Abstract
Stroke is a major cause of neurologic morbidity in neonates and children. Because neonatal and pediatric stroke frequently present with seizures, the question of which anticonvulsant best blocks acute ischemic seizures and reduces injury is clinically relevant. The purpose of this study was to determine the extent to which gabapentin is neuroprotective and suppresses acute seizures in this model of ischemic injury in the immature brain. Postnatal day 12 CD1 mice underwent right common carotid artery ligation and immediately after ligation received a 0, 50, 100, 150, or 200 mg/kg dose of gabapentin intraperitoneally. Acute seizure activity was behaviorally scored and hemispheric brain atrophy measured. In vehicle-treated mice, severity of acute seizures correlated with hemispheric brain atrophy 4 wks later. Gabapentin significantly decreased acute seizures at 200 mg/kg and reduced brain atrophy at doses of 150 and 200 mg/kg but not at lower doses. These results suggest that gabapentin effectively reduces acute seizures and injury after ischemia in the immature brain. When analyzed by animal sex, the data suggest that gabapentin may more effectively reduce acute seizures and injury in male pups vs. female pups.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- P12:
-
postnatal day 12
References
Lynch JK, Nelson KB 2001 Epidemiology of perinatal stroke. Curr Opin Pediatr 13: 499–505
Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R 1995 Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features fromto 1993 to 1985. J Clin Epidemiol 48: 1343–1348
Schoenberg BS 1979 Risk factors for stroke in infants and children. Adv Neurol 25: 313–324
Comi AM, Weisz CJ, Highet BH, Johnston MV, Wilson MA 2004 A new model of stroke and ischemic seizures in the immature mouse. Pediatr Neurol 31: 254–257
Comi AM, Johnston MV, Wilson MA 2005 Strain variability, injury distribution and seizure onset in a mouse model of stroke in the immature brain. Dev Neurosci 27: 127–133
Comi AM, Highet BH, Mehta P, Hana CT, Johnston MV, Wilson MA 2006 Dextromethorphan protects male but not female mice with brain ischemia. Neuroreport 17: 1319–1322
Koelfen W, Freund M, Varnholt V 1995 Neonatal stroke involving the middle cerebral artery in term infants: clinical presentation, EEG and imaging studies, and outcome. Dev Med Child Neurol 37: 204–212
Delsing BJ, Catsman-Berrevoets CE, Appel IM 2001 Early prognostic indicators of outcome in ischemic childhood stroke. Pediatr Neurol 24: 283–289
Johnston MV, Hoon AH Jr 2000 Possible mechanisms in infants for selective basal ganglia damage from asphyxia, kernicterus, or mitochondrial encephalopathies. J Child Neurol 15: 588–591
Downen M, Belkowski S, Knowles H, Cardillo M, Prystowsky MB 1999 Developmental expression of voltage-gated potassium channel beta subunits. Brain Res Dev Brain Res 117: 71–80
Jensen FE 2002 The role of glutamate receptor maturation in perinatal seizures and brain injury. Int J Dev Neurosci 20: 339–347
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH 1994 Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12: 529–540
Rice JE III Vannucci RC, Brierley JB 1981 The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9: 131–141
Comi AM 2005 Neuroprotection for Ischemic injury in the immature brain. Curr Pediatr Rev 1: 135–145
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ 2005 Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365: 663–670
Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA 1996 Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci 16: 1337–1345
Calabresi P, Cupini LM, Centonze D, Pisani F, Bernardi G 2003 Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia. Ann Neurol 53: 693–702
Wasterlain CG, Adams LM, Hattori H, Schwartz PH 1992 Felbamate reduces hypoxic-ischemic brain damage in vivo. Eur J Pharmacol 212: 275–278
Wasterlain CG, Adams LM, Schwartz PH, Hattori H, Sofia RD, Wichmann JK 1993 Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia-ischemia. Neurology 43: 2303–2310
