Occurrence of somnolence and respiratory depression induced by pregabalin and mirogabalin use and the influence of opioid treatment using the Japanese adverse drug event report database.

Background: Gabapentinoid anticonvulsants are standard treatment for neuropathic pain and are often combined with opioids for treating cancer. It is assumed that this combination may heighten somnolence and respiratory depression due to the inhibitory effects of opioids on the central nervous system. Although pregabalin, a gabapentinoid, is known to increase somnolence frequency during opioid therapy, whether mirogabalin exerts similar effects on somnolence frequency under opioid therapy remains unknown. This study examined the signals of somnolence and respiratory depression in response to pregabalin and mirogabalin use by utilizing data from the Japanese Adverse Drug Event Report database and assessed their interaction with strong opioid analgesics. Methods: Information was obtained from the JADER database from April 2004 to August 2023 via the Pharmaceuticals and Medical Devices Agency website. The study focused on neuropathic pain medications, specifically "pregabalin" and "mirogabalin besilate." Adverse events were defined using preferred terms (PTs) from the Medical Dictionary for Regulatory Activities version 26.1. The PTs considered were "Somnolence (10041349)" and "Respiratory depression (10038678)." To investigate the effect of the combination of strong opioid analgesics with pregabalin and mirogabalin on the occurrence of somnolence, a multivariable logistic regression analysis was conducted. Results: Signals for somnolence were detected with the use of both drugs (pregabalin: information component (IC) [95% confidence intervals (CIs)]: 2.89 [2.70 to 3.08]; mirogabalin: IC [95% CIs] 2.50 [1.85 to 3.16]). When evaluating respiratory depression, a typical and serious adverse event of opioid analgesic use, a signal was detected with pregabalin use but not with mirogabalin use (pregabalin: (IC [95% CIs] 1.28 [0.83 to 1.73]; mirogabalin: IC [95% CIs] -0.15 [-2.20 to 1.89]). Multivariable analysis indicated that the use of strong opioid analgesics increased the occurrence of somnolence when combined with pregabalin but not when combined with mirogabalin (p = 0.004). Conclusion: While the safety of concomitant administation of mirogabalin with opioids remains controversial, caution should be exercised when using pregabalin, especially in combination with opioids for neuropathic pain, compared to that for mirogabalin.

Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer.

BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Venetoclax Clinical Pharmacokinetics After Administration of Crushed, Ground or Whole Tablets.

PURPOSE: Venetoclax is a potent, orally bioavailable BCL-2 inhibitor used in the treatment of some hematological malignancies. Crushing tablets may be necessary to help with the administration of venetoclax to patients with swallowing difficulties or patients requiring nasogastric tube feeding. The study was conducted to assess the bioavailability of crushed and finely ground venetoclax tablets relative to whole tablets. METHODS: An open-label, randomized, 3-way, crossover study in 15 healthy adult females was conducted. Venetoclax tablets were administered orally in a crushed, ground or intact form on Day 1 of each period with water following a high-fat breakfast. Pharmacokinetic samples were collected up to 72 hours postdosing. FINDINGS: The crushed and ground tablets met the bioequivalence criteria (0.80-1.25) relative to the intact tablets with respect to area under the concentration-time curve to time of the last measurable concentration (AUCt) and to infinite time (AUCinf) but exhibited a slightly lower maximum plasma concentration (Cmax). This was not considered clinically significant as only venetoclax overall exposure (AUC) has been shown to correlate with clinical efficacy. There was no change in the physical appearance and the evaluated physicochemical properties of crushed and ground venetoclax tablets after 72 hours of storage at 25°C/60% relative humidity. IMPLICATIONS: Crushing or grinding venetoclax tablets before administration could be considered as a viable alternative method of administration for patients who have difficulty swallowing whole venetoclax tablets or patients requiring nasogastric tube feeding. GOV IDENTIFIERS: NCT05909553, registered June 12, 2023.

Potential use of pinenes to improve localized insecticide injections targeting the western drywood termite (Blattodea: Kalotermitidae).

The western drywood termite, Incisitermes minor (Hagen), causes significant economic damage to wood structures in the United States of America, especially California. When infestation is not widespread, localized insecticide injections may be useful for remedial control. However, the extensive gallery structure of drywood termites and their tendency to aggregate at specific parts of the galleries can impact the efficacy of localized insecticide injection. Chemicals that attract termites from a distance may improve the localized insecticide injection by increasing the number of termites contacting the insecticide residues. Two volatile terpenes, α-pinene and ß-pinene, commonly found in many coniferous timber trees, were applied to artificial termite galleries to determine if termites were attracted from their original aggregation site. Furthermore, we examined if adding these pinenes would improve the overall efficacy of some insecticide products for drywood termite control. Behavioral assay results showed that the treatment with pinenes increased the likelihood that drywood termites would leave their original aggregation site and contact the treated part of the gallery. When tested with the pesticide products applied in a small area away from the termite aggregation, ß-pinene significantly accelerated the time course of mortality for the aqueous fipronil. The efficacy of disodium octaborate tetrahydrate dust was not influenced by the addition of pinenes. Implications for drywood termite management and future research directions are discussed.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.

This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15 mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.

Effect of Intrahippocampal Administration of α7 Subtype Nicotinic Receptor Agonist PNU-282987 and Its Solvent Dimethyl Sulfoxide on the Efficiency of Hypoxic Preconditioning in Rats.

We have previously suggested a key role of the hippocampus in the preconditioning action of moderate hypobaric hypoxia (HBH). The preconditioning efficiency of HBH is associated with acoustic startle prepulse inhibition (PPI). In rats with PPI > 40%, HBH activates the cholinergic projections of hippocampus, and PNU-282987, a selective agonist of α7 nicotinic receptors (α7nAChRs), reduces the HBH efficiency and potentiating effect on HBH of its solvent dimethyl sulfoxide (DMSO, anticholinesterase agent) when administered intraperitoneally. In order to validate the hippocampus as a key structure in the mechanism of hypoxic preconditioning and research a significance of α7nAChR activation in the hypoxic preconditioning, we performed an in vivo pharmacological study of intrahippocampal injections of PNU-282987 into the CA1 area on HBH efficiency in rats with PPI ≥ 40%. We found that PNU-282987 (30 µM) reduced HBH efficiency as with intraperitoneal administration, while DMSO (0.05%) still potentiated this effect. Thus, direct evidence of the key role of the hippocampus in the preconditioning effect of HBH and some details of this mechanism were obtained in rats with PPI ≥ 40%. The activation of α7nAChRs is not involved in the cholinergic signaling initiated by HBH or DMSO via any route of administration. Possible ways of the potentiating action of DMSO on HBH efficiency and its dependence on α7nAChRs are discussed.

Additive effects of mGluR2 positive allosteric modulation, mGluR2 orthosteric stimulation and 5-HT2AR antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.

Analysis for data-derived extrapolation factors for procymidone.

The derivation of Chemical Specific Adjustment Factors (CSAFs) (IPCS, 2005; U.S. EPA, 2014) depends on the choice of appropriate dose metric. EPA and IPCS guidance was applied to derive a CSAF for developmental toxicity for procymidone (PCM). Although kinetic data were not available in humans at any dose, sufficient toxicokinetic data are available in a surrogate species, primates, and from chimeric mice with both rat and human liver cells to offer insights. Alternative approaches were explored in the derivation of the CSAG based on review of the available kinetic data. The most likely dosimetric adjustment is the Cmax based on the character of the critical effect - reduced anogenital distance and increased incidence of hypospadias in male rats, which likely occurs during a small window of time during development of the rat fetus. Cmax is also the default dosimeter from U.S. EPA (1991). However, in this case, the use of Cmax is also likely more conservative than the use of area under the curve (AUC), which otherwise is the default recommendation of the IPCS (2005). Despite human data, estimated tentative CSAF value is 0.48 (range, 0.22 to 0.74). The use of any of these values would be supported by the available data.

Mirogabalin, a novel ligand for α2δ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Mirogabalin is a novel potent and selective ligand for the α2δ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.

Developmental toxicity of procymidone to larval zebrafish based on physiological and transcriptomic analysis.

