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Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

ABSTRACT: The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.

SUBMITTER: Seillier C

PROVIDER: S-EPMC9499580 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

Seillier Célia C Lesept Flavie F Toutirais Olivier O Potzeha Fanny F Blanc Manuel M Vivien Denis D

International journal of molecular sciences 20220907 18

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions suc ...[more]

PMID: 36142247

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Project description:BackgroundThe cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer's disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function.MethodsImmunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer's disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP).ResultsIn a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids.ConclusionsThe results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.

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Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

Publications

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

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