Summary
Stearoyl-CoA desaturase (SCD) is a potential therapeutic target for Parkinson’s and related neurodegenerative diseases. SCD inhibition ameliorates neuronal toxicity caused by aberrant ...α-synuclein, a lipid-binding protein implicated in Parkinson’s disease. Its inhibition depletes monounsaturated fatty acids, which may modulate α-synuclein conformations and membrane interactions. Herein, we characterize the pharmacokinetic and pharmacodynamic properties of YTX-7739, a clinical-stage SCD inhibitor. Administration of YTX-7739 to rats and monkeys for 15 days caused a dose-dependent increase in YTX-7739 concentrations that were well-tolerated and associated with concentration-dependent reductions in the fatty acid desaturation index (FADI), the ratio of monounsaturated to saturated fatty acids. An approximate 50% maximal reduction in the carbon-16 desaturation index was observed in the brain, with comparable responses in the plasma and skin. A study with a diet supplemented in SCD products indicates that changes in brain C16 desaturation were due to local SCD inhibition, rather than to changes in systemic fatty acids that reach the brain. Assessment of pharmacodynamic response onset and reversibility kinetics indicated that approximately 7 days of dosing were required to achieve maximal responses, which persisted for at least 2 days after cessation of dosing. YTX-7739 thus achieved sufficient concentrations in the brain to inhibit SCD and produce pharmacodynamic responses that were well-tolerated in rats and monkeys. These results provide a framework for evaluating YTX-7739 pharmacology clinically as a disease-modifying therapy to treat synucleinopathies.
Abstract
Background:
Multiple sclerosis (MS) is a chronic inflammatory disease, affecting more than 2.5 million people worldwide with more 400,000 cases in the United States alone. There has been ...considerable improvement in the treatment of MS, with the introduction of disease-modifying drugs; however, new oral therapies may provide additional benefit by providing an alternative treatment modality and the potential for improved adherence by avoiding the injection-associated side effects and anxiety encountered with some first-line agents. BG-12 (dimethyl fumarate) is an oral agent approved in the United States for the treatment of relapsing forms of MS.
Scope:
We review published literature about what is known about the mechanism of action of BG-12, and key efficacy and safety findings from three clinical studies in patients with relapsing-remitting MS (RRMS).
Findings:
Data from preclinical studies have demonstrated that BG-12 may promote anti-inflammatory and cytoprotective activities that are mediated, at least in part, by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway. Studies in animals have shown a protective effect of BG-12 on neuronal, axonal and myelin integrity. Results from a phase 2 study and two randomized double-blind placebo-controlled phase 3 studies, CONFIRM and DEFINE, have shown that BG-12 provides clinical and radiologic efficacy in patients with RRMS. At 2 years, BG-12 240 mg twice and three times daily reduced annualized relapse rate (CONFIRM primary endpoint) by 44% and 51% and the risk of relapse (DEFINE primary endpoint) by 49% and 50%, respectively, compared with placebo (all p < 0.001). BG-12 was generally well tolerated and had an acceptable safety profile, with a similar incidence of adverse events across treatment groups.
Conclusions:
BG-12 may have cytoprotective and anti-inflammatory properties that contribute to its efficacy among patients with RRMS. Findings from phase 2 and 3 studies further support BG-12 as an effective initial therapy.
ClinicalTrials.gov ID:
NCT00168701; NCT00420212: NCT00451451.
Dynamic regulation of synaptic efficacy is one of the mechanisms thought to underlie learning and memory. Many of the observed changes in efficacy, such as long-term potentiation and long-term ...depression, result from the functional alteration of excitatory neurotransmission mediated by postsynaptic glutamate receptors. These changes may result from the modulation of the receptors themselves and from regulation of protein networks associated with glutamate receptors. Understanding the interactions in this synaptic complex will yield invaluable insight into the molecular basis of synaptic function. This review focuses on the molecular organization of excitatory synapses and the processes involved in the dynamic regulation of glutamate receptors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Many recent studies have shown that excitatory synapses can contain NMDA receptor responses in the absence of functional AMPA receptors and are therefore postsynaptically silent at resting membrane ...potentials. The activation of silent synapses via the rapid acquisition of AMPA receptor responses may be important in synaptic plasticity and neuronal development. Our recent immunocytochemical studies that used cultured hippocampal neurons have provided evidence for "morphological silent synapses" that physically contain NMDA receptors but no AMPA receptors. Here we show that the activation of NMDA receptors by spontaneous synaptic activity results in the rapid recruitment of AMPA receptors into these morphological silent synapses within minutes. In parallel, we find a significant increase in the frequency of AMPA receptor-mediated miniature EPSCs (mEPSCs). NMDA receptor activation also results in a mobilization of calcium/calmodulin (CaM) kinase II to synapses and an increase in the phosphorylation of surface AMPA receptors on the major CaM kinase II phosphorylation site. These results demonstrate that AMPA receptors can be modified and recruited rapidly to silent synapses via the activation of NMDA receptors by spontaneous synaptic activity.
