means to evaluate dynamical flow instability.

Protease-activated receptor 1 (PAR1) that can be activated by serine proteinases such as thrombin has been demonstrated to contribute to the development of cardiac remodeling and hypertrophy after myocardial injury. Here, we investigated the mechanisms by which PAR1 leads to hypertrophic cardiomyocyte growth using cultured rat neonatal ventricular myocytes. PAR1 stimulation with thrombin (1 U/ml) or a synthetic agonist peptide (TFLLR-NH2, 50 μM) for 48 h induced an increase in cell size and myofibril formation associated with BNP (brain natriuretic peptide) production. This actin reorganization assessed by fluorescein isothiocyanate (FITC)-conjugated phalloidin staining appeared at 1 h after PAR1 stimulation, and this response was reduced by a protein kinase C (PKC) inhibitor, chelerythrine, inhibitors of Rho (simvastatin) and Rho-associated kinase (ROCK) (Y-27632), but not by pertussis toxin (PTX). By Western blot analysis, translocation of PKCα or PKCε from the cytosol to membrane fractions was observed in cells stimulated with thrombin or TFLLR-NH2 for 2 – 5 min. In addition, PAR1 stimulation for 3 – 5 min increased the level of active RhoA. Furthermore, inhibitors of PKC and ROCK and Rho abrogated PAR1-mediated increase in cell size. Depletion of PKCα or PKCε by specific small interfering RNA also suppressed both actin reorganization and cell growth. These results suggest that PAR1 stimulation of cardiomyocytes induces cell hypertrophy with actin cytoskeletal reorganization through activation of PKCα and PKCε isoforms and RhoA via PTX-insensitive G proteins. Keywords:: protease-activated receptor 1, cardiac hypertrophy, actin cytoskeleton, protein kinase C, RhoA

We performed this study to determine if curcumin affects pro-inflammatory responses to activation of proteinase-activated receptor-2 (PAR2) in human pulmonary adenocarcinoma A549 cells. Curcumin completely inhibited the PAR2-triggered prostaglandin E2 (PGE2) production, but notably not interleukin-8 release. Cyclooxygenase-2 (COX-2) upregulation, but not its upstream activation of mitogen-activated protein kinases, caused by PAR2 stimulation was partially inhibited by curcumin. Curcumin inhibited the PAR2-triggered phosphorylation of I-κB, an indicator for nuclear factor-κB (NF-κB) activation, and also its upstream signal Akt, which is known to contribute to PAR2-triggered PGE2 formation, but not COX-2 upregulation. Collectively, curcumin inhibits the PAR2-triggered PGE2 production by suppressing COX-2 upregulation and Akt/NF-κB signals in A549 cells. Keywords:: curcumin, proteinase-activated receptor-2, prostaglandin E2

Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src / epidermal growth factor (EGF) receptor / p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element–binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-κB (NF-κB)–related signals in the PAR2-triggered PGE2 release / COX-2 upregulation in A549 cells. The PAR2-triggered PGE2 release was clearly blocked by an inhibitor of the NF-κB pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-κB, an indicator of NF-κB activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3–kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-κB, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-κB pathway is involved in PAR2-triggered PGE2 formation, but not upregulation of COX-2 that is dependent on activation of ERK/CREB and JNK in addition to p38MAPK. Keywords:: proteinase-activated receptor-2 (PAR2), nuclear factor-κB (NF-κB), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), human alveolar epithelial cell line A549