Abstract
Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control se...Continue Reading
References
Feb 11, 1994·Science·M ChalfieD C Prasher
Dec 10, 1996·Proceedings of the National Academy of Sciences of the United States of America·D LevitanI Greenwald
Jan 24, 1998·European Journal of Pharmacology·C Rundfeldt
Feb 27, 2001·Gene·L TimmonsA Fire
Dec 24, 2002·Neuron·Noelle D L'EtoileCornelia I Bargmann
Dec 24, 2002·Neuron·Manabi FujiwaraSteven L McIntire
Feb 26, 2003·Neurobiology of Aging·Christopher D LinkBarbara G Sahagan
Nov 11, 2005·Nature·Yun ZhangCornelia I Bargmann
Mar 21, 2006·Genetics·David M RaizenMeera V Sundaram
May 25, 2007·Learning & Memory·Karla R KaunMarla B Sokolowski
Jul 21, 2007·Proceedings of the National Academy of Sciences of the United States of America·Frederic MeryTadeusz J Kawecki
Jan 10, 2008·Proceedings of the National Academy of Sciences of the United States of America·Shusei HamamichiGuy A Caldwell
Jun 6, 2009·Aging Cell·Jeong-Hoon HahmYoung-Ki Paik
May 4, 2010·Nature Neuroscience·Jie LiuX Z Shawn Xu
Jun 29, 2010·The Journal of Experimental Biology·K Dawson-ScullyM B Sokolowski
Mar 24, 2011·Epilepsia·Wolfgang Löscher, Dieter Schmidt
Nov 10, 2011·Invertebrate Neuroscience : in·Fernando Calahorro, Manuel Ruiz-Rubio
Jan 1, 2010·Clinical Pharmacology : Advances and Applications·Vincenzo BarreseMaurizio Taglialatela
Nov 12, 1986·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·J G WhiteS Brenner
May 11, 2012·Neurology·M J BrodieP Kwan
Nov 9, 2012·Journal of Neurophysiology·Stacee Lee CaplanKen Dawson-Scully
Jul 23, 2013·PLoS Genetics·Michelle C KrzyzanowskiDenise M Ferkey
Dec 18, 2013·Epilepsia·Renzo GuerriniCarmen Barba
Mar 1, 2014·Korean journal of pediatrics·June-Bum Kim
Aug 22, 2014·Neuropsychiatric Disease and Treatment·Jerzy P SzaflarskiLaura E Dreer
Jan 28, 2015·Journal of Epilepsy Research·Sang Kun Lee
Jan 29, 2016·Journal of Epilepsy Research·L K FriedmanS S Ali
Sep 27, 2016·PloS One·Monica G RisleyKen Dawson-Scully
Apr 27, 2017·Cell Reports·Karla J OppermanBrock Grill