As a broad-spectrum with low toxicity, procymidone (PCM), is widely used in agriculture and frequently observed in aquatic system, which may cause some impacts on aquatic organisms. Here, to determine the developmental toxicity of PCM, embryonic and larval zebrafish were exposed to PCM at 0, 1, 10, 100 µg/L in dehydrogenated natural water containing 0.01% acetone for 7 days. The results showed that high concentration of PCM could cause the pericardial edema and increase the heart rates in larval zebrafish, suggesting that PCM had developmental toxicity to zebrafish. We also observed that PCM exposure not only changed the physiological parameters including TBA, GLU and pyruvic acid, but also changed the transcriptional levels of glycolipid metabolism related genes. In addition, after transcriptomics analysis, a total of 1065 differentially expressed genes, including 456 up-regulated genes and 609 down-regulated genes, changed significantly in 100 µg/L PCM treated larval zebrafish. Interestingly, after GO (Gene Ontology) analysis, the different expression genes (DEGs) were mainly enriched to the three different biology processes including GABA-nervous, lipid Metabolism and response to drug. We also observed that the levels of GABA receptor related genes including gabrg2, gabbr1α, gabbr1 and gabra6α were inhibited by PCM exposure. Interestingly, the swimming distance of larval zebrafish had the tendency to decrease after PCM exposure, indicating that the nervous system was affected by PCM. Taken together, the results confirmed that the fungicide PCM could cause developmental toxicity by influencing the lipid metabolism and GABA mediated nervous system and behavior in larval zebrafish. We believed that the results could provide an important data for the influence of PCM on aquatic animals.

Mirogabalin activates the descending noradrenergic system by binding to the α2δ-1 subunit of voltage-gated Ca2+ channels to generate analgesic effects.

Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the α2δ subunit of voltage-gated Ca2+ channels, are used for first-line treatment of neuropathic pain. Here, we examined the analgesic effect of mirogabalin besilate (referred to simply as mirogabalin), a novel gabapentinoid, focusing on its action on the spinal cord and the descending noradrenergic pain inhibitory system. When administered systemically (10 and 30 mg/kg, intraperitoneally (i.p.)) and locally (10 and 30 µg, intracerebroventricularly (i.c.v.) or intrathecally (i.t.)) to mice, mirogabalin was found to exert analgesic effects on thermal (plantar test) and mechanical (von Frey test) hypersensitivity developing after partial sciatic nerve ligation. Notably, its analgesic effects (30 mg/kg, i.p. and 30 µg, i.c.v.) disappeared in mice pretreated with yohimbine hydrochloride (3 µg, i.t.). Moreover, in mice harboring a mutation in the α2δ-1 subunit resulting in substitution of arginine at position 217 with alanine to prevent gabapentinoid binding (R217A mutant mice), the analgesic effects of pregabalin and mirogabalin (30 µg, i.c.v., respectively) on mechanical hypersensitivity were almost completely suppressed. These results clearly demonstrate that mirogabalin also operates via the descending noradrenergic system, and that binding to the α2δ-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids.

Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice.

INTRODUCTION: The two-pore domain potassium channel TREK-1 is a member of background K+ channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of TREK-1 in the action of antidepressants, and its antagonists might be potentially effective antidepressants. However, the mechanisms underlying the actions of TREK-1 are not yet fully understood. METHODS: The expression of TREK-1 was examined in a mouse model of chronic unpredictable mild stress (CUMS) using immunoblotting. Neuron-specific genetic manipulation of TREK-1 was performed through adeno-associated virus. Behavioral tests were performed to evaluate depression-related behaviors. Electrophysiological recordings were used to evaluate synaptic plasticity. Golgi staining was used to examine neuroplasticity. RESULTS: TREK-1 expression was increased in the mouse hippocampus after CUMS. Knockdown of TREK-1 in hippocampal neurons significantly attenuated depressive-like behaviors and prevented the decrease of CUMS-induced synaptic proteins in mice. Further examination indicated that neuron-specific knockdown of TREK-1 in the hippocampus prevented stress-induced impairment of glutamatergic synaptic transmission in the CA1 region. Moreover, chronic TREK-1 inhibition protected against CUMS-induced depressive-like behaviors and impairment of synaptogenesis in the hippocampus. CONCLUSION: Our results indicate a role for TREK-1 in the modulation of synaptic plasticity in a mouse model of depression. These findings will provide insight into the pathological mechanism of depression and further evidence for a novel target for antidepressant treatment.

Predictors of the usefulness of mirogabalin for neuropathic pain: a single-institution retrospective study.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin® (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

Activation of α7nACh receptor protects against acute pancreatitis through enhancing TFEB-regulated autophagy.

