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 GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke

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. Our multi-electrode array (MEA) recordings clearly showed neurons generated spontaneous, spike-like activity within 2 days of plating, which peaked at one week, and rapidly decreased over the second week to remain at low levels up to one month. Extracellularly recorded spikes were reversibly inhibited by tetrodotoxin. Patch-clamp experiments showed that iCell neurons generated spontaneous action potentials and expressed voltage-gated Na and K channels with membrane capacitances, resistances and membrane potentials that are consistent with native neurons. Our single neuron recordings revealed that reduced spiking observed in the MEA after the first week results from development of a dominant inhibitory tone from GABAergic neuron circuit maturation. GABA evoked concentration-dependent currents that were inhibited by the convulsants, bicuculline and picrotoxin, and potentiated by the positive allosteric modulators, diazepam, chlordiazepoxide, phenobarbital, allopregnanolone and mefenamic acid, consistent with native neuronal GABAA receptors. We also show that glycine evoked robust concentration-dependent currents that were inhibited by the neurotoxin, strychnine. Glutamate, AMPA, Kainate and NMDA each evoked concentration-dependent currents in iCell neurons that were blocked by their selective antagonists, consistent with the expression of ionotropic glutamate receptors. The NMDA currents required the presence of the co-agonist glycine and were blocked in a highly voltage-dependent manner by Mg2+ consistent with the properties of native neuronal NMDA receptors. Together, our data suggest that such human iPSC-derived neurons may have significant value in drug discovery and development and may eventually largely replace the need for animal tissues in human biomedical research

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 GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke

A time-dependent perturbative analysis for a quantum particle in a cloud chamber

We consider a simple model of a cloud chamber consisting of a test particle (the alpha-particle) interacting with two other particles (the atoms of the vapour) subject to attractive potentials centered in $a_1, a_2 \in \mathbb{R}^3$. At time zero the alpha-particle is described by an outgoing spherical wave centered in the origin and the atoms are in their ground state. We show that, under suitable assumptions on the physical parameters of the system and up to second order in perturbation theory, the probability that both atoms are ionized is negligible unless $a_2$ lies on the line joining the origin with $a_1$. The work is a fully time-dependent version of the original analysis proposed by Mott in 1929.Comment: 23 page

Winter 1970

A Closer Look at Watering by Holman M. Griffin (page 3) Sulphur in Turfgrass Fertilization by J.D. Beaton (5) Those Extras on a Golf Course by Jack Fairhurst (9) Turf Bulletin\u27s Photo Quiz by Fred Cheney (9) Progress in Research on Live Oak Decline by E.P. Van Arsdel and Robert S. Halliwell (10) Editorial (15) The Perfermance Characteristics of Kentucky Bluegrass Mixtures by F.V. Juska and A.A. Hanson (16) Moss (23

CODE-1 : moored array and large-scale data report

The Coastal Ocean Dynamics Experiment (CODE) was undertaken to identify and study the important dynamical processes which govern the wind-driven motion of coastal water over the continental shelf. The initial effort in this multi-year, multi-institutional research program was to obtain high-quality data sets of all the relevant physical variables needed to construct accurate kinematic and dynamic descriptions of the response of shelf water to strong wind forcing in the 2 to 10 day band. A series of two small-scale, densely-instrumented field experiments of approximately four months duration (called CODE-1 and CODE-2) were designed to explore and to determine the kinematics and momentum and heat balances of the local wind-driven flow over a region of the northern California shelf which is characterized by both relatively simple bottom topography and large wind stress events in both winter and summer. A more lightly instrumented, long-term, large-scale component was designed to help separate the local wind-driven response in the region of the small-scale experiments from motions generated either offshore by the California Current system or in some distant region along the coast, and also to help determine the seasonal cycles of the atmospheric forcing, water structure, and coastal currents over the northern California shelf. The first small-scale experiment (CODE-1) was conducted between April and August, 1981 as a pilot study in which primary emphasis was placed on characterizing the wind-driven "signal" and the "noise" from which this signal must be extracted. In particular, CODE-1 was designed to identify the key features of the circulation and its variability over the northern California shelf and to determine the important time and length scales of the wind-driven response. This report presents a basic description of the moored array data and some other Eulerian data collected during CODE-1. A brief description of the CODE-1 field program is presented first, followed by a description of the common data analysis procedures used to produce the various data sets presented here. Then basic descriptions of the following data sets are presented: (a) the coastal and moored meteorological measurements, (b) the moored current measurements, (c) the moored temperature and conductivity observations, (d) the bottom pressure measurements, and (e) the wind and adjusted coastal sea level observations obtained as part of the CODE-1 large-scale component.Prepared for the National Science Foundation under Grant OCE 80-14941

