Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"The long and winding road of schizophrenia drug development.","authors":"Ben S Huang","doi":"10.1016/j.jpet.2025.103391","DOIUrl":"10.1016/j.jpet.2025.103391","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103391"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374216","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":"Cocaine reinstates extinguished food responding in male cynomolgus monkeys with a history of self-administering cocaine under a concurrent drug versus food choice paradigm.","authors":"Brianna F Roberts, Michael A Nader, Mia I Allen","doi":"10.1016/j.jpet.2025.103387","DOIUrl":"10.1016/j.jpet.2025.103387","url":null,"abstract":"<p><p>The rate-dependency principle postulates that \"stimulants\" tend to increase low baseline rates of response and decrease high baseline responses. One exception to this principle is that stimulants do not typically increase responses that has been extinguished. However, drug self-administration studies showed that stimulant pretreatments reinstated extinguished drug-maintained responses. The goal of this study was to determine the effects of noncontingent cocaine on extinguished food-maintained responding in 3 male cynomolgus monkeys with extensive cocaine self-administration experience. Monkeys had a >4-year history of self-administering cocaine under a concurrent cocaine versus food schedule of reinforcement. For this study, only the discriminative stimulus (S^D) signaling a fixed-ratio 30 schedule of food reinforcement was studied, and the previous cocaine-associated S^D was not illuminated (inactive). In experiment 1, the effect of noncontingent food (1-5 pellets) and cocaine (0.03-0.3 mg/kg i.v.) on extinguished food-maintained responses was studied. In all 3 monkeys, 5 pellets and at least 1 cocaine dose significantly increased extinguished responding; the effects of cocaine were larger than those of food. In experiment 2, the behavioral mechanisms mediating these cocaine-induced increases in extinguished responses were studied. Following administration of 0.3 mg/kg cocaine, with no S^D illuminated, responses occurred on both the previously active (food) and inactive (cocaine) manipulanda. When cocaine was given and both S^Ds were illuminated, more responses occurred on the inactive (cocaine) versus previously active (food) switch. These findings suggest that a cocaine self-administration history can influence the direct behavioral effects of cocaine. Increases in previously extinguished nondrug-reinforced behaviors could have clinical implications related to relapse. SIGNIFICANCE STATEMENT: Following long-term cocaine self-administration in the context of a nondrug alternative, noncontingent cocaine administration reinstated previously extinguished responses maintained by delivery of food pellets, suggesting that reinstatement studies may not be measuring relapse of \"drug-seeking.\" Importantly, the effects of self-administered cocaine on the brain and behavior cannot be determined in the absence of systematically studying ongoing behavior.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103387"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365167","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":"Reperfusion of ischemia in the heart or brain.","authors":"Victor Gurewich, David Segarnick","doi":"10.1016/j.jpet.2025.103392","DOIUrl":"10.1016/j.jpet.2025.103392","url":null,"abstract":"<p><p>The current treatment of choice for an acute myocardial infarction (AMI) is an interventional procedure like percutaneous coronary intervention (PCI), which takes 2 to 3 hours and is not appropriate for clots in arteries smaller than the catheter. Because PCI requires inpatient catheterization, there is an inevitable delay in reperfusion of the ischemia. This delay was shown to have a linear relationship with AMI mortality. The longer the delay, from <5 minutes to >3 hours, the greater the cardiovascular disease mortality. Instead of PCI, a sequential combination of tissue-type plasminogen activator and prourokinase is the most effective treatment for conditions like AMI and ischemic stroke that mirrors the endogenous fibrinolytic process.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103392"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391210","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":"Antidepressants for inflammatory bowel disease? Multimodal effects of amitriptyline in murine colitis.","authors":"Diane E Peters","doi":"10.1016/j.jpet.2024.103382","DOIUrl":"10.1016/j.jpet.2024.103382","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103382"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074578","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":"Metformin alleviates sphingolipids dysregulation and improves obesity-related kidney disease in high-fat diet rats.","authors":"Lin Xing, Shanyu Wu, Ying Shi, Lin Wei, Fangzhi Yue, Sin Man Lam, Guanghou Shui, Ryan Russell, Dongmei Zhang","doi":"10.1016/j.jpet.2025.103388","DOIUrl":"10.1016/j.jpet.2025.103388","url":null,"abstract":"<p><p>Obesity-related kidney disease (ORKD) has recently become a global health issue. Metformin is widely used in patients with type 2 diabetes with concomitant obesity, but its effects on ORKD are insufficiently understood. Accumulation of lipid species including sphingolipids has been reported to disrupt glomerular functions and drive progression of chronic kidney disease. The present study aimed to test the hypothesis that metformin could exert beneficial effects on ORKD, which may be associated with changes in renal lipidomics. Male Sprague-Dawley rats were divided into normal chow diet (ND) group or high-fat diet (HFD)-fed group. After 8 weeks, HFD-fed group was subdivided into metformin treatment (HFD-Met) group and control (HFD-C) group for an additional 8 weeks. Sphingolipids and phospholipids in renal cortex were measured by targeted lipidomics. Compared with ND group, HFD-C group developed histopathological features of ORKD. Metformin alleviated dyslipidemia, renal dysfunction, proteinuria, glomerular hypertrophy, podocyte damage, and renal fibrosis in HFD-fed rats. Renal sphingolipid analysis showed elevations of total ceramide, sphingosine, glucosylceramide, and galactosylceramide levels in HFD-C versus ND group. Specific species, such as ceramide d18:1/22:0, glucosylceramide d18:1/20:0, and galactosylceramide d18:1/16:0, which were positively associated with oxidative stress and insulin resistance, were reduced in HFD-Met versus HFD-C group. Renal phospholipid analysis showed increased levels of total phosphatidylcholine and lysophosphatidylcholine (LPC) in HFD-C rats versus ND rats. The ratio of saturated and monounsaturated LPCs to polyunsaturated LPCs was significantly reduced in HFD-Met rats. These results suggest that metformin alleviates sphingolipids dysregulation and improves ORKD in HFD-fed rats. SIGNIFICANCE STATEMENT: To date, this is the first report to explore effects of metformin on renal lipidomics. These findings reveal specific changes of renal lipid species, which are crucial for deeper understanding the underlying mechanisms of obesity-related kidney disease and effects of metformin on it. The associated signature sphingolipids and phospholipids in the study may have significant implications for developing targeted therapeutic strategies for obesity-related kidney disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103388"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374206","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":"Study of the correlation between the anti-ischemic stroke mechanism of 4-hydroxybenzaldehyde and its response to reactive oxygen species in brain metabolism.","authors":"Jin Feng, Qian Yang, Ming Chen, Long Ning, Yan Wang, Dan Luo, Dongxiong Hu, Qing Lin, Fangyan He","doi":"10.1016/j.jpet.2025.103395","DOIUrl":"10.1016/j.jpet.2025.103395","url":null,"abstract":"<p><p>The active ingredient of Gastrodia elata, 4-hydroxybenzaldehyde (4-HBd), can rapidly enter the brain and undergo massive oxidation to produce the metabolite 4-hydroxybenzoic acid, which has no significant activity after equal dose gavage. It is crucial to clarify the metabolic pathway of 4-HBd and its correlation with the anti-ischemic stroke mechanism. The objective of this study was to explore the possible mechanism of 4-HBd in clearing reactive oxygen species (ROS) and protecting blood-brain barrier from oxidative stress damage during brain metabolism from the perspective of ROS response. A rat model of cerebral ischemia-reperfusion injury and a cellular oxidative stress response model were replicated to simulate the accumulation process of ROS in the brain. The changes in ROS and peroxidation products before and after 4-HBd intervention were detected, and the changes in oxidative metabolism were also measured to confirm the correlation between antioxidant stress damage and ROS capture/clearance in oxidative metabolism. 4-HBd has significant antioxidant stress resistance both in vitro and in vivo, and can reduce the levels of malondialdehyde and 4-hydroxy-2-nonenal in ischemic brain tissue. It can capture O₂⋅^- and ⋅OH in vitro and use the captured ROS to oxidize and metabolize 4-hydroxybenzoic acid. The oxidative metabolism process of 4-HBd in the brain is one of its mechanisms for exerting antioxidant stress damage and protecting blood-brain barrier. SIGNIFICANCE STATEMENT: The active ingredient 4-hydroxybenzaldehyde of Gastrodia elata can be converted into metabolite 4-hydroxybenzoic acid in the brain mainly through oxidative metabolic pathway. The mechanism of its action against oxidative stress damage of blood-brain barrier is related to the oxidative metabolic process in the brain that traps/clears reactive oxygen species and forms stable intermediates to terminate the free radical chain reaction. This is one of the main mechanisms of 4-hydroxybenzaldehyde's anti-ischemic stroke effect in the brain.