British Journal of Pharmacology最新文献

The cannabinoid receptor 2 (CB2), which is encoded by the Cnr2 gene, is a G-protein-coupled receptor that controls immune responses and has recently emerged as a regulator of renal injury and repair. Over the past 15 years, numerous pharmacological and genetics studies have explored the role of CB2 in acute kidney injury (AKI) and chronic kidney disease (CKD). Although the precise localisation of CB2 within renal compartments remains under debate, pharmacologically mediated CB2 agonism, across a wide array of chemical, metabolic, ischaemia and obstructive mouse models, has consistently preserved tubular epithelial cell integrity, reduced inflammation, and limited tubulointerstitial fibrosis. These protective effects of CB2 activation are further supported by the opposing outcomes in Cnr2 knockout mice, which showed worsened injury. More selective CB2 ligands with defined pharmacokinetic and pharmacodynamic profiles in preclinical animal models along with late-stage clinical studies have further substantiated the safety and efficacy of this type of therapeutic approach. Nevertheless, a few studies have reported conflicting results, suggesting a CB2-dependent contribution towards tubular damage, although these findings are complicated by differences in ligand selectivity, possible off-target activity, and experimental design. With this in mind, the prevailing evidence supports CB2 activation as beneficial in both AKI and CKD and warrants continued translational progress to develop CB2 agonists for therapeutic applications in kidney disease.

Background and purpose: Although there is a decline in the overall incidence of chronic gastritis through antibiotic treatment, the public health burden remains significant because of low eradication rates. Herein, we explore the role of sphingosine-1-phosphate receptor-2 (S1P₂ receptor) in mediating the development of chronic gastritis, as well as the effect of S1P₂ receptor antagonists in attenuating its development.

Experimental approach: Chronic gastritis model was established through long-term exposure to lipopolysaccharide (LPS) in mice. S1P₂ receptor antagonists were administrated via gavage. Western blotting and immunohistochemistry assays analysed S1P₂ receptor and paralemmin-3 (PALM3). Co-immunoprecipitation and immunofluorescence staining assays identified the binding of S1P₂ receptor with NF-kappa-B-activating protein (NKAP) or PALM3 in the nuclei. Haematoxylin-eosin staining assessed gastric tissues. 16S ribosomal RNA gene amplicon sequencing analysed gastric microbiota compositions.

Key results: Long-term exposure to LPS developed chronic gastritis by activating S1P₂ receptors in gastric epithelial cells. Mechanistically, LPS stimulated PALM3-mediated nuclear translocation of S1P₂ receptors, which then bound to NKAP; leading to the upregulation of NF-κB/IL-6 pathway. Inhibition of S1P₂ receptors blocked LPS-induced nuclear translocation, resulting in downregulation of NF-κB/IL-6 pathway. Administration of S1P₂ receptor antagonists attenuated the LPS-induced chronic gastritis. Additionally, abundance of pathogenic Gram-negative gastric bacteria (e.g., Enterobacter) was significantly reduced following treatment with S1P₂ receptor antagonists.

Conclusions and implications: Long-term exposure to LPS developed chronic gastritis by stimulating S1P₂ receptors. S1P₂ receptors thus represent a potential target for treatment of chronic gastritis. S1P₂ receptor antagonist blocks the LPS-induced nuclear translocation of S1P₂ receptors, thus attenuating chronic gastritis.

Background and purpose: Here we evaluated, in healthy adults, the pharmacokinetics and safety of monoclonal antibody EP9001A against nerve growth factor, which may be effective for treating chronic pain and osteoarthritis.

Experimental approach: In this phase I trial, 32 healthy adults received a single subcutaneous injection of EP9001A at doses of 1-25 mg, while 12 adults received placebo. Analysis of pharmacokinetic parameters indicated dose-proportional systemic exposure, with terminal half-life ranging from 207.47 h at 1 mg to 548.76 h at 25 mg.

Key results: All adverse events were mild and none necessitated discontinuation. The most frequent adverse events were upper respiratory tract infection, elevated liver enzymes and musculoskeletal pain. Musculoskeletal symptoms were likely attributable to nerve growth factor inhibition. These results indicate predictable pharmacokinetics and good safety of EP9001A in healthy subjects.

Conclusions and implications: The dose-dependent pharmacokinetics and long half-life suggest the possibility of longer dosing intervals. Future trials should optimise dosing and evaluate long-term safety, particularly with respect to adverse musculoskeletal events arising through inhibition of nerve growth factor.