Hayakawa T, Hamada Y, Maihara T, Hattori H, Mikawa H 1994 Phenytoin reduces neonatal hypoxic-ischemic brain damage in rats. Life Sci 54: 387–392
Lampley EC Jr Mishra OP, Graham E, Delivoria-Papadopoulos M 1995 Neuroprotective effect of phenytoin against in utero hypoxic brain injury in fetal guinea pigs. Neurosci Lett 186: 192–196
Hayakawa T, Higuchi Y, Nigami H, Hattori H 1994 Zonisamide reduces hypoxic-ischemic brain damage in neonatal rats irrespective of its anticonvulsive effect. Eur J Pharmacol 257: 131–136
Papazisis G, Kallaras K, Kaiki-Astara A, Pourzitaki C, Tzachanis D, Dagklis T, Kouvelas D 2007 Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy. Int J Neuropsychopharmacol 1–9
Liu Y, Qin N, Reitz T, Wang Y, Flores CM 2006 Inhibition of the rat brain sodium channel Nav1.2 after prolonged exposure to gabapentin. Epilepsy Res 70: 263–268
Bertrand S, Nouel D, Morin F, Nagy F, Lacaille JC 2003 Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells. Synapse 50: 95–109
Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC 2007 Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci 28: 220–228
Bucay AH 2007 Use of gabapentin during pregnancy to reduce brain damage in new-born infants that are premature or at risk of perinatal asphyxia. Med Hypotheses 68: 1422
Johnston MV, Hagberg H 2007 Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol 49: 74–78
Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, Hagberg H 2006 Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J Neurochem 96: 1016–1027
Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RS 2004 Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem 279: 38563–38570
Renolleau S, Fau S, Goyenvalle C, Joly LM, Chauvier D, Jacotot E, Mariani J, Charriaut-Marlangue C 2007 Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender. J Neurochem 100: 1062–1071
Bowles DK 2001 Gender influences coronary L-type Ca(2+) current and adaptation to exercise training in miniature swine. J Appl Physiol 91: 2503–2510
Bowles DK, Maddali KK, Ganjam VK, Rubin LJ, Tharp DL, Turk JR, Heaps CL 2004 Endogenous testosterone increases L-type Ca2+ channel expression in porcine coronary smooth muscle. Am J Physiol Heart Circ Physiol 287: H2091–H2098
Hall J, Jones TH, Channer KS, Jones RD 2006 Mechanisms of agonist-induced constriction in isolated human mesenteric arteries. Vascul Pharmacol 44: 427–433
Boyd RA, Turck D, Abel RB, Sedman AJ, Bockbrader HN 1999 Effects of age and gender on single-dose pharmacokinetics of gabapentin. Epilepsia 40: 474–479
Radulovic LL, Turck D, von Hodenberg A, Vollmer KO, McNally WP, DeHart PD, Hanson BJ, Bockbrader HN, Chang T 1995 Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab Dispos 23: 441–448
Acknowledgements
The authors thank Andrew Hooper for his technical assistance and Lisa Ferenc for editing this manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was supported by grants from the Howard Hughes Summer Undergraduate Research Fellowship program, National Institutes of Health National Institute of Neurological Disorders and Stroke K02 NS052166, Hunter's Dream for a Cure Foundation; and NINDS grant NS028208.
Rights and permissions
About this article
Cite this article
Traa, B., Mulholland, J., Kadam, S. et al. Gabapentin Neuroprotection and Seizure Suppression in Immature Mouse Brain Ischemia. Pediatr Res 64, 81–85 (2008). https://doi.org/10.1203/PDR.0b013e318174e70e
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e318174e70e
This article is cited by
-
Cenobamate: Neuroprotective Potential of a New Antiepileptic Drug
Neurochemical Research (2021)
-
Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy
Journal of Neuroinflammation (2015)
-
Gabapentin reduces infarct volume but does not suppress peri-infarct depolarizations
Journal of Cerebral Blood Flow & Metabolism (2011)
-
Chemotherapy-induced peripheral neuropathy: clinical features, diagnosis, prevention and treatment strategies
Clinical and Translational Oncology (2010)
