Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets.
BACKGROUND
Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection.


METHODS
Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining).


RESULTS
There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals.


CONCLUSIONS
Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.
Schubert
Susanne
S
Department of Neuropediatrics, Children Hospital, Universitätsklinikum Jena, Friedrich Schiller University, Jena, Germany.
Brandl
Ulrich
U
Brodhun
Michael
M
Ulrich
Christiane
C
Spaltmann
Jens
J
Fiedler
Nico
N
Bauer
Reinhard
R
D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D034421:Sus scrofa; D000077236:Topiramate; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose