Lauryn Adair, Rebecca Han, Ruth Fulton, Anna Figueroa, Manisha Patel
{"title":"A multielectrode array reveals therapeutic potential of translocator protein ligands in a zebrafish model of Dravet syndrome.","authors":"Lauryn Adair, Rebecca Han, Ruth Fulton, Anna Figueroa, Manisha Patel","doi":"10.1016/j.jpet.2025.103614","DOIUrl":"10.1016/j.jpet.2025.103614","url":null,"abstract":"<p><p>Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy caused by de novo mutations in the sodium channel Nav1.1 gene, SCN1A. Here, we used a translational zebrafish (ZF) model of DS (Scn1Lab) which exhibits key characteristics known to occur in patients with DS to evaluate drugs with therapeutic potential. Previous work in our laboratory has shown metabolic deficits in Scn1Lab ZF and identified 1-(2-chlorophenyl)-N-[<sup>11</sup>C] methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), a mitochondrial translocator protein (TSPO) ligand, as the lead compound which decreased neuronal hyperexcitability and metabolic deficits observed in Scn1Lab mutants. In this study, we examined the effects of additional TSPO ligands, etifoxine and XBD173, on modulating behavioral and electrophysiological seizure parameters and reversing the metabolic deficits previously reported in Scn1Lab ZF. Additionally, we sought to optimize and validate a noninvasive, higher throughput multiwell multielectrode array (MEA) system to record and quantify hyperexcitability. Etifoxine and XBD173 decreased \"seizure-like\" swim behavior in Scn1Lab mutants. The MEA assay was validated in wild-type ZF using pentylenetetrazol and Scn1Lab mutants using PK11195 and stiripentol. The MEA assay revealed that etifoxine and XBD173 significantly inhibited neuronal hyperexcitability parameters including neuronal spikes, mean firing rate of spikes, and electrographic events. Moreover, XBD173 increased basal and maximal mitochondrial respiration. These findings suggest that TSPO may be a novel therapeutic target for treating developmental and epileptic encephalopathies such as DS. SIGNIFICANCE STATEMENT: Developmental and epileptic encephalopathies are highly drug-refractory and are in urgent need of new therapies. Current methodologies for drug discovery in larval zebrafish are limited in throughput and are highly invasive. We optimized and validated a higher throughput methodology for seizure detection in Scn1Lab mutants, identifying translocator protein, a mitochondrial protein, as a potential therapeutic target for developmental and epileptic encephalopathies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103614"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dorian Teissandier, Geoffroy Rousseau, Camille Lucchini, Boris Teulade, Camille Joly, Jeannot Schmidt, Bruno Pereira, Aurélien Lebreton, Farès Moustafa
{"title":"Sonorheometry parameters during dabigatran reversal with idarucizumab for major bleeding.","authors":"Dorian Teissandier, Geoffroy Rousseau, Camille Lucchini, Boris Teulade, Camille Joly, Jeannot Schmidt, Bruno Pereira, Aurélien Lebreton, Farès Moustafa","doi":"10.1016/j.jpet.2025.103605","DOIUrl":"10.1016/j.jpet.2025.103605","url":null,"abstract":"<p><p>Bleeding during oral anticoagulant therapy is currently codified by expert guidelines. Monitoring coagulation during bleeding events remains challenging. This study aimed to assess viscoelastic hemostatic assays (VHAs) using the Quantra analyzer (HemoSonics) in dabigatran-treated patients with International Society on Thrombosis and Haemostasis major bleeding. We conducted a prospective, multicenter study at 2 university hospitals from January 2021 to December 2023. VHA were evaluated using whole blood sample collected upon emergency admission and 30 minutes after reversal therapy. Six dabigatran-treated patients with major bleeding were included in this study and received idarucizumab: 4 patients with an intracranial bleeding and 2 with gastrointestinal major bleeding. Prior to reversal therapy, clot time (CT) and clot time with heparinase coagulation time (CTH) were prolonged beyond normal range for all patients but clot stiffness (CS) was notably low, indicating a hypocoagulable state. After idarucizumab administration, both CT (median [interquartile range], 179.5 s [169.3-238.5 s] vs 126 s [96-135.5 s]; P = .002) and CTH (181.5 s [166.3-224.3 s] vs 118.5 s [99.5-121.3 s], P = .002) significantly decreased, whereas CS increased significantly (median [interquartile range], 18 hPa [12.3-24.3 hPa] vs 26.6 hPa [25.5-33.8 hPa]; P = .03), all values falling within the normal range. Median anti-IIa activity at emergency arrivals decreased under 30 ng/mL 30 minutes, 6 hours, and 24 hours after idarucizumab administration (P = .0008). No complications were reported during follow-up. After idarucizumab administration, VHA demonstrated significant reductions in CT and CTH, with a corresponding increase in CS within normal ranges. These findings suggest that VHA using the Quantra analyzer may be a valuable tool in assessing the presence of dabigatran and the efficacy of idarucizumab reversal in patients with major bleeding. SIGNIFICANCE STATEMENT: This study highlights viscoelastic hemostatic assays using the Quantra analyzer to monitor reversal therapy in dabigatran-treated patients with major bleeding. It demonstrates the efficacy of idarucizumab in restoring coagulation parameters, offering insights into clinical management.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103605"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bryan W Jenkins, Catherine F Moore, Elise M Weerts
{"title":"Cannabidiol interactions with Δ-9-tetrahydrocannabinol on antinociception after carrageenan-induced inflammatory pain in male and female rats.","authors":"Bryan W Jenkins, Catherine F Moore, Elise M Weerts","doi":"10.1016/j.jpet.2025.103625","DOIUrl":"10.1016/j.jpet.2025.103625","url":null,"abstract":"<p><p>Cannabis products used for pain typically contain Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) in varied amounts, but data on the effects of specific cannabinoid formulations on different pain types are lacking. This study used the carrageenan-induced inflammatory pain model to test oral Δ9-THC, CBD, or their combination on acute edema and pain hypersensitivity. Male and female Sprague-Dawley rats (n = 10-14 per sex/group) were pretreated (1 hour) with vehicle (sesame oil), Δ9-THC (1, 3, and 10 mg/kg, p.o.), CBD (10, 30, 100 mg/kg, p.o.), or select doses of Δ9-THC + CBD combinations prior to an intraplantar λ-carrageenan injection into the hind paw. The nonsteroidal anti-inflammatory drug ketoprofen (10 and 20 mg/kg i.p.) or its vehicle (1:1:18 ethanol:Cremophor EL:saline [Millipor Sigma]) was administered to a separate group as a positive control. Measurements were conducted at baseline and 1, 3, and 5 hours after carrageenan injection. Carrageenan produced edema and hypersensitivity to radiant heat (hyperalgesia) and mechanical pressure (allodynia). Δ9-THC alone sex- and dose-dependently decreased hyperalgesia and allodynia but not inflammation, with effects of Δ9-THC being greater in females than males, and the lowest Δ9-THC dose was proinflammatory in males. CBD alone did not affect pain sensitivity but had modest anti-inflammatory effects in males. Isobolographic and dose addition analyses indicated Δ9-THC + CBD was subadditive relative to Δ9-THC alone. These data demonstrate that prophylactic oral Δ9-THC alleviates acute inflammatory pain with sex-dependent effects, and CBD diminishes Δ9-THC antinociception when combined. The findings suggest oral Δ9-THC is superior to CBD or combined Δ9-THC + CBD for acute inflammatory pain. SIGNIFICANCE STATEMENT: Despite the popularity of cannabis for pain management, empirical data on how specific cannabinoid formulations affect acute inflammatory pain are limited. This study in rats found that pure Δ-9-tetrahydrocannabinol (Δ9-THC) formulations were most effective at improving inflammatory pain compared to pure cannabidiol or Δ9-THC + cannabidiol combinations, and females were more sensitive than males to the antinociceptive effects of Δ9-THC.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103625"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sera Sermet, Brianna M Finn, Robert B Crawford, Norbert E Kaminski
{"title":"Δ<sup>9</sup>-Tetrahydrocannabinol and cannabidiol selectively suppress toll-like receptor (TLR) 7- and TLR8-mediated interleukin-1β production by human CD16<sup>+</sup> monocytes by inhibiting its post-translational maturation.","authors":"Sera Sermet, Brianna M Finn, Robert B Crawford, Norbert E Kaminski","doi":"10.1016/j.jpet.2025.103615","DOIUrl":"10.1016/j.jpet.2025.103615","url":null,"abstract":"<p><p>Monocytes are innate immune cells that release inflammatory factors upon detection of infectious and injurious stimuli. CD16<sup>+</sup> monocytes, a subset of the total monocyte population, are associated with acute and chronic inflammation in human immunodeficiency virus-associated neurocognitive disorder and rheumatoid arthritis. Given the role monocytes play in regulating the host immune response, this investigation explored the effects of cannabinoids on the monocyte secretome for potential therapeutic applications. Δ<sup>9</sup>-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are major cannabis-derived compounds established to have immune-modulating properties. Despite a rise in medical cannabis use, the specific mechanism by which THC and CBD modulate the inflammatory response, including by human monocytes remains poorly understood. We hypothesized that THC and CBD suppress toll-like receptor (TLR) 7- or TLR8-induced inflammatory profiles by CD16<sup>+</sup> and CD16<sup>-</sup> monocytes, specifically interleukin (IL) 1β maturation. Cannabinoid receptor 2 selective agonist, JWH-015, was used to deduce whether cannabinoid receptor 2 signaling alone can mimic immune-modulating properties of THC. Primary human CD16<sup>+</sup> and CD16<sup>-</sup> monocytes were pretreated with THC, CBD, or JWH-015 and then activated through TLR7 or TLR8. Activated monocytes mainly produced IL-1β, tumor necrosis factor-⍺, and IL-6. We show that THC and CBD, but not JWH-015, exert anti-inflammatory effects on primary human monocyte apoptosis-associated speck-like protein-incorporating inflammasome formation and subsequent caspase-1 activity, contributing to suppressed IL-1β production. In addition, mRNA expression of IL1B, CASP1, NLRP3, and PYCARD were unaffected by THC. Minimal THC effects were observed on TLR8-mediated AIM2 mRNA expression. Collectively, results from these studies suggest THC and CBD may be useful in mitigating IL-1β-mediated acute or chronic inflammation. SIGNIFICANCE STATEMENT: This current investigation aimed to understand the role of Δ<sup>9</sup>-tetrahydrocannabinol (THC) and cannabidiol (CBD) in mediating virally activated CD16<sup>+</sup> monocyte inflammatory cytokine production. Further, the results indicated that THC and CBD selectively suppress monocyte interleukin 1β production, though THC is more efficacious, through its maturation, as evidenced by suppressed caspase-1 activity and apoptosis-associated speck-like protein-incorporating inflammasome formation. This work provides evidence to support that THC, and to an extent CBD, exert anti-inflammatory effects that could be useful in mitigating monocyte interleukin 1β-mediated chronic inflammation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103615"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Locomotor and discriminative stimulus effects of fluorinated analogs of amphetamine and methamphetamine in mice and rats.","authors":"Olivia Anchondo, Ritu A Shetty, Michael B Gatch","doi":"10.1016/j.jpet.2025.103617","DOIUrl":"10.1016/j.jpet.2025.103617","url":null,"abstract":"<p><p>The prevalence of fluorinated amphetamine and methamphetamine analogs on the illicit market has continued to increase in the past decade. The perceived ability of these compounds to bypass legal regulation has resulted in an increasing popularity among drug users; however, their use produces significant adverse effects, including heart failure, cerebral hemorrhage, and death. This study aimed to investigate the effects of phenyl ring fluorination on the abuse potential of 5 synthetic stimulant compounds: 2- and 3-fluoroamphetamine (FA) and 2-, 3-, and 4-fluoromethamphetamine (FMA). The open-field assay was used to observe the locomotor effects of the compounds and to evaluate effective dose ranges and time courses for psychoactive effects in male Swiss-Webster mice. Discriminative stimulus effects were evaluated using male Sprague-Dawley rats trained to discriminate methamphetamine from saline using an fixed-ratio 10 food-maintained reinforcement schedule in a 2-lever operant box. The compounds tested all resulted in time- and dose-dependent stimulation of locomotor activity. Potencies (ED<sub>50</sub>) ranged from 0.38 to 7.38 mg/kg, with rank-order potency of 2-FMA > methamphetamine > 3-FMA = 3-FA = 2-FMA > 4-FMA. Peak effects varied, with 2-FA, 3-FA, and 3-FMA showing peak effects similar to methamphetamine (5905-7758 counts), while 2-FMA and 4-FMA were weak stimulants with lower peak effects (2200-3980 counts). All fluorinated compounds elicited dose-dependent full substitution for methamphetamine with comparable potencies (ED<sub>50</sub> values = 0.32-0.71 mg/kg). The present study indicates that these analogs may have a potential for abuse comparable to that of methamphetamine, although self-administration studies need to be conducted to confirm this, and the locomotor activity data highlight possible mechanistic differences between the positional analogs through the contrasting potencies and efficacies. SIGNIFICANCE STATEMENT: Fluorinated amphetamine analogs have appeared on the illicit market and produce significant adverse effects. The present study shows that these analogs produce methamphetamine-like locomotor stimulant and discriminative stimulus effects and so may have a potential for abuse comparable to that of methamphetamine and other psychostimulants.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103617"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Role of quinoline and indole-based heterocycles in revolutionizing Alzheimer's drug discovery: Promising futuristic structural designs.","authors":"Atukuri Dorababu","doi":"10.1016/j.jpet.2025.103606","DOIUrl":"10.1016/j.jpet.2025.103606","url":null,"abstract":"<p><p>Imagine a world where memories fade, loved ones become strangers, and the sense of self dissolves. This is the harsh reality for nearly 50 million people worldwide suffering from Alzheimer's disease (AD), a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and behavioral changes. With global prevalence on the rise, the demand for effective therapies is urgent. Yet, despite decades of research, a cure remains out of reach, and current treatments offer only temporary relief, failing to address the root causes of the disease. AD's complex pathology, including amyloid-β plaque accumulation, tau protein tangles, oxidative stress, and neurotransmitter deficits, calls for innovative, multitargeted therapeutic approaches. In this pursuit, heterocyclic compounds have emerged as promising candidates. These molecules, defined by ring structures containing heteroatoms, exhibit broad biological activity. Among them, quinoline and indole derivatives have shown particular promise for their anti-Alzheimer's potential. This review explores the therapeutic relevance of these 2 heterocyclic scaffolds, examining their ability to counter key AD hallmarks and highlighting the link between their chemical structure and biological efficacy. By analyzing structure-activity relationships, we aim to spotlight compounds with the greatest potential to advance AD treatment. SIGNIFICANCE STATEMENT: Quinoline and indole derivatives showed strong dual cholinesterase inhibition and good blood-brain barrier permeability. Piperazine- and piperidine-based hybrids improved bioavailability and central nervous system penetration. Heterocyclic fusion and bioisosteres improved metabolic stability and solubility.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103606"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Faria Khurshid, Javeid Iqbal, Fiaz-Ud-Din Ahmad, Sana Javaid, Almas Kanwal, Abdul Malik, Suhail Akhtar, Marvi Imam Bux, Zainab Ahmad, Nikhat J Siddiqui, Robert D E Sewell
{"title":"Synergistic protective activity of sodium hydrosulfide and L-arginine against cisplatin-induced nephrotoxicity, even during nitric oxide synthase inhibition.","authors":"Faria Khurshid, Javeid Iqbal, Fiaz-Ud-Din Ahmad, Sana Javaid, Almas Kanwal, Abdul Malik, Suhail Akhtar, Marvi Imam Bux, Zainab Ahmad, Nikhat J Siddiqui, Robert D E Sewell","doi":"10.1016/j.jpet.2025.103618","DOIUrl":"10.1016/j.jpet.2025.103618","url":null,"abstract":"<p><p>Cisplatin is a chemotherapeutic drug that induces nephrotoxicity through inflammation and oxidative stress. Hydrogen sulfide (H<sub>2</sub>S) and nitric oxide (NO) are gaseous signaling molecules with cytoprotective potential in renal damage. The current study evaluated the nephroprotective potential of sodium hydrosulfide (NaHS), an H<sub>2</sub>S donor, and L-arginine, a NO precursor, against cisplatin-induced nephrotoxicity, even under NO synthase inhibition. Wistar rats were treated with cisplatin (5 mg/kg) to induce nephrotoxicity while administered with L-N<sup>G</sup>-nitro-L-arginine methyl (L-NAME), NaHS, and L-arginine either alone or in combination for 28 days. Renal function was assessed by monitoring various parameters, including body weight and urinary flow. Moreover, H<sub>2</sub>S, NO, creatinine level and clearance, blood urea nitrogen (BUN), electrolyte levels, and oxidative stress were monitored in body fluids. The findings revealed that L-NAME exacerbated cisplatin-induced nephrotoxicity, which was evident from reduced weights (P < .0001) and elevated urine output (P < .01), H<sub>2</sub>S (P < .0001), NO (P < .0001), creatinine (P < .01), and BUN (P < .0001) levels, along with reduced sodium and potassium (P < .0001) and elevated oxidative stress markers (P < .001) in plasma compared with healthy rats. The treatment with NaHS and