CODE-2 : moored array and large-scale data report

The Coastal Ocean Dynamics Experiment (CODE) was undertaken to identify and study the important dynamical processes which govern the wind-driven motion of coastal water over the continental shelf. The initial effort in this multi-year, multi-institutional research program was to obtain high-quality data sets of all the relevant physical variables needed to construct accurate kinematic and dynamic descriptions of the response of shelf water to strong wind forcing in the 2 to 10 day band. A series of two small-scale, densely- instrumented field experiments of approximately four months duration (called CODE-1 and CODE-2) were designed to explore and to determine the kinematics and momentum and heat balances of the local wind-driven flow over a region of the northern California shelf which is characterized by both relatively simple bottom topography and large wind stress events in both winter and summer. A more lightly instrumented, long -term, large-scale component was designed to help separate the local wind-driven response in the region of the small-scale experiments from motions generated either offshore by the California Current system or in some distant region along the coast, and also to help determine the seasonal cycles of the atmospheric forcing, water structure, and coastal currents over the northern California shelf. The first small-scale experiment (CODE-1) was conducted between April and August, 1981 as a pilot study in "which primary emphasis was placed on characterizing the wind-driven "signal" and the "noise" from which this signal must be extracted. In particular, CODE-1 was designed to identify the key features of the circulation and its variability over the northern California shelf and to determine the important time and length scales of the wind-driven response. The second small-scale experiment (CODE-2) was conducted between April and August, 1982 and was designed to sample more carefully the mesoscale horizonta1 variability observed in CODE-1. This report presents a basic description of the moored array data and some other Eulerian data collected during CODE-2. A brief description of the CODE-2 field program is presented first, followed by a description of the common data analysis procedures used to produce the various data sets presented here. Then basic descriptions of the following data sets are presented: (a) the coastal and moored meteorological measurements, (b) the moored current measurements, (c) array plots of the surface wind stress and near-surface current measurements, (d) the moored temperature and conductivity observations, (e) the bottom pressure measurements, and (f) the wind and adjusted coastal sea level observations obtained as part of the CODE-2 large-scale component.This work has been supported by the National Science Foundation

Spontaneous decompactification

Positive vacuum energy together with extra dimensions of space imply that our four-dimensional Universe is unstable, generically to decompactification of the extra dimensions. Either quantum tunneling or thermal fluctuations carry one past a barrier into the decompactifying regime. We give an overview of this process, and examine the subsequent expansion into the higher- dimensional geometry. This is governed by certain fixed-point solutions of the evolution equations, which are studied for both positive and negative spatial curvature. In the case where there is a higher-dimensional cosmological constant, we also outline a possible mechanism for compactification to a four-dimensional de Sitter cosmology.Comment: 27 pages, 5 figures, harvmac. v2: refs added, minor notation change

Applications of a New Proposal for Solving the "Problem of Time" to Some Simple Quantum Cosmological Models

We apply a recent proposal for defining states and observables in quantum gravity to simple models. First, we consider a Klein-Gordon particle in an ex- ternal potential in Minkowski space and compare our proposal to the theory ob- tained by deparametrizing with respect to a time slicing prior to quantiza- tion. We show explicitly that the dynamics of the deparametrization approach depends on the time slicing. Our proposal yields a dynamics independent of the choice of time slicing at intermediate times but after the potential is turned off, the dynamics does not return to the free particle dynamics. Next we apply our proposal to the closed Robertson-Walker quantum cosmology with a massless scalar field with the size of the universe as our time variable, so the only dynamical variable is the scalar field. We show that the resulting theory has the semi-classical behavior up to the classical turning point from expansion to contraction, i.e., given a classical solution which expands for much longer than the Planck time, there is a quantum state whose dynamical evolution closely approximates this classical solution during the expansion. However, when the "time" gets larger than the classical maximum, the scalar field be- comes "frozen" at its value at the maximum expansion. We also obtain similar results in the Taub model. In an Appendix we derive the form of the Wheeler- DeWitt equation for the Bianchi models by performing a proper quantum reduc- tion of the momentum constraints; this equation differs from the usual one ob- tained by solving the momentum constraints classically, prior to quantization.Comment: 30 pages, LaTeX 3 figures (postscript file or hard copy) available upon request, BUTP-94/1