Pathophysiological Ionotropic Glutamate Signalling in Neuroinflammatory Disease as a Therapeutic Target

Glutamate signalling is an essential aspect of neuronal communication involving many different glutamate receptors, and underlies the processes of memory, learning and synaptic plasticity. Despite neuroinflammatory diseases covering a range of maladies with very different biological causes and pathophysiologies, a central role for dysfunctional glutamate signalling is becoming apparent. This is not just restricted to the well-described role of glutamate in mediating neurodegeneration, but also includes a myriad of other influences that glutamate can exert on the vasculature, as well as immune cell and glial regulation, reflecting the ability of neurons to communicate with these compartments in order to couple their activity with neuronal requirements. Here, we discuss the role of pathophysiological glutamate signalling in neuroinflammatory disease, using both multiple sclerosis and Alzheimer’s disease as examples, and how current steps are being made to harness our growing understanding of these processes in the development of neuroprotective strategies. This review focuses in particular on N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisooxazol-4-yl) propionate (AMPA) type ionotropic glutamate receptors, although metabotropic, G-protein-coupled glutamate receptors may also contribute to neuroinflammatory processes. Given the indispensable roles of glutamate-gated ion channels in synaptic communication, means of pharmacologically distinguishing between physiological and pathophysiological actions of glutamate will be discussed that allow deleterious signalling to be inhibited whilst minimising the disturbance of essential neuronal function.

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The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

Journal of Clinical Medicine ◽

10.3390/jcm10071475 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1475

Author(s):

Waldemar Kryszkowski ◽

Tomasz Boczek

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Glutamate Release ◽

Molecular Targets ◽

Brain Regions ◽

Psychotic Symptoms ◽

Unknown Etiology ◽

Metabotropic Glutamate ◽

G Protein Coupled

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

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Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.797253 ◽

2022 ◽

Vol 14 ◽

Author(s):

Shuang Chen ◽

Da Xu ◽

Liu Fan ◽

Zhi Fang ◽

Xiufeng Wang ◽

...

Keyword(s):

Synaptic Plasticity ◽

Glutamate Receptors ◽

Neurological Disorders ◽

Nerve Conduction ◽

Ionotropic Glutamate Receptors ◽

Future Studies ◽

Excitatory Neurotransmission ◽

The Relationship ◽

Neuron Injury

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

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Respiratory Role of Ionotropic Glutamate Receptors in the Rostral Ventral Respiratory Group of the Rabbit

Advances in Experimental Medicine and Biology - Post-Genomic Perspectives in Modeling and Control of Breathing ◽

10.1007/0-387-27023-x_27 ◽

2004 ◽

pp. 177-182

Author(s):

Donatella Mutolo ◽

Fulvia Bongianni ◽

Tito Pantaleo

Keyword(s):

Glutamate Receptors ◽

Ionotropic Glutamate Receptors ◽

Ventral Respiratory Group

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The CCL20-CCR6 Axis in Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms21155186 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5186 ◽

Cited By ~ 3

Author(s):

Suguru Kadomoto ◽

Kouji Izumi ◽

Atsushi Mizokami

Keyword(s):

Cancer Progression ◽

Immune Cell ◽

G Protein Coupled Receptors ◽

Virus Infections ◽

Cancer Breast ◽

Inflammatory Protein ◽

Immunodeficiency Virus ◽

G Protein Coupled ◽

Macrophage Inflammatory Protein

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.

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Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

Cardiovascular Research ◽

10.1093/cvr/cvz303 ◽

2019 ◽

Vol 116 (14) ◽

pp. 2226-2238 ◽

Cited By ~ 5

Author(s):

Tetsuo Horimatsu ◽

Andra L Blomkalns ◽

Mourad Ogbi ◽

Mary Moses ◽

David Kim ◽

...

Keyword(s):

Immune Cells ◽

Inflammatory Cell ◽

Immune Cell ◽

Inflammatory Responses ◽

Aortic Aneurysms ◽

Cell Infiltration ◽

Protective Effects ◽

Abdominal Aortic ◽

G Protein Coupled

Abstract Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

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