While selective neuronal death has been an influential theme in Huntington's disease (HD), there is now a preponderance of evidence that significant neuronal dysfunction precedes frank neuronal ...death. The best evidence for neuronal dysfunction is the observation that gene expression is altered in HD brain, suggesting that transcriptional dysregulation is a central mechanism. Studies of altered gene expression began with careful observations of postmortem human HD brain and subsequently were accelerated by the development of transgenic mouse models. The application of DNA microarray technology has spurred tremendous progress with respect to the altered transcriptional processes that occur in HD, through gene expression studies of both transgenic mouse models as well as cellular models of HD. Gene expression profiles are remarkably comparable across these models, bolstering the idea that transcriptional signatures reflect an essential feature of disease pathogenesis. Finally, gene expression studies have been applied to human HD, thus not only validating the approach of using model systems, but also solidifying the idea that altered transcription is a key mechanism in HD pathogenesis. In the future, gene expression profiling will be used as a readout in clinical trials aimed at correcting transcriptional dysregulation in Huntington's disease.
Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes ...neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.
We have developed a silicon oxynitride (SiON) deposition process using a plasma-enhanced chemical vapor deposition system for the gate dielectric of GaN-on-Si metal-insulator-semiconductor ...field-effect transistors (MISFETs). The optimized SiON film had a relative dielectric constant of 5.3 and a breakdown field of 12 MV/cm. A normally-off GaN-on-Si MISFET fabricated with a 33-nm SiON gate dielectric exhibited a threshold voltage of ~2 V, an ON-resistance of 7.85 mQ · cm 2 , and a breakdown voltage of ~640 V at the OFF-state current density of 1 μA/mm. The extracted interface trap density was 1 × 10 12 cm -2 · eV -1 at E c - E t = 0.442 eV, which resulted in negligible hysteresis and excellent dynamic characteristics.
In Huntington's disease (HD; MIM ID #143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and ...animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression. However, the question remains whether changes in histone modifications correlate with transcriptional abnormalities across the entire transcriptome. Using chromatin immunoprecipitation paired with microarray hybridization (ChIP-chip), we interrogated AcH3-gene interactions genome-wide in striata of 12-week old wild-type (WT) and transgenic (TG) R6/2 mice, an HD mouse model, and correlated these interactions with gene expression levels. At the level of the individual gene, we found decreases in the number of sites occupied by AcH3 in the TG striatum. In addition, the total number of genes bound by AcH3 was decreased. Surprisingly, the loss of AcH3 binding sites occurred within the coding regions of the genes rather than at the promoter region. We also found that the presence of AcH3 at any location within a gene strongly correlated with the presence of its transcript in both WT and TG striatum. In the TG striatum, treatment with histone deacetylase (HDAC) inhibitors increased global AcH3 levels with concomitant increases in transcript levels; however, AcH3 binding at select gene loci increased only slightly. This study demonstrates that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in histone H3 acetylation.
J. Neurochem. (2012) 120, 202–209.
Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in ...part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine‐seeking behavior coincides with increased brain‐derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time‐dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear. The goal of these experiments was to determine whether VTA BDNF transcript levels are altered following cocaine abstinence and identify the molecular mechanisms regulating cocaine‐induced changes in VTA BDNF transcription. Rats were allowed to self‐administer cocaine (0.25 mg/infusion, i.v.) for 14 days on a fixed‐ratio schedule of reinforcement followed by 7 days of forced drug abstinence. BDNF protein and exon I‐containing transcripts were significantly increased in the VTA of cocaine‐experienced rats following 7 days of forced drug abstinence compared to yoked saline controls. Cocaine‐induced changes in BDNF mRNA were associated with increased acetylation of histone 3 and binding of CREB‐binding protein to exon I‐containing promoters in the VTA. Taken together, these results suggest that drug abstinence following cocaine self‐administration remodels chromatin in the VTA resulting in increased expression of BDNF, which may contribute to neuroadaptations underlying cocaine craving and relapse.
Cocaine‐induced effects at specific BDNF promoters are mediated by distinct epigenetic mechanisms. The molecular mechanisms that regulate time‐dependent changes in VTA BDNF protein expression during drug abstinence are not clear. Here, we show for the first time that VTA BDNF mRNA, specifically exon I‐containing transcript, is increased following 7 days of drug abstinence and that distinct epigenetic mechanisms regulate BDNF gene transcription. These results indicate that targeting specific epigenetic mechanisms that regulate VTA BDNF expression during drug abstinence may prevent cocaine craving and relapse.
The prevalence of anxiety among patients undergoing arthroscopic surgery and its association with postoperative function has been well documented; however, the level of anxiety and anxiety-related ...characteristics remain unclear. As such, the present study investigated the characteristics of state anxiety in patients undergoing arthroscopic meniscectomy.
Data from 75 patients, who underwent arthroscopic partial meniscectomy under general anesthesia and completed an anxiety status questionnaire between April 2021 and March 2022, were retrospectively collected and reviewed. The State-Trait Anxiety Inventory (STAI)-X was used to measure state anxiety; a total score ≥ 52 was defined as clinically meaningful state anxiety. STAI score, main cause of preoperative anxiety, most anxious period, and most helpful factors for reducing perioperative anxiety were investigated. Patients were divided into 2 groups according to the main cause of preoperative anxiety; surgery or anesthesia (group I n = 47); and postoperative pain or rehabilitation (group II n = 28) Characteristics of state-anxiety between the two groups were compared using independent t-tests.
The mean STAI score of the total population was 39.1 points (range, 20-60 points). The mean STAI score was significantly higher in group I than in group II (41.9 vs. 34.4 points, respectively; P < 0.001). The proportion of patients with clinically meaningful state anxiety was significantly higher in group I than in group II (23.4% vs. 3.6%, respectively, P = 0.02). Most patients (66.0% in group I and 50.0% in group II) responded that trust in medical staff was the most helpful factor in overcoming preoperative anxiety. In group I, 63.8% reported that the surgeon's explanation was the most helpful factor in reducing postoperative anxiety, whereas in group II, 71.4% reported that the natural course after surgery was the most helpful factor.
Surgeons should be aware that anxiety related to arthroscopic meniscectomy differs according to patient characteristics, and a preoperative explanation of the postoperative process with the surgeon is important for patients who experience preoperative anxiety regarding anesthesia or the surgery itself.
This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous ...dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUC
values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the C
values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUC
was 708 h ng/mL and the geometric mean C
was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.
Autophagy Modulators and Neuroinflammation Cho, Kyoung Sang; Lee, Jang Ho; Cho, Jeiwon ...
Current medicinal chemistry,
01/2020, Letnik:
27, Številka:
6
Journal Article
Recenzirano
Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation ...inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders.
The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation.
We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions.
Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders.
Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.
Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to ...as DYT1. We have used a transgenic mouse model of DYT1 dystonia human mutant-type (hMT)1 mice to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with ³Hmazindol, a ligand for the membrane DA transporter, and ³Hdihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using ³HSCH-23390, a ligand for D₁ class receptors, ³HYM-09151-2 and a ligand for D₂ class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 ± 71% vs. 561 ± 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.
Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine ...reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor-dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.
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