Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration‐dependent NMDA receptor modulators would be clinically useful agents with fewer on‐target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage‐dependent effect. Patch‐clamp electrophysiology recordings confirmed agonist concentration‐dependent changes in maximum inducible currents. Dynamic Ca 2+ and Na + imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration‐biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug‐like compounds for the treatment of treatment‐resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.

Current advancements in neurovascular biology relates a mechanoceutics treatment, known as cranial osteopathic manipulation (COM), Alzheimer's disease (AD). COM could be used as an evidence-based treatment strategy to improve the symptoms of AD if molecular mechanisms, which currently remain unclear, are elucidated. In the present pilot study, using transgenic rats, we have identified COM mediated changes in behavioral and biochemical parameters associated with AD phenotypes. We expect these changes may have functional implications that might account for improved clinical outcomes of COM treatment. Further investigations on COM will be helpful to establish an adjunct treatment for AD.

Staphylococcal superantigens (SSAgs), produced by Staphylococcus aureus, non-specifically activate 30–50% of all CD4+ and CD8+ T cells expressing certain T cell receptor (TCR) Vb gene families. SSAg-activated T cells rapidly produce large quantities of cytokines and chemokines resulting in a systemic inflammatory response syndrome (SIRS), which culminates in multi organ failure (MOF) and ultimately death. Through this process, SSAgs play a significant role in the immunopathogenesis of pneumonia, sepsis, and toxic shock syndrome. Because most cytokines produced during SIRS act through the Janus Kinase (JAK) signaling pathway, we hypothesized that therapeutics inhibiting JAK functions would attenuate SIRS, MOF, and lower mortality caused by SSAgs. We tested ruxolitinib (RUXO), an FDA-approved selective JAK 1/2 inhibitor. Several in vitro and in vivo studies were performed using HLA-DR3 transgenic mice because SSAgs bind to HLA class II molecules with higher affinity. In vitro, at 100, 10, and 1 mm concentrations, RUXO significantly inhibited SSAg-induced upregulation of CD25 and CD69 on both CD4+ and CD8+ T cell subsets as well as SSAg-induced production of IL-2, IL-17, and IFN-g in a dose-dependent manner at 24 and 48 hours. For in vivo studies, mice (5–6 per group) were gavaged with RUXO (100 mg/kg) or vehicle, twice daily on days −1, 0 and 1, challenged with SSAg (20 mg/mouse, i.p) on day 0 and euthanized on day 2. SSAg-induced SIRS, thymocyte deletion, upregulation of activation markers (CD69 and CD25), and immunopathology were significantly attenuated in RUXO-treated mice compared to vehicle-treated mice. Overall, JAK inhibitors such as ruxolitinib can be used as an adjunct to treat serious diseases caused by SSAg.

Background and purpose: Precisely controlled synaptic glutamate concentration is essential for normal function of the N-methyl D-aspartate (NMDA) receptors expressed in the brain. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration dependent NMDA receptor modulators will be clinically useful agents with less on-target adverse effects. Experimental approach: Two electrode voltage clamp and patch clamp electrophysiology techniques were used for pharmacological characterization. Dynamic Ca2+ and Na+ imaging were performed using cultured rat brain neurons. MTS cell viability assay was used for to study neurotoxicity. Key results: Identified a compound (coded as CNS4) that potentiates NMDA receptor currents based on the glutamate concentration. This compound increases both glycine and glutamate potency, and exhibits no voltage dependent effect. Electrophysiology recordings confirmed agonist concentration dependent changes in peak and steady state currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 mediated region specific disproportionate influx of Na+ compared to Ca2+ in native NMDA receptors. Direct exposure of CNS4 unaltered the viability of cultured cortical or striatal neurons, neither augmented NMDA induced neuronal death. Conclusion and implications: CNS4 is novel in chemical structure, mechanism of action and agonist concentration biased modulatory effect. This compound or its future analogs will be useful for the treatment of brain disorders associated with hypoglutamatergic neurotransmission.