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Clinically relevant niclosamide concentrations modulate TMEM16A and CaV1.2 channels to control artery tone and capillary diameter
AbstractBackground and PurposeTMEM16A Ca2+‐gated Cl− channels mediate depolarisation of contractile vascular cells. The anthelmintic niclosamide was reported to modulate the TMEM16A channel, suggesting possible repurposing for vascular pharmacology. Here, we investigate the mechanism of TMEM16A modulation by niclosamide and explore its effect on the function of a range of vessel types.Experimental ApproachPatch‐clamp electrophysiology, alongside genetically encoded systems to modulate plasmalemmal PIP2 content, was used to define the mechanism of action of niclosamide on the TMEM16A channel. Vascular contractility was investigated using isometric tension recordings of isolated rat arteries and differential interference contrast imaging of capillary diameter in rat brain slices.Key ResultsIn low intracellular free Ca2+ concentrations ([Ca2+]i), clinically relevant niclosamide concentrations inhibited or enhanced heterologous TMEM16A currents at positive or negative membrane potentials (Vm), respectively. In saturating [Ca2+]i, niclosamide inhibited the channel at each Vm tested, independent of plasmalemmal PIP2 levels. Niclosamide caused a transient contraction of isolated aortae and mesenteric and pulmonary arteries but dampened responses to phenylephrine, a Gq protein‐coupled receptor (GqPCR) agonist. Niclosamide reduced brain cortical pericyte constriction evoked by endothelin‐1. Unlike Ani9, a selective TMEM16A inhibitor, niclosamide reduced arterial response to elevated extracellular K+. Niclosamide also inhibited heterologous and native voltage‐gated Ca2+ (CaV) currents in smooth muscle cells.Conclusion and ImplicationsNiclosamide dampened vascular responses to GqPCR stimulation due to concomitant modulation of TMEM16A and CaV channels. Elucidating the molecular pharmacology of niclosamide supports its potential use in disorders of altered vessel tone including stroke, hypertension and vascular dementia.
Increased c-Fos immunoreactivity in anxiety-related brain regions following paroxetine discontinuation.
Selective serotonin reuptake inhibitor (SSRI) therapy cessation often induces a disabling discontinuation syndrome, including increased anxiety. We recently reported that SSRI discontinuation induced behavioural changes in mice, which we hypothesise arose from activated anxiety circuitry. Here, we investigated the effect of discontinuation from the SSRI paroxetine on the expression of the activity-dependent gene c-fos in selected anxiety-related midbrain and forebrain regions. Male mice were injected daily with paroxetine (10 mg/kg) or saline for 12 days, then treatment was either continued or discontinued for two or five days. Mice were then tested on the elevated plus maze (EPM) and tissue collected 90 min later. Brain sections including the dorsal (DRN) and median raphe nucleus, periaqueductal grey, hippocampus, prefrontal cortex, and amygdala were processed for c-Fos immunoreactivity. Two days after paroxetine discontinuation, when mice showed elevated anxiety-like behaviour on the EPM, increased c-Fos immunoreactivity was evident in the DRN and ventral hippocampus, but not in any other region examined, compared to saline-treated controls. Increased c-Fos in the DRN was evident in TPH2-immunopositive neurons as well as neurons doubled-labelled for TPH2 and VGLUT3, suggesting activation of 5-HT-glutamate co-releasing neurons. Five days after paroxetine discontinuation, increased c-Fos immunoreactivity was evident in the DRN, but mice no longer exhibited increased anxiety. These findings suggest that, under these conditions, paroxetine discontinuation is associated with a short-lasting activation of anxiety-promoting circuitry limited to DRN 5-HT neurons and the hippocampus. This circuitry may contribute to symptoms such as anxiety that are a feature of SSRI discontinuation syndrome.