L-arginine markedly protected against L-NAME + cisplatin-induced nephrotoxicity as the parameters were reinstated, including urine output (P < .01), H<sub>2</sub>S (P < .01), NO (P < .0001), creatinine (P < .05), and BUN (P < .01) levels compared with L-NAME + cisplatin rats. Moreover, coadministration of NaHS + L-arginine restored the sodium (P < .0001) and potassium (P < .01) levels in plasma and mitigated oxidative stress (P < .05). The results suggested that H<sub>2</sub>S and NO mitigated L-NAME + cisplatin-induced nephrotoxicity by ameliorating the L-NAME + cisplatin-induced oxidative stress. SIGNIFICANCE STATEMENT: The therapeutic validation of the mentioned agents would be beneficial in the treatment of renal dysfunction.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103618"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preclinical pharmacological profiles of vornorexant, a novel potent dual orexin receptor antagonist.","authors":"Hirohiko Hikichi, Yuichi Tokumaru, Atsuki Taruta, Yoshihiro Konno, Jun-Ichi Karasawa, Kenichi Fukumoto, Toshiyuki Marumo, Yasuyuki Fujii, Teisuke Takahashi, Takao Yoshimizu, Shigeyuki Chaki, Noriko Hino, Naoki Kojima","doi":"10.1016/j.jpet.2025.103624","DOIUrl":"10.1016/j.jpet.2025.103624","url":null,"abstract":"<p><p>Dual orexin receptor antagonists are known to inhibit the orexinergic signaling pathway, leading to promotion of sleep. Here, we report the pharmacological profiles of [(2S)-2-{[3-(5-Fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (vornorexant), also known as ORN0829. In in vitro assays, vornorexant exhibited a high affinity for OX<sub>1</sub> and OX<sub>2</sub> receptors, without any meaningful affinity for other receptors, transporters or ion channels, exerting receptor antagonist activity. Vornorexant had pharmacokinetic profiles with a relatively rapid absorption and short half-life, rapidly occupied the OX<sub>1</sub> and OX<sub>2</sub> receptors in the brain of rats after oral administration and rapidly dissociated from these receptors depending on the plasma concentration. In rats, daily oral administration of vornorexant just before the dark phase reduced the sleep onset latency and prolonged sleep time, and no tolerance developed up to 14 days. Vornorexant also reduced the sleep onset latency and prolonged sleep time in rats that had developed tolerance after daily treatment with the GABA<sub>A</sub> receptor modulator, zolpidem. In addition, vornorexant also enhanced the sleep-promoting effects of zolpidem in rats. Moreover, vornorexant did not impair motor coordination in monotherapy and combination with ethanol in rats. These results indicate that vornorexant has desirable profiles with a rapid sleep onset latency and a short half-life, thereby a lowered risk of next-morning residual activity. Vornorexant could be a promising alternative therapeutic option to GABA<sub>A</sub> receptor modulators for the treatment of insomnia. SIGNIFICANCE STATEMENT: Vornorexant is a novel and potent dual orexin receptor antagonist that was demonstrated to exert sleep-promoting effects by occupying the OX<sub>1</sub> and OX<sub>2</sub> receptors in the brain of rats. Moreover, vornorexant promoted sleep even after switching treatment from zolpidem or when administered in combination with zolpidem in rats. These results suggest that vornorexant possesses properties that are desirable for insomnia drugs.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103624"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia I Allen, Emory Lewis, Cameron F Rough, Michael A Nader
{"title":"Ethanol self-administration prior to cocaine self-administration reduces sensitivity to cocaine reinforcement in socially housed monkeys.","authors":"Mia I Allen, Emory Lewis, Cameron F Rough, Michael A Nader","doi":"10.1016/j.jpet.2025.103608","DOIUrl":"10.1016/j.jpet.2025.103608","url":null,"abstract":"<p><p>Co-use of alcohol is highly prevalent among individuals who use cocaine. However, the behavioral mechanisms underlying co-use are not fully characterized. Thus, this study aimed to examine how ethanol (EtOH) self-administration prior to cocaine self-administration influenced the maintenance of cocaine self-administration in socially housed male (n = 4) and female (n = 4) cynomolgus monkeys responding under a fixed-ratio schedule of reinforcement. For these experiments, food (1.0 g flavored pellets) and cocaine dose-response curves (0.001-0.3 mg/kg) were determined when monkeys had access to 1.5 g/kg of a sweetened EtOH solution or an equal volume of a sweetened vehicle