This Article Full Text Full Text (PDF) All Versions of this Article: 35/6/1460    most recent 01.STR.0000128029.50221.fav1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Silverstein, F. S. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Silverstein, F. S. Related Collections Animal models of human disease Behavioral Changes and Stroke Emergency treatment of Stroke Stroke in Children and the Young Neuroprotectors Other Stroke Treatment - Medical

(Stroke. 2004;35:1460.)
© 2004 American Heart Association, Inc.

Original Contributions

Topiramate Extends the Therapeutic Window for Hypothermia-Mediated Neuroprotection After Stroke in Neonatal Rats

From the Departments of Pediatrics and Neurology, University of Michigan, Ann Arbor, Mich.

Correspondence to Faye S. Silverstein, MD, 8301 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0646. E-mail fsilvers{at}med.umich.edu

Background and Purpose— Critical factors influencing the neuroprotective efficacy of postischemic hypothermia include depth, duration, and time of onset of cooling. In clinical practice, there is an unavoidable lag between the hypoxic-ischemic (HI) insult and the opportunity to initiate cooling. We hypothesized that early administration of a neuroprotective agent in combination with later-onset cooling could represent an effective therapeutic intervention after neonatal HI. We evaluated whether treatment with topiramate, a clinically available anticonvulsant, increased the efficacy of delayed post-HI hypothermia in a neonatal rat stroke model.

Methods— Postnatal day 7 (P7) rats underwent right carotid artery ligation followed by 1.5 hours of exposure to 8% oxygen. Fifteen minutes post-HI, animals received injections of topiramate (30 mg/kg) or PBS. Cooling was initiated 3 hours later ("delayed hypothermia") in all animals (3 hours, in 27°C incubator). Functional outcome (forepaw response to vibrissae stimulation) and pathology (morphometric lesion measurements) were evaluated at P15 and P35.

Results— Neither topiramate nor delayed hypothermia alone conferred protection in this protocol. Combined treatment with topiramate and delayed hypothermia improved both performance and pathological outcome in P15 and P35 rats compared with PBS-treated animals that underwent delayed hypothermia concurrently. At P15, functional measures were better in topiramate-treated animals (mean correct forepaw response 9.3/10 versus 4.8/10; P<0.001), and there was >50% reduction in tissue loss (P<0.001); trends were similar at P35.

Conclusions— Our data provide the impetus for further evaluation of therapeutic approaches that combine drug therapy with delayed-onset cooling after neonatal HI brain injury.

Key Words: cerebral ischemia • cooling • perinatal

This article has been cited by other articles:

				H. C. Glass and E. Wirrell Controversies in Neonatal Seizure Management J Child Neurol, May 1, 2009; 24(5): 591 - 599. [Abstract] [PDF]

				R. D. Sanders, D. Ma, P. Brooks, and M. Maze Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity Br. J. Anaesth., November 1, 2008; 101(5): 597 - 609. [Abstract] [Full Text] [PDF]

				J. Rennie and G. Boylan Treatment of neonatal seizures Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2007; 92(2): F148 - F150. [Abstract] [Full Text] [PDF]

				M. Derrick, A. Drobyshevsky, X. Ji, and S. Tan A Model of Cerebral Palsy From Fetal Hypoxia-Ischemia Stroke, February 1, 2007; 38(2): 731 - 735. [Abstract] [Full Text] [PDF]

				D. M. Ferriero Neonatal Brain Injury N. Engl. J. Med., November 4, 2004; 351(19): 1985 - 1995. [Full Text] [PDF]