Topiramate protects against glutamate- and kainate-induced neurotoxicity in primary neuronal-astroglial cultures.
Potential neuroprotective effects of the antiepileptic drug (AED) topiramate (TPM) were evaluated using primary neuronal-astroglial cultures or astroglial-enriched cultures from newborn rats exposed to excitotoxic concentrations of glutamate (Glu) or kainate. Neurons expressed functional Glu receptors of the NMDA and AMPA/kainate types as evaluated by immunocytochemistry and Ca(2+) imaging. When Glu (10 mM) was added to 9-10-day cultures incubated with the fluorescent dye calcein/AM for 5h, there was a marked cell loss in both culture types, but was more pronounced in the neuronal-astroglial cultures. When TPM (5-10 microM) was included in the medium together with Glu, the amount of surviving cells was significantly higher in the neuronal-astroglial cultures, but not in the astroglial-enriched cultures. Immuno-labeling of the cultures revealed an enhanced survival of MAP positive neuronal cells when TPM was included in the Glu containing medium. As TPM has a proven negative modulatory effect on kainate activated receptors, neuronal-astroglial cultures were further exposed to excitotoxic concentrations of kainate (100 microM) and analyzed immunohistochemically. Significantly more MAP positive neurons survived in the TPM containing medium and showed a morphology similar to untreated cells. Valproate and phenytoin were used as reference AEDs. In conclusion, our results demonstrate a protective effect of TPM upon neuronal cells in primary culture, exposed to excitotoxic levels of Glu or kainate.
Institute of Clinical Neuroscience, Göteborg University, P.O. Box 420, SE-405 30, Göteborg, Sweden. mikael.angehagen@anatcell.gu.se
Mikael
M
Angehagen
Elinor
E
Ben-Menachem
Lars
L
Rönnbäck
Elisabeth
E
Hansson
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000096:biosynthesis; D000077236:Topiramate; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D002118:Calcium; D005632:Fructose; D018698:Glutamic Acid; D007608:Kainic Acid; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010672:Phenytoin; D018092:Kainic Acid Receptors; D000077236:Topiramate; D014635:Valproic Acid