solution for one hour prior to cocaine self-administration. EtOH and the sweetened vehicle were readily self-administered by all monkeys, and consumption did not affect fixed-ratio food-maintained responding. When cocaine was studied, EtOH significantly decreased the potency of cocaine to function as a reinforcer relative to when the sweetened vehicle was self-administered. This relationship also appeared dose-dependent such that monkeys that drank more EtOH prior to the session had greater rightward shifts in the cocaine dose-response curve. Neither sex nor social rank influenced these outcomes. These data may suggest that EtOH decreased the reinforcing effects of cocaine, and/or attenuated the discriminative stimulus effects of cocaine. Future research is needed to examine how EtOH may modify cocaine use in the presence of a nondrug alternative reinforcer and to evaluate whether interventions aimed at reducing drug use are less effective in the context of co-use. SIGNIFICANCE STATEMENT: Cocaine users commonly report co-using alcohol simultaneously or in close succession. The present study found that ethanol (EtOH) self-administration prior to cocaine self-administration decreased the potency of cocaine to function as a reinforcer in nonhuman primates. These findings suggest that EtOH may decrease the effects of cocaine, and although not directly assessed in this study, EtOH may be used in combination with cocaine to mitigate the negative effects associated with cocaine use.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103608"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Uncovering the pharmacological mechanisms of bifendate against chronic kidney disease using computational pharmacology and experimental verification.","authors":"Hrushikesh Kulkarni, Neha Dagar, Anil Bhanudas Gaikwad","doi":"10.1016/j.jpet.2025.103609","DOIUrl":"10.1016/j.jpet.2025.103609","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a progressive ailment identified by renal fibrosis, inflammation, and mitochondrial dysfunction, necessitating the development of novel therapeutic interventions. Bifendate (dimethyl diphenyl bicarboxylate [DDB]), a known hepatoprotective agent, has shown promising antifibrotic properties, but its potential in CKD remains unexplored. This study integrates computational pharmacology, molecular docking, and experimental validation to explicate the mechanisms of renoprotection by DDB. Curative targets for CKD and DDB were identified from DisGeNET, GeneCards, and SwissTargetPrediction. Potential DDB targets against CKD were analyzed via STRING for protein interactions. Gene ontology and pathway enrichment (Database for Annotation, Visualization, and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes) were conducted, followed by network construction and analysis using Cytoscape (Institute for Systems Biology, USA). Network analysis identified 89 overlapping targets between DDB and CKD, including key regulators such as NF-κB1, PTGS2, and PPARG, which were enriched in multiple pathways, including calcium, Ras, ROS, NF-κB, and cAMP signaling. To validate these findings, a unilateral ureteral obstruction model in Sprague-Dawley rats was employed. DDB administration significantly mitigated kidney fibrosis, improved renal function markers, and preserved kidney morphology. Histological analyses confirmed that DDB attenuated tubular injury, glomerulosclerosis, and excessive collagen deposition. Furthermore, immunohistochemical assessments demonstrated that DDB suppressed epithelial-mesenchymal transition by restoring E-cadherin and reducing α-smooth muscle actin expression. Mitochondrial biogenesis was enhanced through PGC-1α upregulation, while inflammatory responses were dampened via NF-κB pathway inhibition. These findings highlight DDB's multifaceted therapeutic potential in CKD, acting through fibrosis inhibition, mitochondrial protection, and anti-inflammatory mechanisms. This study provides a strong foundation for further clinical investigations into DDB as a potential treatment for CKD, offering new insights into its mechanistic pathways. SIGNIFICANCE STATEMENT: This study demonstrates bifendate's therapeutic potential for chronic kidney disease through network pharmacology, identifying 89 common targets. Experimental validation in a unilateral ureteral obstruction model confirmed its renoprotective effects, revealing multi-target mechanisms against renal fibrosis and injury.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103609"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}