Do Young Kim1, Fang-Xiong Zhang2,3, Stan T Nakanishi4, Timothy Mettler1, Ik-Hyun Cho1, Younghee Ahn5,6, Florian Hiess2,7, Lina Chen2, Patrick G Sullivan8, S R Wayne Chen2,7, Gerald W Zamponi2,3, Jong M Rho2,3,5,6,9. 1. Departments of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, U.S.A. 2. Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. 3. Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. 4. Department of Biology, University of Hawaii at Hilo, Hilo, Hawaii, U.S.A. 5. Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada. 6. Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada. 7. Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 8. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky, U.S.A. 9. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Abstract
OBJECTIVES: Carisbamate (CRS) is a novel monocarbamate compound that possesses antiseizure and neuroprotective properties. However, the mechanisms underlying these actions remain unclear. Here, we tested both direct and indirect effects of CRS on several cellular systems that regulate intracellular calcium concentration [Ca2+ ]i . METHODS: We used a combination of cellular electrophysiologic techniques, as well as cell viability, Store Overload-Induced Calcium Release (SOICR), and mitochondrial functional assays to determine whether CRS might affect [Ca2+ ]i levels through actions on the endoplasmic reticulum (ER), mitochondria, and/or T-type voltage-gated Ca2+ channels. RESULTS: In CA3 pyramidal neurons, kainic acid induced significant elevations in [Ca2+ ]i and long-lasting neuronal hyperexcitability, both of which were reversed in a dose-dependent manner by CRS. Similarly, CRS suppressed spontaneous rhythmic epileptiform activity in hippocampal slices exposed to zero-Mg2+ or 4-aminopyridine. Treatment with CRS also protected murine hippocampal HT-22 cells against excitotoxic injury with glutamate, and this was accompanied by a reduction in [Ca2+ ]i . Neither kainic acid nor CRS alone altered the mitochondrial membrane potential (ΔΨ) in intact, acutely isolated mitochondria. In addition, CRS did not affect mitochondrial respiratory chain activity, Ca2+ -induced mitochondrial permeability transition, and Ca2+ release from the ER. However, CRS significantly decreased Ca2+ flux in human embryonic kidney tsA-201 cells transfected with Cav 3.1 (voltage-dependent T-type Ca2+ ) channels. SIGNIFICANCE: Our data indicate that the neuroprotective and antiseizure activity of CRS likely results in part from decreased [Ca2+ ]i accumulation through blockade of T-type Ca2+ channels. Wiley Periodicals, Inc.
OBJECTIVES:Carisbamate (CRS) is a novel monocarbamate compound that possesses antiseizure and neuroprotective properties. However, the mechanisms underlying these actions remain unclear. Here, we tested both direct and indirect effects of CRS on several cellular systems that regulate intracellular calcium concentration [Ca2+ ]i . METHODS: We used a combination of cellular electrophysiologic techniques, as well as cell viability, Store Overload-Induced Calcium Release (SOICR), and mitochondrial functional assays to determine whether CRS might affect [Ca2+ ]i levels through actions on the endoplasmic reticulum (ER), mitochondria, and/or T-type voltage-gated Ca2+ channels. RESULTS: In CA3 pyramidal neurons, kainic acid induced significant elevations in [Ca2+ ]i and long-lasting neuronal hyperexcitability, both of which were reversed in a dose-dependent manner by CRS. Similarly, CRS suppressed spontaneous rhythmic epileptiform activity in hippocampal slices exposed to zero-Mg2+ or 4-aminopyridine. Treatment with CRS also protected murine hippocampal HT-22 cells against excitotoxic injury with glutamate, and this was accompanied by a reduction in [Ca2+ ]i . Neither kainic acid nor CRS alone altered the mitochondrial membrane potential (ΔΨ) in intact, acutely isolated mitochondria. In addition, CRS did not affect mitochondrial respiratory chain activity, Ca2+ -induced mitochondrial permeability transition, and Ca2+ release from the ER. However, CRS significantly decreased Ca2+ flux in humanembryonic kidney tsA-201 cells transfected with Cav 3.1 (voltage-dependent T-type Ca2+ ) channels. SIGNIFICANCE: Our data indicate that the neuroprotective and antiseizure activity of CRS likely results in part from decreased [Ca2+ ]i accumulation through blockade of T-type Ca2+ channels. Wiley Periodicals, Inc.
Authors: Meir Bialer; Svein I Johannessen; René H Levy; Emilio Perucca; Torbjörn Tomson; H Steve White Journal: Epilepsy Res Date: 2010-12 Impact factor: 3.045
Authors: Wenqian Chen; Ruiwu Wang; Biyi Chen; Xiaowei Zhong; Huihui Kong; Yunlong Bai; Qiang Zhou; Cuihong Xie; Jingqun Zhang; Ang Guo; Xixi Tian; Peter P Jones; Megan L O'Mara; Yingjie Liu; Tao Mi; Lin Zhang; Jeff Bolstad; Lisa Semeniuk; Hongqiang Cheng; Jianlin Zhang; Ju Chen; D Peter Tieleman; Anne M Gillis; Henry J Duff; Michael Fill; Long-Sheng Song; S R Wayne Chen Journal: Nat Med Date: 2014-01-19 Impact factor: 53.440