nmdar inhibitors

The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression...

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor (GEF) that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics...

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent forms of autoimmune encephalitis, characterized by a series of neurological and psychiatric symptoms, including cognitive impairment, seizures and psychosis. The underlying mechanism of anti-NMDAR encephalitis remains unclear. In the current study, the mouse model of anti-NMDAR encephalitis with active immunization was performed. We first uncovered excessive mitochondrial fission in the hippocampus and temporal cortex of anti-NMDAR encephalitis mice, indicated by elevated level of Phospho-DRP1 (Ser616) (p-Drp1-S616)...

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2 S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2 S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN)...

The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function...

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression, and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent...

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N-methyl-d-aspartate (NMDA) receptors (NMDAR)...

The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction)...

In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other effects that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. We recently observed that the SSRIs fluvoxamine and fluoxetine prevent the acute adverse effects of pro-inflammatory stimulation on long-term potentiation (LTP) in the CA1 hippocampal region. Sertraline showed markedly different effects, acutely inhibiting LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs)...

Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1G93A ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy...

BACKGROUND: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. METHODS: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices...

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation...

Epilepsy is characterized by a sustained depolarization and repeated discharge of neurons, attributed to overstimulation of N-methyl-D-aspartate receptors (NMDAr). Herein, we propose that probenecid (PROB), an inhibitor of the activity of some ATP binding-cassette transporters (ABC-transporters) can modify NMDAr activity and expression in amygdaloid kindled model. Some studies have suggested that NMDAr expression could be regulated by inhibiting the activity of P-glycoprotein (MDR1) and drug resistance protein-1 (MRP1)...

Chronic pain constitutes an abnormal pain state that detrimentally affects the quality of life, daily activities, occupational performance, and stability of mood. Despite the prevalence of chronic pain, effective drugs with potent abirritation and minimal side effects remain elusive. Substantial studies have revealed aberrant activation of the matrix metalloproteinases (MMPs) in multiple chronic pain models. Additionally, emerging evidence has demonstrated that the downregulation of MMPs can alleviate chronic pain in diverse animal models, underscoring the unique and crucial role of MMPs in different stages and types of chronic pain...

Glutamate-NMDAR receptors (GRINs) have been reported to influence cancer immunogenicity; however, the relationship between GRIN alterations and the response to immune checkpoint inhibitors (ICIs) has not been determined. This study combined clinical characteristics and mutational profiles from multiple cohorts to form a discovery cohort (n = 901). The aim of this study was to investigate the correlation between the mutation status of the GRIN gene and the response to ICI therapy. Additionally, an independent ICI-treated cohort from the Memorial Sloan Kettering Cancer Center (MSKCC, N = 1513) was used for validation...

N-methyl-D-aspartic acid receptors (NMDARs) are the most studied receptors in mammalian brains. Their role in depression, cognition, schizophrenia, learning and memorization, Alzheimer's disease, and more is well documented. In the search for new drug candidates in depression, intensive studies have been conducted. Compounds that act by influencing NMDARs have been particularly intensively investigated following the success of ketamine in clinics. Unfortunately, the side effects associated with ketamine do not allow it to be useful in all cases...

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated, voltage-dependent channels of the ionotropic glutamate receptor family. The present study explored whether NMDAR activation induced ferroptosis in vascular endothelial cells and its complicated mechanisms in vivo and in vitro. Various detection approaches were used to determine the ferroptosis-related cellular iron content, lipid reactive oxygen species (LOS), siRNA molecules, RNA-sequence, MDA, GSH, and western blotting. The AMPK activator Acadesine (AICAR), HMGB1 inhibitor glycyrrhizin (GLY), PP2A inhibitor LB-100, and NMDAR inhibitor MK801 were used to investigate the involved in vivo and in vitro pathways...

The involvement of the N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, in promoting the invasive growth of cancer cells is an area of ongoing investigation. Our previous findings revealed a physical interaction between NMDAR and MET, the hepatocyte growth factor (HGF) receptor. However, the molecular mechanisms underlying this NMDAR/MET interaction remain unclear. In this study, we demonstrate that the NMDAR2B subunit undergoes proteolytic processing, resulting in a low-molecular-weight form of 100 kDa...

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR)...

In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more frequently, be damaged together with other areas of the nervous system (e.g. Guillain-Barré syndrome). Patients with autoimmune encephalitis and paraneoplastic neurological syndromes (PNS) often develop dysautonomia; however, the frequency and spectrum of autonomic signs and symptoms remain ill defined except for those scenarios in which dysautonomia is a core feature of the disease...