Browsing by Author "Jin, X."

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    Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: Improved bioavailability enhances anticonvulsant efficacy
    (Elsevier, 2018-07) Witkin, Jeffrey M.; Smith, Jodi L.; Ping, X.; Gleason, S. D.; Poe, M. M.; Li, G.; Jin, X.; Hobbs, J.; Schkeryantz, J. M.; McDermott, J. S.; Alatorre, A. I.; Siemian, J. N.; Cramer, J. W.; Airey, D. C.; Methuku, K. R.; Tiruveedhula, V. V. N. P. B.; Jones, T. M.; Crawford, J.; Krambis, M. J.; Fisher, J. L.; Cook, J. M.; Cerne, R.; Neurological Surgery, School of Medicine
    HZ-166 has previously been characterized as an α2,3-selective GABAA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in all models in which they were evaluated. We further evaluated KRM-II-81 in human cortical epileptic tissue where it was found to significantly-attenuate picrotoxin- and AP-4-induced increases in firing rate across an electrode array. These molecules generally had a wider margin of separation in potencies to produce anticonvulsant effects vs. motor impairment on an inverted screen test than did diazepam. Ester bioisosters of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy acting via selective positive allosteric amplification of GABAA signaling through α2/α3-containing GABA receptors. The in vivo data from the present study can serve as a guide to dosing parameters that predict engagement of central GABAA receptors.
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    Magnetic-field-synchronized wireless modulation of neural activity by magnetoelectric nanoparticles
    (Elsevier, 2022) Zhang, E.; Abdel-Mottaleb, M.; Liang, P.; Navarrete, B.; Akin Yildirim, Y.; Alberteris Campos, M.; Smith, I. T.; Wang, P.; Yildirim, B.; Yang, L.; Chen, S.; Smith, I.; Lur, G.; Nguyen, T.; Jin, X.; Noga, B. R.; Ganzer, P.; Khizroev, S.; Anesthesia, School of Medicine
    The in vitro study demonstrates wirelessly controlled modulation of neural activity using magnetoelectric nanoparticles (MENPs), synchronized to magnetic field application with a sub-25-msec temporal response. Herein, MENPs are sub-30-nm CoFe2O4@BaTiO3 core-shell nanostructures. MENPs were added to E18 rat hippocampal cell cultures (0.5 μg of MENPs per 100,000 neurons) tagged with fluorescent Ca2+ sensitive indicator cal520. MENPs were shown to wirelessly induce calcium transients which were synchronized with application of 1200-Oe bipolar 25-msec magnetic pulses at a rate of 20 pulses/sec. The observed calcium transients were similar, in shape and magnitude, to those generated through the control electric field stimulation with a 50-μA current, and they were inhibited by the sodium channel blocker tetrodotoxin. The observed MENP-based magnetic excitation of neural activity is in agreement with the non-linear M - H hysteresis loop of the MENPs, wherein the MENPs' coercivity value sets the threshold for the externally applied magnetic field.