Antiseizure properties of fenamate NSAIDs determined in mature human stem-cell derived neuroglial circuits.

Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy.

Impact of a Neuropsychiatric Therapeutics Course and a Case-Based Course on Pharmacy Students' Mental Health Stigma.

Objective: Mental health education can reduce the stigma held by medical and nursing students; however, findings in this regard are limited in pharmacy academia. This study investigated the impact of a neuropsychiatric therapeutics course followed by a case-based course on the mental health stigma held by pharmacy students.

Methods: A survey was conducted of second-year pharmacy students (n = 202) on the first and last day of a neuropsychiatric therapeutics course and 4 months later, at the end of a case-based course.

Neuropharmacology of human TERA2.cl.SP12 stem cell-derived neurons in ultra-long-term culture for antiseizure drug discovery.

Modeling the complex and prolonged development of the mammalian central nervous system remains a profound challenge. Most studies of human stem cell derived neurons are conducted over days to weeks and may or may not include glia. Here we have utilized a single human pluripotent stem cell line, TERA2.

An Electrophysiological and Pharmacological Study of the Properties of Human iPSC-Derived Neurons for Drug Discovery.

Human stem cell-derived neurons are increasingly considered powerful models in drug discovery and disease modeling, despite limited characterization of their molecular properties. Here, we have conducted a detailed study of the properties of a commercial human induced Pluripotent Stem Cell (iPSC)-derived neuron line, iCell [GABA] neurons, maintained for up to 3 months in vitro. We confirmed that iCell neurons display neurite outgrowth within 24 h of plating and label for the pan-neuronal marker, βIII tubulin within the first week.

Adolescent Substance Abuse, Transgenerational Consequences and Epigenetics.

Adolescence is the transitional period between childhood and adulthood and a critical period in brain development. Adolescence in humans is also associated with increased expression of risk-taking behaviors. Epidemiological and clinical studies, for example, show a surge of drug abuse and raise the hypothesis that the adolescent brain undergoes critical changes resulting in diminished control.

Adolescent drug exposure: A review of evidence for the development of persistent changes in brain function.

Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse.

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke.

Stroke is a devastating neurological event with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABA receptors, activators of I potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome.

Electrophysiological properties of neurons derived from human stem cells and iNeurons in vitro.

Functional studies of neurons have traditionally used nervous system tissues from a variety of non-human vertebrate and invertebrate species, even when the focus of much of this research has been directed at understanding human brain function. Over the last decade, the identification and isolation of human stem cells from embryonic, tissue (or adult) and induced pluripotent stem cells (iPSCs) has revolutionized the availability of human neurons for experimental studies in vitro. In addition, the direct conversion of terminally differentiated fibroblasts into Induced neurons (iN) has generated great excitement because of the likely value of such human stem cell derived neurons (hSCNs) and iN cells in drug discovery, neuropharmacology, neurotoxicology and regenerative medicine.

An evaluation of a human stem cell line to identify risk of developmental neurotoxicity with antiepileptic drugs.

Determination of the impact of a drug on human brain development relies instead on surrogate animal studies. Here we have exploited the human stem cell line, TERA2.cl.

Neuropharmacological properties of neurons derived from human stem cells.

Human pluripotent stem cells have enormous potential value in neuropharmacology and drug discovery yet there is little data on the major classes and properties of receptors and ion channels expressed by neurons derived from these stem cells. Recent studies in this lab have therefore used conventional patch-clamp electrophysiology to investigate the pharmacological properties of the ligand and voltage-gated ion channels in neurons derived and maintained in vitro from the human stem cell (hSC) line, TERA2.cl.

Evidence for neuroprotection by the fenamate NSAID, mefenamic acid.

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. The aim of this study was to investigate the hypothesis that the fenamate, mefenamic acid, is neuroprotective in an in vitro and in vivo model of stroke.

Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.

Ligands that bind to the benzodiazepine binding site on the GABA A receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha5beta2gamma2 and alpha1beta2gamma2 GABA A receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study.

The product of the gene GEF1 of Saccharomyces cerevisiae transports Cl- across the plasma membrane.

Expression of GEF1 in Xenopus laevis oocytes and HEK-293 cells gave rise to a Cl- channel that remained permanently open and was blocked by nitro-2-(3-phenyl-propylamino) benzoic acid and niflumic acid. NPPB induced petite-like colonies, resembling the GEF1 knock-out. The fluorescent halide indicator SPQ was quenched in a wild-type strain, in contrast to both a GEF1 knock-out strain and yeast grown in the presence of NPPB.

Characterization of the interaction between fenamates and hippocampal neuron GABA(A) receptors.

Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons.

A short history of the rise of the molecular pharmacology of ionotropic drug receptors.

Remarkably, perhaps, for many pharmacologists today, just over 25 years ago, receptors were still considered hypothetical entities. The isolation and identification of Langley's receptive substance (Ehrlich's side-chains) required efforts from diverse groups; serendipity also facilitated its purification and subsequent biochemical and molecular characterization. In this review, I consider some of the key individuals and breakthrough technical developments from the late 1950s to the early 1990s that lead to the cloning of the first receptors.

An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons.

Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE.

Modifying quinolone antibiotics yields new anxiolytics.

Patients taking fluoroquinolone antibiotics such as norfloxacin exhibit a low incidence of convulsions and anxiety. These side effects probably result from antagonism of the neurotransmitter gamma-aminobutyric acid (GABA) at the brain GABA(A) receptor complex (GRC). Modification of norfloxacin yields molecules such as compound 4 that potentiate GABA action with alpha(2) subunit selectivity.

The emergence of the drug receptor theory.

Today, the concept of specific receptors for drugs and transmitters lies at the very heart of pharmacology. Less than one hundred years ago, this novel idea met with considerable resistance in the scientific community. To mark the 150th anniversary of the birth of John Newport Langley, one of the founders of the receptor concept, we highlight his most important observations, and those of Paul Ehrlich and Alfred Joseph Clark, who similarly helped to establish the receptor theory of drug action.