Acute pancreatitis (AP) is associated with impaired acinar cell autophagic flux, intracellular zymogen activation, cell necrosis and inflammation. Activation of the cholinergic system of vagus nerve has been shown to attenuate AP, but the effect of organ-intrinsic cholinergic system on pancreatitis remains unknown. In this study, we aim to examine the effect of α7 nicotinic acetylcholine receptor (α7nAChR) stimulation within the pancreas during AP. In vivo, AP was induced by caerulein plus LPS or ethanol plus palmitoleic acid in mice. In vitro, pancreatic acini were isolated and subjected to cholecystokinin (CCK) stimulation. Mice or acini were pre-treated with PNU-282987 (selective α7nAChR agonist) or methyllycaconitine citrate salt (selective α7nAChR antagonist). Pancreatitis severity, acinar cell injury, autophagic flux, and transcription factor EB (TFEB) pathway were analyzed. Both caerulein plus LPS in vivo and CCK in vitro led to an up-regulation of α7nAChR, indicating activation of pancreas-intrinsic α7nAChR signaling during AP. PNU-282987 decreased acinar cell injury, trypsinogen activation and pancreatitis severity. Conversely, methyllycaconitine citrate salt increased acinar cell injury and aggravated AP. Moreover, activation of α7nAChR by PNU-282987 promoted autophagic flux as indicated by reduced p62, increased LysoTracker staining and decreased number of autolysosomes with undegraded contents. Furthermore, PNU-282987 treatment significantly increased TFEB activity in pancreatic acinar cells. α7nAChR activation also attenuated pancreatic inflammation and NF-κB activation. Our results showed that activation of α7nAChR protected against experimental pancreatitis through enhancing TFEB-mediated acinar cell autophagy, suggesting that activation of pancreas-intrinsic α7nAChR may serve as an endogenous protective mechanism during AP.

Combined administration of SHP2 inhibitor SHP099 and the α7nAChR agonist PNU282987 protect mice against DSS­induced colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition with complex pathogenesis that currently has no cure. α7 nicotinic acetylcholine receptor (α7nAChR) is known to regulate multiple aspects of immune function. The present study aimed to evaluate the protective effects of PNU282987 and SHP099, which are a selective agonist of α7nAChR and an SHP2 inhibitor, respectively, in dextran sulfate sodium (DSS)­induced colitis in mice. Acute colitis was induced in mice using 3% DSS, and weight loss, colonic histology and cytokine production from colonic lamina propria were analyzed to evaluate disease severity. Bone marrow­derived macrophages were treated with lipopolysaccharide (LPS) to induce an inflammatory response. Cytokine expression and reactive oxygen species (ROS) levels were quantified. The α7nAChR agonist, PNU282987, and the SHP2 inhibitor, SHP099, were administered alone or in combination to LPS­induced macrophages or to colitic model mice to evaluate the inflammatory response and protective efficacy in colitis. α7nAChR protein levels were found to be markedly increased in the colon of DSS­induced colitic mice, and were found to co­localize with macrophages. Consistently, α7nAChR mRNA and protein levels were upregulated with colitis progression in DSS­induced colitic mice. Colonic inflammation was attenuated by PNU282987 treatment in DSS­induced mice, as evidenced by reduced weight loss and alleviated colonic epithelial cell disruption. These effects of PNU282987 on colitis were enhanced when it was combined with SHP099. Cytokine production and ROS levels induced by LPS in macrophages were decreased by a combination treatment of PNU282987 and SHP099. These findings identified α7nAChR as an essential element in the role of intestinal macrophages in colonic repair and demonstrated a synergistic effect of PNU282987 and SHP099, suggesting a new potential therapy for IBD.

Group II metabotropic glutamate receptor agonist promotes retinal ganglion cell survival by reducing neuronal excitotoxicity in a rat chronic ocular hypertension model.

Glaucoma, the second leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). The group II metabotropic glutamate receptor (mGluR II) activation has been linked to RGC survival, however, the mechanism by which it promotes neuronal survival remains poorly defined. In the present work, we show that extracellular application of LY341495, an mGluR II antagonist could increase the RGC firing frequency, suggesting that activation of mGluR II by endogenously released glutamate could modulate RGC excitability. LY354740, an mGluR II agonist, significantly decreased RGC excitability and the reduced presynaptic excitatory inputs and post-synaptic Ca2+-permeable currents mediated the LY354740-induced effects. By using a well-characterized in vivo male Sprague-Dawley rat glaucoma model, we further demonstrate that in the early stage of experimental glaucoma, the expression of mGluR II dimer-formed protein was significantly reduced, and pre-activation of mGluR II by intravitreal injection of LY354740 before establishment of the glaucoma model could effectively reduce excitatory inputs, thereby reversing hyperexcitability induced by elevated intraocular pressure. Furthermore, LY354740 could increase the expression level of brain-derived neurotrophic factor in the glaucomatous retinas, further protecting RGCs. Our study indicates that the abnormal expression of mGluR II may accelerate RGC apoptosis in glaucoma, and demonstrates that mGluR II agonist LY354740 can be used as a novel method to counter RGC apoptosis in glaucoma.

Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4ß2 Receptor Antagonist for the Treatment of Depression.

A series of chemical optimizations guided by in vitro affinity at the α4ß2 receptor in combination with selectivity against the α3ß4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4ß2 receptor ligand with a Ki value of 1.5 nM. It showed >10 µM binding affinity toward the ganglionic α3ß4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.

5-HT2A receptors modulate dopamine D2-mediated maternal effects.

Serotonin 5-HT2A receptors are expressed throughout the mesolimbic and mesocortical dopamine pathways, and manipulation of this receptor system has a profound impact on dopamine functions and dopamine-mediated behaviors. It is highly likely that 5-HT2A receptors may also modulate the D2-mediated maternal effects. The present study investigated this issue and also explored the possible behavioral mechanisms. We tested the effects of two D2 drugs (an agonist quinpirole: 0.5, 1.0 mg/kg, and a potent D2 antagonist haloperidol: 0.05, 0.10 mg/kg, sc) and their combinations with two 5-HT2A drugs (a selective 5-HT2A agonist TCB-2: 2.5 mg/kg, and 5-HT2A antagonist MDL100907, 1.0 mg/kg, sc) on maternal behavior in Sprague-Dawley postpartum females. Individually, TCB-2 (2.5 mg/kg, sc) and quinpirole (0.5 and 1.0 mg/kg, sc) reduced pup preference and disrupted home-cage maternal behavior. In contrast, haloperidol (0.10 mg/kg, sc) only disrupted home-cage maternal behavior, but did not suppress pup preference. MDL100907 (1.0 mg/kg, sc) by itself had no effect on either pup preference or maternal behavior. When administered in combination, pretreatment of TCB-2 did not alter quinpirole's disruption of pup preference and home-cage maternal behavior (possibly due to the floor effect), however, it did enhance haloperidol's disruption of pup retrieval in the home cage. MDL100907 had no effect both quinpirole's and haloperidol's disruption of pup preference and home-cage maternal behavior. Interestingly, haloperidol attenuated TCB-2's disruptive effect on pup preference. These findings suggest that activation of 5-HT2A receptors tends to enhance D2-mediated maternal disruption, whereas blockade of 5-HT2A receptors is less effective. They also suggest that 5-HT2A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors. The possible behavioral and neural mechanisms by which 5-HT2A- and D2-mediated maternal effects and their interaction are discussed.

Revealing the biodiversity and the response of pathogen to a combined use of procymidone and thiamethoxam in tomatoes.

The dissipation kinetics of a combined use of procymidone and thiamethoxam, and their impact on the biodiversity and pathogen on surface of tomatoes were studied. The half-lives of procymidone and thiamethoxam, used either on their own or in combination with each other, were 2.94 or 3.26 days and 2.41 or 2.67 days, respectively. The residues dropped below the maximum residue limit (MRL) after 7 or 10 days (MRL 2 mg·kg-1 for procymidone), and 10 or 14 days (MRL 0.2 mg·kg-1 for thiamethoxam), respectively. The phylum Bacteroidetes, Cyanobacteria, and Proteobacteria, were dominantly present in all studied samples. The genus Escherichia-Shigella was found and exposed to the dissipation of procymidone (r = -0.9209 for procymidone on its own, and r = -0.8611 for procymidone in combination with thiamethoxam). These results will contribute to establish adequate monitoring of pesticides residues and their incorporation in surface ecology and pathogen management strategies in tomatoes.