Alberto E Musto1, Mark Samii. 1. Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, Louisiana 70112, USA. musto@lsuhsc.edu
Abstract
PURPOSE: Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation, participates in physiologic signaling in the brain. However, after seizures, PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility, and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models. METHODS: The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle, was administrated each day of kindling or daily during the 4 weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage, and inflammation in the hippocampi of both treated groups. KEY FINDINGS: LAU-0901 limits the progression of kindling and attenuates seizure susceptibility 1 week after the kindling procedure. In addition, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation. SIGNIFICANCE: Our results indicate that modulation of PAF overactivity attenuates seizure susceptibility, hippocampal hyperexcitability, and neuroinflammation. Wiley Periodicals, Inc.
PURPOSE:Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation, participates in physiologic signaling in the brain. However, after seizures, PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility, and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models. METHODS: The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle, was administrated each day of kindling or daily during the 4 weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage, and inflammation in the hippocampi of both treated groups. KEY FINDINGS:LAU-0901 limits the progression of kindling and attenuates seizure susceptibility 1 week after the kindling procedure. In addition, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation. SIGNIFICANCE: Our results indicate that modulation of PAF overactivity attenuates seizure susceptibility, hippocampal hyperexcitability, and neuroinflammation. Wiley Periodicals, Inc.
Authors: Ludmila Belayev; Larissa Khoutorova; Kristal Atkins; William C Gordon; Julio Alvarez-Builla; Nicolas G Bazan Journal: Exp Neurol Date: 2008-08-28 Impact factor: 5.330
Authors: Krista M Rodgers; Mark R Hutchinson; Alexis Northcutt; Steven F Maier; Linda R Watkins; Daniel S Barth Journal: Brain Date: 2009-06-30 Impact factor: 13.501
Authors: Giorgio A Ascoli; Lidia Alonso-Nanclares; Stewart A Anderson; German Barrionuevo; Ruth Benavides-Piccione; Andreas Burkhalter; György Buzsáki; Bruno Cauli; Javier Defelipe; Alfonso Fairén; Dirk Feldmeyer; Gord Fishell; Yves Fregnac; Tamas F Freund; Daniel Gardner; Esther P Gardner; Jesse H Goldberg; Moritz Helmstaedter; Shaul Hestrin; Fuyuki Karube; Zoltán F Kisvárday; Bertrand Lambolez; David A Lewis; Oscar Marin; Henry Markram; Alberto Muñoz; Adam Packer; Carl C H Petersen; Kathleen S Rockland; Jean Rossier; Bernardo Rudy; Peter Somogyi; Jochen F Staiger; Gabor Tamas; Alex M Thomson; Maria Toledo-Rodriguez; Yun Wang; David C West; Rafael Yuste Journal: Nat Rev Neurosci Date: 2008-07 Impact factor: 34.870
Authors: Denis E Bragin; Jennifer L Sanderson; Steven Peterson; John A Connor; Wolfgang S Müller Journal: Eur J Neurosci Date: 2009-08-10 Impact factor: 3.386
Authors: Yulong Liu; Lisa B E Shields; Zhongwen Gao; Yuanyi Wang; Yi Ping Zhang; Tianci Chu; Qingsan Zhu; Christopher B Shields; Jun Cai Journal: Mol Neurobiol Date: 2016-09-09 Impact factor: 5.590
Authors: Ludmila Belayev; Tiffany N Eady; Larissa Khoutorova; Kristal D Atkins; Andre Obenaus; Marta Cordoba; Juan J Vaquero; Julio Alvarez-Builla; Nicolas G Bazan Journal: Transl Stroke Res Date: 2011-10-27 Impact factor: 6.829