Systematic review and meta-analysis of microbiota-gut-astrocyte axis perturbation in neurodegeneration, brain injury, and mood disorders
Background: Astrocytes are essential for preserving homeostasis, maintaining the blood-brain barrier, and they are a key element of the tripartite neuronal synapse. Despite such multifaceted roles, their importance as contributors to the microbiota-gut-brain axis studies, which typically focus on microglia and neurons, has been largely overlooked. This meta-analysis provides the first systematic review of the microbiota-gut-astrocyte (MGA) axis in vivo, integrating findings across distinct neurological diseases. Methods: A systematic narrative review was conducted per PRISMA guidelines. The search term employed for PubMed was “Microbiota"[MeSH] AND (astrocyte OR glial) NOT (Review[Publication Type]) and for Web of Science, Embase, and Scopus, “Microbio∗ AND (astrocyte OR glial)” with filters applied to exclude review articles. Searches were completed by May 9th, 2024. Data extracted included study models, interventions, and outcomes related to astrocyte biology and rodent behaviour. SYRCLE's risk of bias tool was used to assess individual study designs. Results: 53 studies met the inclusion criteria, covering rodent models of stroke and traumatic (acute) brain injury, chronic neurodegenerative diseases including Alzheimer's and Parkinson's disease and other heterogeneous models of cognitive impairment and affective disorders. Significant heterogeneity in methodology was observed between studies. Five studies had a high risk of bias, and 15 were low risk. Astrocyte biology, typically measured by GFAP expression, was increased in neurodegeneration and acute brain injury models but varied significantly in mood disorder models, depending on the source of stress. Common findings across diseases included altered gut microbiota, particularly an increased Bacteroidetes/Firmicutes ratio and compromised gut barrier integrity, linked to increased GFAP expression. Faecal microbiota transplants and microbial metabolite analyses suggested a direct impact of the gut microbiota on astrocyte biology and markers of neuroinflammation. Conclusions: This review and meta-analysis describes the impact of the gut microbiota on astrocyte biology, and argues that the MGA axis is a promising therapeutic target for neurological disorders. However, it is clear that our understanding of the relationship between the gut microbiota and astrocyte behaviour is incomplete, including how different subtypes of astrocytes may be affected. Future studies must adopt new, multi-dimensional studies of astrocyte function and dysfunction, to elucidate their role in disease and explore the therapeutic potential of gut microbiota modulation.
Neuropsychopharmacology of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists.
Psychedelic drugs such as LSD and psilocin were once relegated to the fringes of medical research because of their association with counterculture movements and a perceived concern about harm through recreational use, and their consequent legal prohibition in the early 1970s. However, these drugs are now experiencing a renaissance in the field of psychiatry based on increasing evidence that they can produce long-lasting improvements in health across a wide variety of mental illnesses, including major depression, addictions and anxiety disorders. These drugs interact with many different 5-HT receptor subtypes but the powerful psychedelic experience, which (depending on set and setting) includes profound alterations in perception, mood and cognition, accompanied by vivid hallucinations, is now widely considered mediated by an agonist action at 5-HT2A receptors. However, the link between the psychedelic experience, 5-HT2A receptor agonism and therapeutic effects is currently uncertain. Indeed, recent research has revealed a new class of 5-HT2A receptor agonists which appear to retain the therapeutic potential of psychedelics drugs without inducing disorienting hallucinatory experiences. Biased signalling, partial agonism and non-selectivity at the 5-HT2A receptor are amongst the possible explanations for the differential properties of these drugs, whereas increased neuroplasticity offers a likely account of their common therapeutic effects. This article explores the neuropsychopharmacological properties of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists in the context of their promise as novel drug treatments in psychiatry.
Vancomycin-Resistant E. faecium: Addressing Global and Clinical Challenges
Antimicrobial resistance (AMR) poses a profound threat to modern healthcare, with vancomycin-resistant Enterococcus faecium (VREfm) emerging as a particularly resilient and clinically significant pathogen. This mini-review examines the biological mechanisms underpinning VREfm resistance, including biofilm formation, stress tolerance, and the acquisition of resistance genes such as vanA and vanB. It also explores the behavioural, social, and healthcare system factors that facilitate VREfm transmission, highlighting disparities in burden across vulnerable populations and low-resource settings. Prevention strategies are mapped across the disease pathway, spanning primary, secondary, and tertiary levels, with a particular focus on the role and evolving challenges of antimicrobial stewardship programmes (ASP). We highlight emerging threats, such as rifaximin-induced cross-resistance to daptomycin, which challenge conventional stewardship paradigms. Finally, we propose future directions to enhance global surveillance, promote equitable stewardship interventions, and accelerate the development of innovative therapies. Addressing VREfm requires a coordinated, multidisciplinary effort to safeguard the efficacy of existing antimicrobials and protect at-risk patient populations.
Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport.
