Topiramate Blocks Kainate-Evoked Cobalt Influx into Cultured Neurons

Authors

  • Shana Skradski,

    1. Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City, Utah, U.S.A.
    Search for more papers by this author
  • H. Steve White

    Corresponding author
    1. Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City, Utah, U.S.A.
    Search for more papers by this author

Address correspondence and reprint requests to Dr. H. S. White at Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, College of Pharmacy, Salt Lake City, UT 84112, U.S.A.

Summary:

Purpose: This study evaluated topiramate (TPM) antagonism of glutamate receptors activated by kainate.

Methods: The ability of TPM (3–30 μM) to attenuate kainate (300 μM)-activated cobalt (Co2+) flux through nonselective cation channels permeable to Co2+, Mn2+, and Ca2+ into cultured cerebellar granule neurons [9–14 days in vitro (div)] was investigated. Results were compared with those obtained with the non-N-methyl-d-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxalone-2,3-dione (DNQX) (10 μM).

Results: Topiramate produced a concentration- and time-dependent inhibition of Co2+ uptake into cerebellar granule cells cultured 9–11 div. Inhibition was evident at 10 μM, and complete inhibition was observed at 30 μM. Maximal inhibition of Co2+ uptake required pretreatment with TPM for ges;30 minutes before stimulation by kainate. The effect of 30 μM TPM on Co2+ uptake was similar to that of 10 μM DNQX. However, TPM, unlike DNQX, did not affect kainate-evoked Co2+ uptake into older neurons (i.e., 13–14 div).

Conclusions: These results provide additional support for an antagonistic effect of TPM on some types of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and/or kainate receptors, and specifically suggest that TPM interacts with a Ca2+-permeable non-NMDA receptor that is develop-mentally regulated. This observation may provide insight into the molecular biology underlying the pathophysiology of seizure disorders and antiepileptic drug resistance.

Ancillary