Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE-52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.

Can GPR4 Be a Potential Therapeutic Target for COVID-19?

“…With regard to the safety profile and adverse effects of the GPR4 antagonists, an oral dose of 30–100 mg/kg (b.i.d.) is well tolerated in preclinical animal models without overt adverse effects ( 15 , 17 , 18 , 20 , 23 , 29 ). The optimized GPR4 antagonist 13 (NE 52-QQ57) has no documented serious adverse effects on the cardiovascular and respiratory systems in mouse and rat models ( 23 ).…”

“…Biochemically, GPR4 can be activated by extracellular protons (acidosis), with acidotic conditions commonly existing in inflamed tissues due to hypoxia and glycolytic cell metabolism ( 27 , 28 ). Importantly, genetic and pharmacological inhibition of GPR4 alleviates inflammatory responses, reduces leukocyte infiltration, and decreases tissue edema in several animal models of inflammatory disorders including arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), and ischemic diseases ( 14 , 15 , 17 – 20 , 29 ). Many of the GPR4-regulated inflammatory processes described above share cardinal pathological features observed in COVID-19 patients ( 7 – 9 ).…”

“…Derivatives of imidazo-pyridine and pyrazolopyrimidine compounds have been identified as novel GPR4 antagonists ( 16 – 18 , 54 ). Studies have shown that GPR4 antagonists reduce inflammation in the antigen-induced arthritis rat model, the DSS-induced acute colitis mouse model, and the short-term emphysema-exacerbation COPD mouse model as well as alleviate inflammatory pain in the complete Freund's adjuvant-induced hyperalgesia rat model ( 15 , 17 , 18 , 29 ). In the DSS-induced acute colitis model, GPR4 antagonist 13 (NE-52-QQ57) ameliorates intestinal inflammation and decreases the expression of TNF-α in the inflamed mouse colon tissues ( 15 ).…”

“…Studies have shown that GPR4 antagonists reduce inflammation in the antigen-induced arthritis rat model, the DSS-induced acute colitis mouse model, and the short-term emphysema-exacerbation COPD mouse model as well as alleviate inflammatory pain in the complete Freund's adjuvant-induced hyperalgesia rat model ( 15 , 17 , 18 , 29 ). In the DSS-induced acute colitis model, GPR4 antagonist 13 (NE-52-QQ57) ameliorates intestinal inflammation and decreases the expression of TNF-α in the inflamed mouse colon tissues ( 15 ). In the COPD mouse model, treatment with GPR4 antagonist reduces leukocyte infiltration, inflammatory cytokine expression, mucin production, and protease expression in the lung ( 29 ).…”

The Neuroprotective Effect of GPR4 Inhibition through Attenuation of Caspase Mediated Apoptotic Cell Death in MPTP Induced Mouse Model of Parkinson’s Disease

“…Besides, GPR4 plays critical role in different biological functions such as inflammation, proliferation, paracellular gap formation of endothelial cells, apoptosis, growth, of cancer cells, angiogenesis etc. [15][16][17]. Previously, pharmacological inhibition of GPR4 has been reported to remediate myocardial infarction [18] and genetic deletion of GPR4 improved cardiac function through lowering blood pressure [19], and inhibited apoptosis in renal ischemia reperfusion injury [20] intestinal inflammation [21].…”