The emerging pharmacology and function of GPR35 in the nervous system

Mackenzie, Amanda E.; Milligan, Graeme

doi:10.1016/j.neuropharm.2015.07.035

Cited by 43 publications

(33 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As products of the microbiome, the metabolic connections among tryptophan, serotonin, and kynurenic acid are intriguing, because they echo relations of the gut-brain axis (48,61). Additionally, kynurenic acid has been linked to neuroprotection in the eye (62,63). New studies in mice and humans confirm the important role of gut microbiota in the development of neovascular (wet) AMD (64,65).…”

Section: Discussionmentioning

confidence: 99%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

201

192

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

show abstract

Section: Discussionmentioning

confidence: 99%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

201

192

View full text Add to dashboard Cite

show abstract

“…Lastly, the potential actions of kynurenic acid on the Aryl Hydrocarbon Receptors (Opitz et al ) or the orphan G‐protein‐coupled receptor G‐protein‐coupled receptor‐35 (GPR35) (Wang et al ; Mackenzie and Milligan ; Shore and Reggio, ) were not considered by Stone () since kynurenines had not yet been linked with their activity. AHRs have received little attention in the CNS since primary interest has been in their role in immune system cells and the regulation of kynurenine pathway activation in tolerogenesis.…”

Section: Functional Studies On Kynurenic Acidmentioning

confidence: 99%

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Stone

2019

Journal of Neurochemistry

View full text Add to dashboard Cite

As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.

show abstract

“…KYNA, whose mammalian brain concentrations in adulthood are in the nanomolar to low micromolar range, exerts neuroactive properties as an antagonist of the alpha 7 nicotinic acetylcholine (α7nACh) receptors (Hilmas et al, 2001) and N-methyl-D-aspartate (NMDA) receptors (Perkins and Stone, 1982). KYNA also acts as a ligand of G protein-coupled receptor (GPR) 35 and the aryl hydrocarbon receptor (AhR), two signaling receptors that are functional in both the brain and peripheral organs (Divorty et al, 2015; Julliard et al, 2014; Mackenzie and Milligan, 2015; Moroni et al, 2012; Noakes, 2015). The second branch of the KP is predominantly metabolized in microglial cells (Guillemin et al, 2001, 2003; Heyes et al, 1996; Saito and Heyes, 1996), where the enzyme kynurenine 3-monooxygenase (KMO) metabolizes kynurenine to 3-hydroxykynurenine (3-HK), and the downstream catabolite 3-hydroxyanthranilic acid is formed by the enzyme kynureninase.…”

Section: Introductionmentioning

confidence: 99%

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Notarangelo

Pocivavsek

2017

Neuropharmacology

View full text Add to dashboard Cite

The kynurenine pathway (KP) of tryptophan degradation contains several neuroactive metabolites that may influence brain function in health and disease. Mounting focus has been dedicated to investigating the role of these metabolites during neurodevelopment and elucidating their involvement in the pathophysiology of psychiatric disorders with a developmental component, such as schizophrenia. In this review, we describe the changes in KP metabolism in the brain from gestation until adulthood and illustrate how environmental and genetic factors affect the KP during development. With a particular focus on kynurenic acid, the antagonist of α7 nicotinic acetylcholine (α7nACh) and N-methyl-D-aspartate (NMDA) receptors, both implicated in modulating brain development, we review animal models designed to ascertain the role of perinatal KP elevation on long-lasting biochemical, neuropathological, and behavioral deficits later in life. We present new data demonstrating that combining perinatal choline-supplementation, to potentially increase activation of α7nACh receptors during development, with embryonic kynurenine manipulation is effective in attenuating cognitive impairments in adult rat offspring. With these findings in mind, we conclude the review by discussing the advancement of therapeutic interventions that would target not only symptoms, but potentially the root cause of central nervous system diseases that manifest from a perinatal KP insult.

show abstract

The emerging pharmacology and function of GPR35 in the nervous system

Abstract: Abbreviations: AHO, Albright's hereditary osteodystrophy; AMPA, α-amino-3-hydroxy-5-methyl-

Cited by 43 publications

References 114 publications

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Contact Info

Product

Resources

About