title: Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.
abstract: Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability.
authors.affiliation: Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, A.P. 70228, Ciudad Universitaria, 04510, Mexico, DF, Mexico. sitges@biomedicas.unam.mx.
authors.forename: Maria
authors.initials: M
authors.lastname: Sitges
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Blanca Irene
authors.initials: BI
authors.lastname: Aldana
authors.affiliation: Department of Pharmacy Practice, Husson University, One College Circle, Bangor, ME, 04401-2999, USA.
authors.forename: Ronald Charles
authors.initials: RC
authors.lastname: Reed
mesh_terms: D015761:4-Aminopyridine / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects* / Q000379:methods; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D020280:Sertraline / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014748:Vinca Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D000928:Antidepressive Agents; D014748:Vinca Alkaloids; C013983:vinpocetine; D015761:4-Aminopyridine; D020280:Sertraline
keywords: Carbamazepine; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenytoin; Topiramate; Valproic acid
references.citation: Life Sci. 1994;54(16):PL271-5
references.pmid: 8152336
references.citation: Epilepsy Res. 2003 Mar;53(3):245-54
references.pmid: 12694934
references.citation: Epilepsia. 2003 Nov;44(11):1375-9
references.pmid: 14636343
references.citation: BMJ. 2014 Feb 28;348:g254
references.pmid: 24583319
references.citation: Brain. 2008 Oct;131(Pt 10):2765-82
references.pmid: 18765418
references.citation: Int J Neuropsychopharmacol. 2002 Sep;5(3):229-37
references.pmid: 12366875
references.citation: J Neurochem. 2014 Sep;130(6):770-9
references.pmid: 24903676
references.citation: Clin Neurophysiol. 2004 Dec;115(12):2711-7
references.pmid: 15546779
references.citation: FASEB J. 2008 Mar;22(3):659-61
references.pmid: 17942826
references.citation: Nat Rev Neurol. 2012 Apr 17;8(5):252-3
references.pmid: 22508232
references.citation: CNS Drugs. 2002;16(10):669-94
references.pmid: 12269861
references.citation: Epilepsy Res. 2004 Jun;60(1):63-71
references.pmid: 15279871
references.citation: Clin Neurophysiol. 2008 Nov;119(11):2608-14
references.pmid: 18829385
references.citation: J Neurochem. 2012 Apr;121(2):197-205
references.pmid: 22288826
references.citation: Epilepsy Behav. 2012 Dec;25(4):511-6
references.pmid: 23153716
references.citation: J Neurochem. 1989 Dec;53(6):1693-9
references.pmid: 2553862
references.citation: Curr Treat Options Neurol. 2011 Aug;13(4):371-9
references.pmid: 21472437
references.citation: J Neurochem. 1991 Jun;56(6):1827-35
references.pmid: 1851203
references.citation: Neuropharmacology. 2007 Dec;53(7):854-62
references.pmid: 17904592
references.citation: Nature. 1977 Jun 23;267(5613):720-1
references.pmid: 195224
references.citation: Neurochem Res. 2004 Feb;29(2):347-55
references.pmid: 15002730
references.citation: Curr Opin Neurol. 2008 Apr;21(2):190-4
references.pmid: 18317279
references.citation: Int Clin Psychopharmacol. 2009 Mar;24(2):43-60
references.pmid: 21456103
references.citation: Neurochem Int. 2006 Jul;49(1):55-61
references.pmid: 16621162
references.citation: Epilepsy Behav. 2010 Oct;19(2):156-8
references.pmid: 20817613
references.citation: Epilepsy Res. 2011 Oct;96(3):257-66
references.pmid: 21737246
references.citation: Exp Neurol. 2012 Jan;233(1):22-32
references.pmid: 21684275
references.citation: Epilepsy Behav. 2003 Dec;4 Suppl 4:S26-30
references.pmid: 14654425
references.citation: Neuroreport. 1998 Jun 1;9(8):1849-53
references.pmid: 9665614
references.citation: Epilepsy Behav. 2012 Jun;24(2):156-68
references.pmid: 22632406
references.citation: Neurochem Res. 2005 Dec;30(12):1557-65
references.pmid: 16362775
references.citation: Drugs Today (Barc). 2010 Apr;46(4):265-77
references.pmid: 20502724
references.citation: Neuropharmacology. 2007 Feb;52(2):598-605
references.pmid: 17070874
references.citation: Drug Metab Dispos. 1989 Sep-Oct;17(5):542-50
references.pmid: 2573498
references.citation: Prog Neurobiol. 1999 May;58(1):31-59
references.pmid: 10321796
references.citation: Neurochem Res. 1999 Dec;24(12):1585-91
references.pmid: 10591410
references.citation: Epilepsy Res. 1992 Mar;11(1):9-16
references.pmid: 1563341
references.citation: Neurosci Lett. 2006 Oct 9;406(3):276-80
references.pmid: 16930834
references.citation: Epilepsy Behav. 2012 Aug;24(4):426-9
references.pmid: 22683245
references.citation: Neurochem Int. 2005 Jun;46(7):533-40
references.pmid: 15843047
references.citation: Epilepsia. 2011 Aug;52(8):e75-8
references.pmid: 21692790