Glycosphingolipids are endocytosed and targeted to the Golgi apparatus but are mistargeted to lysosomes in sphingolipid storage disorders. Substrate reduction therapy utilizes imino sugars to inhibit glucosylceramide synthase and potentially abrogate the effects of storage. Niemann-Pick type C (NPC) disease is a disorder of intracellular transport where glycosphingolipids (GSLs) and cholesterol accumulate in endosomal compartments. The mechanisms of altered intracellular trafficking are not known but may involve the mistargeting and disrupted function of proteins associated with GSL membrane microdomains. Membrane microdomains were isolated by Triton X-100 and sucrose density gradient ultracentrifugation. High pressure liquid chromatography and mass spectrometric analysis of NPC1(-/-) mouse brain revealed large increases in GSL. Sphingosine was also found to be a component of membrane microdomains, and in NPC liver and spleen, large increases in cholesterol and sphingosine were found. GSL and cholesterol levels were increased in mutant NPC1-null Chinese hamster ovary cells as well as U18666A and progesterone induced NPC cell culture models. However, inhibition of GSL synthesis in NPC cells with N-butyldeoxygalactonojirimycin led to marked decreases in GSL but only small decreases in cholesterol levels. Both annexin 2 and 6, membrane-associated proteins that are important in endocytic trafficking, show distorted distributions in NPC cells. Altered BODIPY lactosylceramide targeting, decreased endocytic uptake of a fluid phase marker, and mistargeting of annexin 2 (phenotypes associated with NPC) are reversed by inhibition of GSL synthesis. It is suggested that accumulating GSL is part of a mislocalized membrane microdomain and is responsible for the deficit in endocytic trafficking found in NPC disease.
The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1.
The gene encoding the insulin-like growth-factor type-2 receptor (Igf2r) is maternally expressed and imprinted. A CpG island in Igf2r intron 2 that carries a maternal-specific methylation imprint was shown in a transgenic model to be essential for Igf2r imprinting and for the production of an antisense RNA from the paternal allele. We report here that the endogenous region2 is the promoter for this antisense RNA (named Air, for antisense Igf2r RNA) and that the 3' end lies 107,796 bp distant in an intron of the flanking, but non-imprinted, gene Mas1.
Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.
Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. In this multicentre study, we measured plasma phosphorylated-tau217 in controls (n = 60), Niemann-Pick disease type C (n = 71) and Alzheimer's disease (n = 30 positive for amyloid and negative for tau in CSF [A+T-] and n = 30 positive for both [A+T+]). Annual Severity Increment Score and Lysotracker measurements were evaluated in the Niemann-Pick disease type C group to estimate the rate of progression and lysosomal enlargement, respectively. In the cross-sectional analysis, plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset (R = -0.54, P < 0.001). In the longitudinal analysis, plasma phosphorylated-tau217 was associated with disease progression determined by Annual Severity Increment Score (R = 0.48, P < 0.001) and lysosomal enlargement (R = 0.26, P = 0.004). We found no differences between A+T- Alzheimer's disease and Niemann-Pick disease type C (2.67 ± 1.18 versus 2.52 ± 1. 93 pg/mL, P = 0.31); however, A+T+ Alzheimer's disease had significantly higher levels than Niemann-Pick disease type C (3.26 ± 1.36 versus 2.52 ± 1.93 pg/mL, P = 0.001). Our findings suggest that plasma p-tau217 can increase in brain disorders with isolated tau pathology. Plasma p-tau217 associations with disease progression and severity make it a potential marker in Niemann-Pick disease type C.
Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease.
This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3β-hydroxy,7β-N-acetylglucosaminyl-5-cholenoic acid) and NPCBA2 (probably 3β,5α,6β-trihydroxycholanoyl-glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40- and 10-fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker.
Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials.
BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression. RESULTS: In this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores. CONCLUSION: ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy.
Glycosphingolipid metabolism and its role in ageing and Parkinson's disease.
It is well established that lysosomal glucocerebrosidase gene (GBA) variants are a risk factor for Parkinson's disease (PD), with increasing evidence suggesting a loss of function mechanism. One question raised by this genetic association is whether variants of genes involved in other aspects of sphingolipid metabolism are also associated with PD. Recent studies in sporadic PD have identified variants in multiple genes linked to diseases of glycosphingolipid (GSL) metabolism to be associated with PD. GSL biosynthesis is a complex pathway involving the coordinated action of multiple enzymes in the Golgi apparatus. GSL catabolism takes place in the lysosome and is dependent on the action of multiple acid hydrolases specific for certain substrates and glycan linkages. The finding that variants in multiple GSL catabolic genes are over-represented in PD in a heterozygous state highlights the importance of GSLs in the healthy brain and how lipid imbalances and lysosomal dysfunction are associated with normal ageing and neurodegenerative diseases. In this article we will explore the link between lysosomal storage disorders and PD, the GSL changes seen in both normal ageing, lysosomal storage disorders (LSDs) and PD and the mechanisms by which these changes can affect neurodegeneration.