Background and purpose: Traditional Chinese Medicine (TCM) has become a prominent and challenging area within the field of clinical decision support. However, most existing approaches fail to adequately address two critical issues: the inherent noise in TCM prescription data and the potential risks associated with excessive prescription modifications.

Experimental approach: To address these challenges, we propose a deep learning framework named DA-TCMPO (Data Augmentation for TCM Prescription Optimization), which aims to optimize TCM prescriptions using tailored data augmentation techniques. The model incorporates two data augmentation modules: a Diffusion Model Based on Double Attention (DAD), which enhances sample diversity, and a Variable Noise Embedding Module (VNE), which focuses on denoising and refining the augmented data.

Key results: To address the limitations of existing datasets, we constructed the Chinese Herbal Prescriptions for Diseases (CH) dataset, specifically designed for training models in TCM prescription optimization. Comprehensive experimental results on the CH dataset demonstrate that the proposed DA-TCMPO achieves performance significantly superior to the best-performing baseline, with precision, accuracy, recall, and F1-score representing relative improvements of 67.8%, 83.3%, 83.3%, and 83.6%. Furthermore, in vivo validation using Ulcerative colitis (UC) mouse models confirmed that DA-TCMPO-optimized prescriptions, such as CYKKL-2, produced statistically significant improvements in body weight, Disease activity index (DAI) score, and colon length compared with the model group, demonstrating the practical efficacy of the optimized prescriptions.

Conclusion and implications: These findings indicate that DA-TCMPO holds promise for supporting diagnostic and therapeutic decision-making in practical TCM clinical scenarios.

Background and purpose: Plasma glucocorticoids increase acutely after MI, thereafter tissue levels are amplified selectively within cells expressing 11-ßhydroxysteroid dehydrogenase type 1 (11-ßHSD1) that regenerates active glucocorticoids from circulating metabolites. Glucocorticoids initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress wound repair leading to functional decline. We investigate 11-ßHSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair.

Experimental approach: Adult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11-ßHSD1 inhibitor AZD8329 (n = 11) or vehicle (n = 9), from 2 until 27 days later, with concurrent administration of relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor).

Key results: AZD8329 treatment increased plasma accumulation of cortisone substrate showing successful 11-ßHSD1 inhibition. Gadolinium-enhanced magnetic resonance imaging (MRI) showed equivalent infarct size in both groups prior to commencing treatment. Twenty-eight days after MI cardiac function and left ventricle area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11-ßHSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix processing was highlighted by birefringence microscopy and proteomic analysis.

Conclusions and implications: Pharmacological inhibition of 11-ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11-ßHSD1 inhibitors have safely reached Phase 2 clinical trials in diabetes and dementia, and could be repurposed as an addition to standard care after MI to prevent the development of heart failure.

Background and purpose: Whereas the effects of Trypanosoma cruzi (T. cruzi) infection are well-characterised in the heart, its impact on the vasculature has received little attention. In this study, we investigated the effects of acute and chronic T. cruzi infection on vascular responsiveness and the underlying mechanisms.

Experimental approach: Male Wistar Hannover rats were infected intraperitoneally with 1 × 10⁵ trypomastigotes of the T. cruzi Y strain. Vascular function was evaluated in the thoracic aorta during the acute (9 days post-infection, dpi) and chronic (60 dpi) phases of infection.

Key results: No changes in vascular responsiveness were observed during the chronic phase. However, acute T. cruzi infection induced endothelial dysfunction, leading to vascular hypercontractility, although it did not alter the anti-contractile effect of perivascular adipose tissue (PVAT). Infected rats exhibited increased levels of TNF-α in the aorta, but not in the PVAT or serum. TNF-α inhibition with etanercept (1 mg·kg^-1·day^-1; i.p.) prevented both endothelial dysfunction and oxidative stress (upregulation of NOX2/superoxide [O₂•^-] generation), as well as the increase in thromboxane A₂ (TXA₂).

Conclusions and implications: Our results demonstrate that TNF-α mediates vascular dysfunction during the acute phase of T. cruzi infection. Our results indicate that TNF-α contributes to endothelial dysfunction and vascular hypercontractility by promoting O₂•^- generation, upregulating NOX2 and increasing TXA₂ production. Although PVAT is not dysfunctional during acute infection, increased myeloperoxidase (MPO) activity was detected within it, suggesting it may act as a reservoir for neutrophils.

