Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?

Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia. Both findings could be due to abnormal neurodevelopmental trajectories, affecting local neuronal networks and long-range synchrony and leading to cognitive deficits. In this review, we present data from animal models demonstrating that redox dysregulation, neuroinflammation and/or NMDAR hypofunction (as observed in patients) impairs the normal development of both parvalbumin interneurons and oligodendrocytes. These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits. Moreover, we propose that the redox, neuroimmune, and glutamatergic systems form a "central hub" where an imbalance within any of these "hub" systems leads to similar anomalies of parvalbumin interneurons and oligodendrocytes due to the tight and reciprocal interactions that exist among these systems. A combination of vulnerabilities for a dysregulation within more than one of these systems may be particularly deleterious. For these reasons, molecules, such as N-acetylcysteine, that possess antioxidant and anti-inflammatory properties and can also regulate glutamatergic transmission are promising tools for prevention in ultra-high risk patients or for early intervention therapy during the first stages of the disease

Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.

Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology

Improvements in no evidence of disease activity with ublituximab vs. teriflunomide in the ULTIMATE phase 3 studies in relapsing multiple sclerosis.

BACKGROUND: Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24-96 with ublituximab vs. teriflunomide. METHODS: In ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age ( ≤ 38 or >38 years), early or later disease (<3 or ≥3 years following diagnosis), treatment history (treatment naïve or previously treated), 0 or ≥1 Gd+ T1 lesions at baseline, and Expanded Disability Status Scale score ≤ 3.5 or >3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks. RESULTS: NEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0-96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24-96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48-96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0-24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0-48) experienced NEDA in the second year of treatment (Weeks 48-96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24-96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001). CONCLUSIONS: ULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations

Glutathione Restores the Mechanism of Synaptic Plasticity in Aged Mice to That of the Adult

Glutathione (GSH), the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs) through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory

Age-Dependent Targeting of Protein Phosphatase 1 to Ca2+/Calmodulin-Dependent Protein Kinase II by Spinophilin in Mouse Striatum

Mechanisms underlying age-dependent changes of dendritic spines on striatal medium spiny neurons are poorly understood. Spinophilin is an F-actin- and protein phosphatase 1 (PP1)-binding protein that targets PP1 to multiple downstream effectors to modulate dendritic spine morphology and function. We found that calcium/calmodulin-dependent protein kinase II (CaMKII) directly and indirectly associates with N- and C-terminal domains of spinophilin, but F-actin can displace CaMKII from the N-terminal domain. Spinophilin co-localizes PP1 with CaMKII on the F-actin cytoskeleton in heterologous cells, and spinophilin co-localizes with synaptic CaMKII in neuronal cultures. Thr286 autophosphorylation enhances the binding of CaMKII to spinophilin in vitro and in vivo. Although there is no change in total levels of Thr286 autophosphorylation, maturation from postnatal day 21 into adulthood robustly enhances the levels of CaMKII that co-immunoprecipitate with spinophilin from mouse striatal extracts. Moreover, N- and C-terminal domain fragments of spinophilin bind more CaMKII from adult vs. postnatal day 21 striatal lysates. Total levels of other proteins that interact with C-terminal domains of spinophilin decrease during maturation, perhaps reducing competition for CaMKII binding to the C-terminal domain. In contrast, total levels of α-internexin and binding of α-internexin to the spinophilin N-terminal domain increases with maturation, perhaps bridging an indirect interaction with CaMKII. Moreover, there is an increase in the levels of myosin Va, α-internexin, spinophilin, and PP1 in striatal CaMKII immune complexes isolated from adult and aged mice compared to those from postnatal day 21. These changes in spinophilin/CaMKII interactomes may contribute to changes in striatal dendritic spine density, morphology, and function during normal postnatal maturation and aging

Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma

Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca 2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca 2+ channel inhibitor Lomerizine (Lom), the Ca 2+ permeable AMPA receptor inhibitor YM872 and the P2X 7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs

Ras-association domain of sorting nexin 27 is critical for regulating expression of GIRK potassium channels

G protein-gated inwardly rectifying potassium (GIRK) channels play an important role in regulating neuronal excitability. Sorting nexin 27b (SNX27b), which reduces surface expression of GIRK channels through a PDZ domain interaction, contains a putative Ras-association (RA) domain with unknown function. Deleting the RA domain in SNX27b (SNX27b-DRA) prevents the down-regulation of GIRK2c/GIRK3 channels. Similarly, a point mutation (K305A) in the RA domain disrupts regulation of GIRK2c/GIRK3 channels and reduces H-Ras binding in vitro. Finally, the dominant-negative H-Ras (S17N) occludes the SNX27b-dependent decrease in surface expression of GIRK2c/GIRK3 channels. Thus, the presence of a functional RA domain and the interaction with Ras-like G proteins comprise a novel mechanism for modulating SNX27b control of GIRK channel surface expression and cellular excitability