Topiramate prevents excitotoxic damage in the newborn rodent brain.
Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) and S-bromowillardiine (acting on AMPA-kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Topiramate (TPM), already used in children to manage newly diagnosed and refractory epilepsy, has potential neuroprotective effects that may be useful in human perinatal brain lesions. In the excitotoxic newborn mouse model, TPM provided dose-dependent and long-lasting protection of developing white matter and cortical plate against S-bromowillardiine. TPM had no significant effect on ibotenate-induced brain lesions. TPM-induced neuroprotection potentially involved increased survival of pre-oligodendrocytes, decreased neuronal apoptosis, inhibition of microglial activation and astrogliosis, and decreased seizure activity. Diazepam, phenytoin, and carbamazepine had no neuroprotective effect in this model. The present study provides experimental support for the consideration of TPM as a candidate therapy for excitotoxic perinatal brain lesions.
Sfaello
Ignacio
I
INSERM U 676, Hôpital Robert Debré, 48 Boulevard Sérurier, F-75019 Paris, France.
Baud
Olivier
O
Arzimanoglou
Alexis
A
Gressens
Pierre
P
D000409:Alanine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D002547:Cerebral Palsy / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D007051:Ibotenic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077236:Topiramate; D016896:Treatment Outcome
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D000077236:Topiramate; C068592:5-bromowillardiine; D007051:Ibotenic Acid; D005632:Fructose; D018698:Glutamic Acid; D000409:Alanine