Abstract Background Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for ...relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time. Objective The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor. Methods Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored. Results DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0–10h , or Cmax . Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D2 (PGD2 ) metabolite were increased. Conclusions In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
Increasing evidence has shown that Parkinson’s disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich ...α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K (“3K”) αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood–brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.
PSD-95, DLG, ZO-1 (PDZ) domain-mediated protein interactions have been shown to play important roles in the regulation of glutamate receptor function at excitatory synapses. Recent studies ...demonstrating the rapid regulation of AMPA receptor function during synaptic plasticity have suggested that AMPA receptor interaction with PDZ domain-containing proteins may be dynamically modulated. Here we show that PKC phosphorylation of the AMPA receptor GluR2 subunit differentially modulates its interaction with the PDZ domain-containing proteins GRIP1 and PICK1. The serine residue serine-880 (Ser880) in the GluR2 C-terminal sequence (IESVKI) critical for PDZ domain binding is a substrate of PKC and is phosphorylated in vivo. In vitro binding and coimmunoprecipitation studies show that phosphorylation of serine-880 within the GluR2 PDZ ligand significantly decreases GluR2 binding to GRIP1 but not to PICK1. Immunostaining of cultured hippocampal neurons demonstrates that the Ser880-phosphorylated GluR2 subunits are enriched and colocalized with PICK1 in the dendrites, with very little staining observed at excitatory synapses. Interestingly, PKC activation in neurons increases the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to excitatory synapses. Moreover, PKC stimulation in neurons results in rapid internalization of surface GluR2 subunits. These results suggest that GluR2 phosphorylation of serine-880 may be important in the regulation of the AMPA receptor internalization during synaptic plasticity.
Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta ...(IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE).
EAE was induced in C57BL/6 mice by immunization with MOG35–55-peptide. Murine IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action.
Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells.
Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.
•We investigated mechanisms and efficacy of a combination therapy with DMF and IFN-β in EAE•DMF/IFN-β significantly ameliorated course of EAE compared to controls and monotherapy•Histological analyses revealed beneficial effects of DMF/IFN-β on immune cell infiltration•DMF/IFN-β resulted in significantly higher number of axon densities in inflamed lesions•ELISA and FACS analyses revealed no immunosuppressive mechanism of IFN-β and DMF
Amyloid beta (Aβ), a key component in the pathophysiology of Alzheimer's disease, is thought to target excitatory synapses early in the disease. However, the mechanism by which Aβ weakens synapses is ...not well understood. Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for Aβ to weaken synapses. In mice lacking PICK1, elevations of Aβ failed to depress synaptic transmission in cultured brain slices. In dissociated cultured neurons, Aβ failed to reduce surface α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor subunit 2, a subunit of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors that binds with PICK1 through a PDZ ligand–domain interaction. Lastly, a novel small molecule (BIO922) discovered through structure‐based drug design that targets the specific interactions between GluA2 and PICK1 blocked the effects of Aβ on synapses and surface receptors. We concluded that GluA2–PICK1 interactions are a key component of the effects of Aβ on synapses.
Aβ reduces synaptic and surface GluA2‐containing AMPA‐Rs in wild‐type but not PICK1‐/‐ tissue. A synthetic compound blocking GluA2‐PICK1 interactions blocks effects of Aβ. These data are consistent with a model in which Aβ drives signaling leading to intracellular retention of GluA2‐containing AMPA‐Rs by PICK1.
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