title: Proconvulsant actions of intrahippocampal botulinum neurotoxin B in the rat.
abstract: Botulinum neurotoxins (BoNTs) may affect the excitability of brain circuits by inhibiting neurotransmitter release at central synapses. There is evidence that local delivery of BoNT serotypes A and E, which target SNAP-25, a component of the release machinery specific to excitatory synapses, can inhibit seizure generation. BoNT serotype B (BoNT/B) targets VAMP2, which is expressed in both excitatory and inhibitory terminals. Here we assessed the effects of unilateral intrahippocampal infusion of BoNT/B in the rat on intravenous pentylenetetrazol (PTZ) seizure thresholds, and on the expression of spontaneous behavioral and electrographic seizures. Infusion of BoNT/B (500 and 1,000 unit) by convection-enhanced delivery caused a reduction in myoclonic twitch and clonic seizure thresholds in response to intravenous PTZ beginning about 6 days after the infusion. Handling-evoked and spontaneous convulsive seizures were observed in many BoNT/B-treated animals but not in vehicle-treated controls. Spontaneous electrographic seizure discharges were recorded in the dentate gyrus of animals that received local BoNT/B infusion. In addition, there was an increased frequency of interictal epileptiform spikes and sharp waves at the same recording site. BoNT/B-treated animals also exhibited tactile hyperresponsivity in comparison with vehicle-treated controls. This is the first demonstration that BoNT/B causes a delayed proconvulsant action when infused into the hippocampus. Local infusion of BoNT/B could be useful as a focal epilepsy model.
authors.affiliation: Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bröer
authors.forename: D
authors.initials: D
authors.lastname: Zolkowska
authors.forename: M
authors.initials: M
authors.lastname: Gernert
authors.forename: M A
authors.initials: MA
authors.lastname: Rogawski
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000008:administration & dosage / Q000009:adverse effects*; D019274:Botulinum Toxins, Type A; D018481:Convection; D003292:Convulsants / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*
chemical_list: D003292:Convulsants; C096323:rimabotulinumtoxinB; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; D010433:Pentylenetetrazole
keywords: ANOVA; BoNT; CED; EEG; PEEK; PTZ; SNAP-25; U; VAMP2; analysis of variance; botulinum neurotoxin; convection-enhanced delivery; electroencephalogram; epilepsy; hippocampus; pentylenetetrazol; polyaryletheretherketone; seizure; synaptosomal-associated protein of 25 kDa; unit; vesicle-associated membrane protein 2
references.citation: J Pharmacokinet Pharmacodyn. 2008 Jun;35(3):251-67
references.pmid: 18551355
references.citation: J Biol Chem. 1992 Oct 25;267(30):21338-43
references.pmid: 1356988
references.citation: Annu Rev Microbiol. 1999;53:551-75
references.pmid: 10547701
references.citation: J Pharmacol Methods. 1985 Apr;13(2):135-46
references.pmid: 3920448
references.citation: J Neurosci Methods. 2010 Mar 15;187(1):46-51
references.pmid: 20026357
references.citation: J Pharmacol Exp Ther. 2013 Sep;346(3):528-34
references.pmid: 23772062
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1981 Jun;316(3):244-51
references.pmid: 6114440
references.citation: Brain Res. 1997 Mar 28;752(1-2):197-202
references.pmid: 9106457
references.citation: Hippocampus. 2000;10(3):305-24
references.pmid: 10902900
references.citation: J Neurosci. 2005 Feb 23;25(8):1943-51
references.pmid: 15728834
references.citation: Neuropharmacology. 1991 Jul;30(7):797-802
references.pmid: 1681451
references.citation: Neuropharmacology. 2011 Feb-Mar;60(2-3):505-12
references.pmid: 21075125
references.citation: Neurotoxicology. 2012 Jan;33(1):127-37
references.pmid: 22209701
references.citation: Neuropharmacology. 1982 Sep;21(9):851-5
references.pmid: 7145039
references.citation: Neurotherapeutics. 2009 Apr;6(2):344-51
references.pmid: 19332329
references.citation: Curr Neurol Neurosci Rep. 2007 Jul;7(4):348-54
references.pmid: 17618543
references.citation: Neuroscience. 2007 Jun 8;146(4):1829-40
references.pmid: 17445987
references.citation: Toxicon. 1986;24(11-12):1065-74
references.pmid: 3564058
references.citation: Biochemistry. 2004 Jan 20;43(2):526-32
references.pmid: 14717608
references.citation: BMC Neurosci. 2011 Nov 17;12:118
references.pmid: 22094010
references.citation: Toxicon. 2009 Oct;54(5):593-9
references.pmid: 19264088
references.citation: Muscle Nerve Suppl. 1997;6:S146-68
references.pmid: 9826987
references.citation: Epilepsy Res. 2009 Aug;85(2-3):142-9
references.pmid: 19362806
references.citation: J Neurochem. 2006 Jun;97(6):1534-45
references.pmid: 16805767
references.citation: Traffic. 2007 Feb;8(2):142-53
references.pmid: 17241445
references.citation: Neuron. 2004 Feb 19;41(4):599-610
references.pmid: 14980208
references.citation: Toxicon. 1995 Apr;33(4):551-7
references.pmid: 7570640
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: Epilepsia. 2009 Apr;50(4):963-6
references.pmid: 19175393
references.citation: Behav Neural Biol. 1993 Jul;60(1):1-4
references.pmid: 8216155
references.citation: J Neurol Neurosurg Psychiatry. 1977 Apr;40(4):404-14
references.pmid: 874516
references.citation: Fundam Appl Toxicol. 1988 Aug;11(2):189-206
references.pmid: 3146518
references.citation: Epilepsy Res. 2013 Feb;103(2-3):135-52
references.pmid: 23196211
references.citation: J Neurophysiol. 1987 Jan;57(1):121-31
references.pmid: 3031230
references.citation: Epilepsy Res. 1996 Dec;26(1):59-66
references.pmid: 8985687
references.citation: J Neurochem. 1988 Jun;50(6):1808-16
references.pmid: 2897427
references.citation: Epilepsia. 1998 Nov;39(11):1148-57
references.pmid: 9821978
references.citation: J Neurosci. 1997 Oct 1;17(19):7190-202
references.pmid: 9295365
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:167-93
references.pmid: 14744243
references.citation: Biochimie. 2000 May;82(5):427-46
references.pmid: 10865130
references.citation: Neuroscience. 2009 Jan 12;158(1):223-30
references.pmid: 18514426
references.citation: J Neurosci Methods. 1996 Aug;67(2):113-20
references.pmid: 8872876
references.citation: Hippocampus. 1991 Oct;1(4):381-90
references.pmid: 1669317
references.citation: J Comp Neurol. 2008 Jan 20;506(3):373-86
references.pmid: 18041776
references.citation: Eur J Pharmacol. 2009 May 21;610(1-3):1-11
references.pmid: 19292981
references.citation: Neuroscience. 1999;92(1):73-82
references.pmid: 10392831
references.citation: Neuroscience. 2010 Feb 3;165(3):934-43
references.pmid: 19909789
references.citation: J Neurosci. 2004 Sep 8;24(36):7829-36
references.pmid: 15356194
references.citation: Neurobiol Dis. 2012 May;46(2):362-76
references.pmid: 22342648