BACKGROUNDNeuroinflammation plays a pivotal role in the pathogenesis of depression. G protein-coupled receptor 35 (GPR35) is expressed in the brain and plays a role in regulating inflammatory processes. However, its specific role in depression remains unclear. Herein, we investigate the role of GPR35 in depressive behaviors induced by lipopolysaccharide (LPS) in mice.METHODSWe employed an LPS-induced depression mouse model and conducted behavioral tests, molecular analyses, and morphological assessments, along with chemogenetic techniques, to investigate the role of GPR35 in depression.RESULTSOur results showed a significant increase in GPR35 expression in the brain of LPS-treated mice. Both pharmacological inhibition and genetic knockdown of GPR35 alleviated LPS-induced depressive-like behaviors by mitigating neuroinflammation, oxidative stress, synaptic plasticity deficits, and TLR4/NF-κB signaling in mice. Conversely, pharmacological activation of GPR35 notably exacerbated LPS-induced depressive-like behaviors in mice. Additionally, the GPR35 antagonist ML-145 effectively prevented LPS-induced inflammation responses in BV-2 microglia cells. Moreover, fluoxetine treatment effectively mitigated the upregulation of hippocampal GPR35 expression induced by LPS in mice. However, administration of the GPR35 agonist zaprinast reversed the antidepressant effects of fluoxetine. Chemogenetic activation of hippocampal glutamatergic neurons attenuated LPS-induced depression-like behaviors, accompanied by decreased GPR35 expression.CONCLUSIONHippocampal GPR35 is closely associated with depressive behaviors in the inflammatory model, highlighting its potential as a therapeutic target for antidepressant drug development.

01 Mar 2025·Pain

GPR35 agonists inhibit TRPA1-mediated colonic nociception through suppression of substance P release

Article

Author: Barker, Katie H. ; Bulmer, David C. ; Urriola-Muñoz, Paulina ; Suzuki, Rie ; Pearce, Abigail ; Ghooraroo, Joshua ; Raine, Tim ; Hockley, James R. F. ; Ladds, Graham ; St John Smith, Ewan ; Rahman, Taufiq ; Higham, James P. ; Paine, Luke ; Gupta, Rohit A. ; Brown, Alastair J. H.

AbstractThe development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn (CS), and phosphodiesterase inhibitor, zaprinast, are agonists at mouse GPR35, promoting the activation of different Gi/o subunits. Pretreatment with either CS or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects were lost in tissue from GPR35−/− mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlights the pronociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and sensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain.

01 Mar 2025·International Immunopharmacology

Inhibiting HMGB1/AGER/NF-κB pathway prevents pro-inflammatory microglia polarization and protect photoreceptors in retinitis pigmentosa

Article

Author: Cui, Tao ; Xu, Zihang ; Cai, Wenting ; Hu, Chengyu ; Wu, Yan ; Yang, Kun ; Qiu, Yaoyan ; Yu, Jing

PURPOSERetinitis pigmentosa (RP) is an inherited retinal neurodegenerative disease which is a significant contributor to blindness. Microglia-mediated inflammation plays a crucial role in retinitis pigmentosa. However, the activation mechanisms of microglia and the role of polarized microglia in RP remain unclear. High-mobility group box 1 (HMGB1) is a key contributor to aseptic inflammation, and glycyrrhizin exerts anti-inflammatory effects by targeting HMGB1. This study aimed to investigate the role of HMGB1 and microglia in RP and explore the protective effects of glycyrrhizin on photoreceptors.METHODSMale C57BL/6 mice and age-matched rd1 mice were used for in vivo models, while zaprinast-treated 661w cells and HMGB1-treated BV-2 cells were used for in vitro models. In this study, the expression of HMGB1 was analyzed using QPCR and western blot (WB). Immunofluorescence staining and ELISA were performed to assess HMGB1 translocation and secretion. Glycyrrhizin was used to inhibit HMGB1, while FPS-ZM1 served as an inhibitor of the receptor for advanced glycation end products (AGER). Microglial polarization was evaluated by QPCR, and the HMGB1/ AGER/ NF-κB signaling pathway was analyzed through WB. Photoreceptor degeneration and visual function were assessed through H&E staining, electroretinography, and TUNEL staining.RESULTSWe observed elevated levels of HMGB1 in the retina of rd1 mice and demonstrated in vitro that photoreceptors may serve as a significant source of HMGB1 in the retina. Additionally, HMGB1 was observed to cause microglial polarization via the HMGB1/AGER/ NF-κB pathway and the polarized microglia secrete inflammatory factors including TNF-α and IL-1β which accelerates the degeneration of photoreceptors. Glycyrrhizin reversed the degeneration of photoreceptors and loss of visual function in rd1 mice through the HMGB1/AGER/ NF-κB pathway.CONCLUSIONOur findings showed that HMGB1 secreted by photoreceptors activated the microglia through the HMGB1/AGER/NF-κB pathway and the polarized microglia accelerates the degeneration of photoreceptors. Glycyrrhizin reversed the polarization caused by HMGB1 in vitro and delayed the progression of RP in vivo, presenting a potential novel approach for treating retinitis pigmentosa.

100 Deals associated with Zaprinast

External Link

KEGG	Wiki	ATC	Drug Bank
-	Zaprinast	-	-

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Preclinical	Japan	Pfizer Japan, Inc.	17 Aug 2006
Rhinitis	Preclinical	Japan	Pfizer Japan, Inc.	17 Aug 2006

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis