G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effects of kynurenic acid and zaprinast

Cosi, Cristina; Mannaioni, Guido; Cozzi, Andrea; Carlà, Vincenzo; Sili, Maria; Cavone, Leonardo; Maratea, Dario; Moroni, Flavio

doi:10.1016/j.neuropharm.2010.11.014

Cited by 110 publications

(97 citation statements)

References 44 publications

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“…Although endogenous KYNA can also activate the G-protein-coupled receptor GPR35 (Cosi et al, 2010;Wang et al, 2006), inhibition of a7nAChRs and, possibly, NMDARs appears to be the primary physiological function of extracellular KYNA in the mammalian brain (see below). As both a7nAChRs and NMDARs are critically involved in many important physiological functions, including cognitive processes (Bannerman et al, 2006;Levin et al, 2006;Robbins and Murphy, 2006;Thomsen et al, 2010), and also have a role in the etiology of neurodegenerative and other catastrophic brain diseases (Kalia et al, 2008;Kantrowitz and Javitt, 2010;Martin and Freedman, 2007;Mudo et al, 2007), detection of KYNA in the mammalian brain (Moroni et al, 1988;Turski et al, 1988) immediately suggested an important role of the metabolite in both physiology and pathology (Pereira et al, 2002;Schwarcz et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

146

158

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

146

158

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“…In part, this has been based simply on the expression patterns of GPR35. However, because a GPR35 knockout line of mice has been reported to have markedly elevated blood pressure (Min et al, 2010), whereas blockade of acetic acid-induced writhing in mice has been shown to be limited by certain ligands, including pamoate (Zhao et al, 2010) and zaprinast (Cosi et al, 2011) that are reported to have agonist potency at GPR35, there are a developing number of supporting physiological studies. Despite this, to date only the studies of Min et al (2010) have used GPR35 knockout animals.…”

Section: Discussionmentioning

confidence: 99%

Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action

Jenkins

Harries

Lappin

et al. 2012

J Pharmacol Exp Ther

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Variation in pharmacology and function of ligands at species orthologs can be a confounding feature in understanding the biology and role of poorly characterized receptors. Substantial selectivity in potency of a number of GPR35 agonists has previously been demonstrated between human and rat orthologs of this G protein-coupled receptor. Via a bioluminescence resonance energy transfer-based assay of induced interactions between GPR35 and ␤-arrestin-2, addition of the mouse ortholog to such studies indicated that, as for the rat ortholog, murine GPR35 displayed very low potency for pamoate, whereas potency for the reference GPR35 agonist zaprinast was intermediate between the rat and human orthologs. This pattern was replicated in receptor internalization and G protein activation assays. The effectiveness and mode of action of two recently reported GPR35 antagonists, methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID-2745687) and 2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino)benzoic acid (ML-145), were investigated. Both CID-2745687 and ML-145 competitively inhibited the effects at human GPR35 of cromolyn disodium and zaprinast, two agonists that share an overlapping binding site. By contrast, although ML-145 also competitively antagonized the effects of pamoate, CID-2745687 acted in a noncompetitive fashion. Neither ML-145 nor CID-2745687 was able to effectively antagonize the agonist effects of either zaprinast or cromolyn disodium at either rodent ortholog of GPR35. These studies demonstrate that marked species selectivity of ligands at GPR35 is not restricted to agonists and considerable care is required to select appropriate ligands to explore the function of GPR35 in nonhuman cells and tissues.

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“…Moreover, systemic inflammation, which is associated with somatization, and the physio-somatic symptoms in depression and ME/CFS, may increase the expression of NMDARs, suggesting inflammatory pain induced sensitization (131). KYNA is also an endogenous ligand for the G protein-coupled receptor-35 (GPR35) (133), which is antinociceptive (134). Therefore, decreased KYNA in somatization will impact on nociception not only via the increased NMDAR activation but also by suppressed GPR35 activity.…”

Section: Oxidative and Nitrosative Stress And Autoimmunitymentioning

confidence: 99%

Biological phenotypes underpin the physio‐somatic symptoms of somatization, depression, and chronic fatigue syndrome

Anderson¹,

Berk

Maes

2013

Acta Psychiatr Scand

102

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G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effects of kynurenic acid and zaprinast

Cited by 110 publications

References 44 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action

Biological phenotypes underpin the physio‐somatic symptoms of somatization, depression, and chronic fatigue syndrome

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