Schizophrenia is regarded as a complex and heterogeneous psychiatric disorder, characterised by diverse symptoms and comorbidities, which complicate both clinical management and drug development. Current pharmacological treatment, primarily based on dopamine D₂ receptor antagonism or partial agonism, which has not markedly progressed since the emergence of chlorpromazine in the 1950s, remains inadequate in addressing the full spectrum of clinical symptoms. Despite decades of preclinical research, many novel compounds with different mechanisms that show efficacy in animal models subsequently fail in Phase II or III clinical trials. This translational gap may reflect limitations in model selection, reliance on behavioural endpoints with poor clinical correspondence and the inherent inability of rodent paradigms to capture the full heterogeneity of human schizophrenia. This review provides a systematic overview of how rodent models and behavioural assays have been applied by the pharmaceutical industry over the past 30 years to evaluate antipsychotic efficacy, both for marketed drugs and investigational compounds entering first-in-human (FIH) clinical trials. We examine the extent to which these models have informed regulatory submissions and clinical development, whilst also analysing the translational challenges that arise from their limited ability to capture the complexity and heterogeneity of schizophrenia, as well as the impact of inclusion criteria on the testing of antipsychotic drug efficacy. By highlighting these limitations, we propose key considerations for refining model selection, behavioural endpoints, and biomarker integration to strengthen the predictive value of preclinical research and improve the likelihood of success for novel antipsychotics in clinical trials.

Background and purpose: Lactate, historically viewed as a metabolic by-product, has emerged as a signalling molecule via the G protein-coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor is primarily expressed in adipocytes but also found in various other tissues. HCAR1 activation has been shown to regulate lipolysis and improve insulin sensitivity, positioning it as a promising therapeutic target for metabolic disorders such as obesity and type 2 diabetes. Despite its potential, its role in cancer progression and the limited availability of characterized ligands necessitate further investigation into its signalling mechanisms. This study aimed to broaden the pharmacological understanding of HCAR1 by investigating previously uncharacterized ligands and profiling their signalling properties.

Experimental approach: We employed enhanced bystander bioluminescence resonance energy transfer (ebBRET) assays to investigate G protein activation and β-arrestin recruitment following ligand stimulation of HCAR1. A panel of compounds was screened to identify more potent agonists and modulators of HCAR1 signalling.

Key results: We identified AZ7136 as a relatively potent HCAR1 agonist, AZ2114 as a partial agonist, and GPR81 agonist 1 as an ago-positive allosteric modulator. HCAR1 preferentially activated Gα_i/o and Gα_s pathways without recruiting β-arrestins, revealing a distinct signalling profile.

Conclusion and implications: These findings expand our understanding of HCAR1 signalling and introduce new molecular tools for probing its physiological and pathological roles. The characterized ligands may support future therapeutic strategies targeting HCAR1 in metabolic disorders while informing approaches to mitigate potential oncogenic effects.

Background and purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and treatment-resistant side effect of platinum-based chemotherapy, characterised by mechanical allodynia. Cannabigerol (CBG), a non-psychoactive cannabinoid, has shown antinociceptive potential, but its site and mechanism of action remain unclear. We investigated whether CBG modulates thalamocortical circuitry to reverse mechanical allodynia in a mouse model of CIPN and whether α_2A-adrenoceptors (α_2AARs) mediate these effects.

Experimental approach: C57BL/6 mice received weekly cisplatin injections to induce neuropathy. Mechanical sensitivity was assessed using von Frey testing. Chemogenetic and optogenetic tools were used to manipulate and monitor ventral posterolateral thalamus (VPL) to hindlimb region of the somatosensory cortex (S1HL) synapses. Whole-cell electrophysiology assessed synaptic properties ex vivo. CBG was administered systemically, locally and via bath application, with and without the α_2A-adrenoceptor antagonist atipamezole or α_2A-adrenoceptor shRNA knockdown in the VPL.

Key results: Cisplatin increased presynaptic neurotransmitter release at VPL-to-S1HL synapses, shown by a decrease in the paired-pulse ratio and reduced AMPA receptor variability. CBG reversed these changes and mechanical allodynia via a dose-dependent and α_2A-adrenoceptor-dependent mechanism. Local and systemic CBG administration failed to reverse allodynia or synaptic changes in mice with α_2A-adrenoceptor knockdown in the VPL. CBG had no effect on locomotor activity.

Conclusions and implications: CBG reverses mechanical allodynia in CIPN by reducing presynaptic neurotransmission at VPL-to-S1HL synapses through the activation of α_2A-adrenoceptors. These findings identify a thalamocortical circuit mechanism and a cannabinoid-sensitive target for neuropathic pain treatment.