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103395"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625056","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":"NP10679: A new horizon for neuroprotection in aneurysmal subarachnoid hemorrhage.","authors":"Lidia Garcia-Bonilla","doi":"10.1016/j.jpet.2025.103390","DOIUrl":"10.1016/j.jpet.2025.103390","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103390"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399413","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":"Combined stress and alcohol exposure: Synergistic effects on alcohol-seeking behaviors and neuroinflammation.","authors":"L J Wills, B Schwartz, B McGuffin, J T Gass","doi":"10.1016/j.jpet.2025.103386","DOIUrl":"10.1016/j.jpet.2025.103386","url":null,"abstract":"<p><p>Posttraumatic stress disorder and alcohol use disorder are frequently co-occurring conditions that can create a synergistic effect, worsening symptoms of both disorders. This heightened comorbidity suggests a shared pathological basis rooted in maladaptive learning process that amplifies drug- and fear-related behaviors. The present study investigates the combined effects of stress and chronic alcohol exposure on alcohol-seeking behaviors and neuroinflammation in male and female rats. Additionally, we investigate the potential of metabotropic glutamate receptor type 5 (mGlu5) modulation as a therapeutic strategy for this co-occurring condition. Adult Wistar rats received restraint stress (Stress), chronic intermittent ethanol (CIE) vapor inhalation, both (Stress + CIE), or no exposure (Control). We assessed ethanol self-administration, extinction learning, reinstatement of alcohol-seeking behavior, and tumor necrosis factor-⍺ protein expression in the infralimbic (IfL) and prelimbic subregions of the prefrontal cortex. Additionally, we examined the effects of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), a mGlu5 positive allosteric modulator, on these outcomes. Stress + CIE exposure significantly increased ethanol self-administration, impaired extinction learning, and heightened reinstatement compared with all other groups. Interestingly, CDPPB treatment improved extinction learning and reduced reinstatement in males but not females. Furthermore, Stress + CIE exposure elevated tumor necrosis factor-⍺ levels specifically in the IfL, and CDPPB normalized this effect in males only. The current study demonstrates a synergistic effect of stress and alcohol exposure on alcohol-seeking behaviors and suggests a potential role for neuroinflammation in the IfL. Our findings also highlight sex-specific therapeutic strategies targeting mGlu5 signaling to prevent relapse in individuals with comorbid posttraumatic stress disorder and alcohol use disorder. SIGNIFICANCE STATEMENT: This research demonstrates that combined stress and alcohol exposure worsen alcohol-seeking behavior in rats, potentially via neuroinflammation in the infralimbic cortex, a region known to be involved in extinction learning. Notably, metabotropic glutamate receptor type 5 modulation was able to prevent alcohol-seeking behaviors and inflammation in a sex-dependent manner. These findings pave the way for developing personalized treatments to prevent relapse in individuals with co-occurring posttraumatic stress disorder/alcohol use disorder.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103386"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255928","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":"DBeQ derivative targets vacuolar protein sorting 4 functions in cancer cells and suppresses tumor growth in mice.","authors":"Kevin A Fundora, Yan Zhuang, Kouta Hamamoto, Guifang Wang, Longgui Chen, Tatsuya Hattori, Xinwen Liang, Lei Bao, Venugopal Vangala, Fang Tian, Yoshinori Takahashi, Hong-Gang Wang","doi":"10.1016/j.jpet.2025.103524","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103524","url":null,"abstract":"<p><p>Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase that catalyzes the endosomal sorting complex required for transport-III disassembly, mediating various cellular membrane-remodeling processes including endolysosomal membrane repair and autophagosome closure. Humans have 2 VPS4 paralogs, VPS4A and VPS4B, and the loss of either paralog has been identified in a significant proportion of cancers, rendering them dependent on the remaining paralog for survival. In this study, we explored VPS4 inhibition as an anticancer strategy by investigating the mechanisms of VPS4 inhibition-induced cell death and developing small-molecule compounds that target VPS4 functions. We found that genetic inhibition of VPS4 triggered both caspase-8 (CASP8)-dependent apoptosis and caspase-independent cell death in osteosarcoma cells. We synthesized approximately 100 derivatives of the VPS4 and related AAA-ATPase valosin-containing protein inhibitor DBeQ and screened for their inhibitory effects on VPS4 ATPase activity using the EnzChek phosphate assay and a high-content assay monitoring GFP-CHMP4B puncta formation. In cells, the lead compound 4-107 caused endolysosomal damage, disrupted subsequent membrane repair, inhibited autophagy, and led to the accumulation of the endosomal sorting complex required for transport on membranes. These effects were accompanied by the stabilization of CASP8 on autophagosomal membranes, leading to the induction of CASP8-mediated apoptosis. Notably, the CASP8-mediated cell death induced by 4-107 was further enhanced by the loss of either VPS4 paralog. Moreover, 4-107 exhibited antitumor activity in a syngeneic mouse model of neuroblastoma. Our findings provide an important step for targeting VPS4 in cancer and developing VPS4 inhibitors as a cancer treatment strategy. SIGNIFICANCE STATEMENT: VPS4A and VPS4B, paralogs of the AAA-ATPase VPS4, are critical for cancer cell survival. This study reports that 4-107, a DBeQ derivative, inhibits VPS4 ATPase activity, induces CASP8-mediated apoptosis, and suppresses tumor growth in mice. This study supports the further development of VPS4A/B inhibitors as a promising anticancer treatment strategy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103524"},"PeriodicalIF":3.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730685","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":"Small molecule interleukin (IL) 17A/A antagonists and antibodies blocking both IL17A/A and IL17A/F demonstrate equivalent degrees of efficacy in preclinical models of skin and joint inflammation.","authors":"Eric R Goedken, Zhi Su, Alex Lipovsky, Arun Kannan, Katharine L Chu, Samantha Ciura, Sage E Foley, Kristine E Frank, Christian A Goess, Sujatha Gopalakrishnan, Stephen N Greszler, Hasan A Khan, Laura J Leys, Jacob J King, Suzanne L Mathieu, Sanjay C Panchal, Stephanie Paulsboe, Matt Perham, Ashley L Ramos, Peter F Slivka, Myron Srikumaran, Matthew P Webster, Emma L Wambeke, Haizhong Zhu, Victoria E Scott, Steve McGaraughty, Prisca Honore","doi":"10.1016/j.jpet.2025.103525","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103525","url":null,"abstract":"<p><p>T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well as the heterodimeric IL17A/F isoform, all having well known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such as secukinumab and ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and are under further investigation as therapies in inflammatory disorders such as hidradenitis suppurativa and giant cell arteritis. Because many patients dislike injections with needles, orally bioavailable small molecule IL17 antagonists are desirable as next-generation drugs as long as they can replicate the degree of efficacy observed with anti-IL17A biologics. We recently described novel small molecules binding as 2 copies to the IL17A/A homodimer with only weak effects on the IL17A/F heterodimer. Because approved antibodies binding IL17A neutralize both IL17A/A and IL17A/F, we assessed whether targeting IL17A/A would be sufficient to bring efficacy comparable to IL17A biologics. In comparison to IL17A/F and IL17F/F, we found that the IL17A/A homodimer is the strongest initiator of signaling and that comparable IL17A/A to IL17A/F ratios are expressed in Th17 cells and in human psoriatic skin tissue. Furthermore, our IL17A/A-specific small molecules block the effects of Th17 cell supernatants on keratinocytes to similar maximal responses as anti-IL17A. Our IL17A/A-selective antagonists deliver comparable efficacy to anti-IL17A biologics in several rodent inflammatory models of psoriasiform dermatitis and arthritis. These results support neutralizing IL17A/A with oral small molecule antagonists is an attractive approach to provide differentiated, next-generation therapies for inflammatory disorders. SIGNIFICANCE STATEMENT: This study found that orally active small molecule antagonists of the proinflammatory cytokine IL17A that preferentially bind the IL17A/A form produced equivalent efficacy to monoclonal antibodies that can neutralize both IL17A/A and IL17A/F. This indicates that the IL17A/A homodimer is the dominant isoform driving inflammation in diseases such as psoriasis and that oral inhibitors targeting IL17A/A may be useful next-generation IL17 therapeutics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103525"},"PeriodicalIF":3.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699565","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}