Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma.

Background: Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.

Aging disrupts locus coeruleus-driven norepinephrine transmission in the prefrontal cortex: Implications for cognitive and motor decline.

The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior.

Sex differences in single neuron function and proteomics profiles examined by patch-clamp and mass spectrometry in the locus coeruleus of the adult mouse.

Aims: This study aimed to characterize the properties of locus coeruleus (LC) noradrenergic neurons in male and female mice. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations.

Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy.

Beyond CBD: Inhibitory effects of lesser studied phytocannabinoids on human voltage-gated sodium channels.

Cannabis contains cannabidiol (CBD), the main non-psychoactive phytocannabinoid, but also many other phytocannabinoids that have therapeutic potential in the treatment of epilepsy. Indeed, the phytocannabinoids cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA) and cannabichromene (CBC) have recently been shown to have anti-convulsant effects in a mouse model of Dravet syndrome (DS), an intractable form of epilepsy. Recent studies demonstrate that CBD inhibits voltage-gated sodium channel function, however, whether these other anti-convulsant phytocannabinoids affect these classic epilepsy drug-targets is unknown.

Levels of Soluble Interleukin 6 Receptor and Asp358Ala Are Associated With Cognitive Performance and Alzheimer Disease Biomarkers.

Background And Objectives: Alzheimer disease (AD) is a neurodegenerative disease process manifesting clinically with cognitive impairment and dementia. AD pathology is complex, and in addition to plaques and tangles, neuroinflammation is a consistent feature. Interleukin (IL) 6 is a multifaceted cytokine involved in a plethora of cellular mechanisms including both anti-inflammatory and inflammatory processes.

A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function.

Background: Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD.

Neurovascular unit pathology is observed very early in disease progression in the mutant SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by motor neuron degeneration that causes neuromuscular denervation, resulting in muscle weakness and atrophy. Work over the decades using ALS mouse models has revealed that while initial pathology may occur within motor neurons, disease pathology is cell non-autologous. Impairment of the blood-spinal cord barrier (BSCB) occurs before motor neuron frank degeneration; however, precisely when the early pathogenesis of the neurovascular units occurs is not fully understood.

Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.

Introduction/aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.

Methods: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures.

The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration.

In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed "senescence". For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively.

Utilising Automated Electrophysiological Platforms in Epilepsy Research.

Genetic mutations have long been implicated in epilepsy, particularly in genes that encode ion channels and neurotransmitter receptors. Among some of those identified are voltage-gated sodium, potassium and calcium channels, and ligand-gated gamma-aminobutyric acid (GABA), neuronal nicotinic acetylcholine (CHRN), and glutamate receptors, making them key therapeutic targets. In this chapter we discuss the use of automated electrophysiological technologies to examine the impact of gene defects in two potassium channels associated with different epilepsy syndromes.

Interleukin 6 (IL6) level is a biomarker for functional disease progression within IL6RAla variant groups in amyotrophic lateral sclerosis patients.

Interleukin-6 (IL6) expression increases in atrophying muscles and lung tissue during compromised function. Considering ALS patients undergo these same pathological changes, IL6 levels may be relevant for prognostication and treatment. The amount of soluble IL6 receptor, dictated by the IL6RAla variant, and local tissue environment in which IL6 signaling occurs is known to influence the ultimate effects of IL6 in multiple diseases.

A P2RX7 single nucleotide polymorphism haplotype promotes exon 7 and 8 skipping and disrupts receptor function.

P2X7 is an ATP-gated membrane ion channel that is expressed by multiple cell types. Brief exposure to ATP induces the opening of a nonselective cation channel; while repeated or prolonged exposure induces formation of a transmembrane pore. This process may be partially regulated by alternative splicing of full-length P2RX7A pre-mRNA, producing isoforms that delete or retain functional domains.

Automated Planar Patch-Clamp Recording of P2X Receptors.

P2X receptors are a structurally and functionally distinctive family of ligand-gated ion channels that play important roles in mediating extracellular adenosine 5'-triphosphate (ATP) signaling in diverse physiological and pathophysiological processes. For several decades, the "manual" patch-clamp technique was regarded as the gold standard assay for investigating ion channel properties. More recently, breakthroughs in the development of automated patch-clamp technologies are enabling the study of ion channels, with much greater throughput capacities.

IL6 receptorAla variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis.

Objective: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (AspAla, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers.

Methods: An observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype.

Extracellular heat shock proteins in neurodegenerative diseases: New perspectives.

One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress.

Racial differences in intervention rates in individuals with ALS: A case-control study.

Objective: This study was conducted to determine whether longer lifespans in African Americans with amyotrophic lateral sclerosis (ALS), compared to white non-Hispanics, are secondary to higher rates of tracheostomy and invasive ventilation (TIV) in African Americans.

Methods: A retrospective case-control study was conducted with 49 African Americans with ALS matched by age, gender, and site of onset to 137 white persons with ALS.

Results: African Americans had longer survival than whites when the outcome was death ( = 0.

A pilot study of neuromuscular ultrasound as a biomarker for amyotrophic lateral sclerosis.

Introduction: This study explores the reliability and responsiveness of neuromuscular ultrasound in amyotrophic lateral sclerosis (ALS).

Methods: Investigations were conducted with 10 healthy controls, 10 patients with ALS (single point in time), and 10 different patients with ALS (followed over 6 months; 4 completed follow-up). Ultrasound was used to measure the thickness of the geniohyoid, bilateral biceps/brachialis, bilateral tibialis anterior, and bilateral hemidiaphragms (at inspiration and expiration).

Selective Na1.1 activation rescues Dravet syndrome mice from seizures and premature death.

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of , which encodes the voltage-gated sodium channel Na1.

Inflammation, immunity, and amyotrophic lateral sclerosis: II. immune-modulating therapies.

With the emerging popularity of immune-modulatory therapies to treat human diseases there is a need to step back from hypotheses aimed at assessing a condition in a single-system context and instead take into account the disease pathology as a whole. In complex diseases, such as amyotrophic lateral sclerosis (ALS), the use of these therapies to treat patients has been largely unsuccessful and likely premature given our lack of understanding of how the immune system influences disease progression and initiation. In addition, we still have an incomplete understanding of the role of these responses in our model systems and how this may translate clinically to human patients.

Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology.

Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. Charcot first described ALS in 1869 ; however, its pathogenesis remains unknown, and effective treatments remain elusive. It is apparent that new paradigms must be investigated to understand the effectors of ALS, including inflammation, immune responses, and the body's response to stress and injury.

KCTD12 modulation of GABA(B) receptor function.

The molecular composition and functional diversity of native GABA receptors (GABAR) are still poorly understood, thus hindering development of selective GABAR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABAR auxiliary subunit and mouse KCTD12 can alter GABAR function. In this study, we sought to characterize the effects of human KCTD12 on GABAR kinetics and pharmacology, using an automated electrophysiological assay.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K channel properties.

Objective: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.

Methods: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation.

Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis.

Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study, we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype (P2RX7 rs140915863:C>T [p.

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling.

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure.

The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts.

Objective: Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels.