title: Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.
abstract: Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.
authors.affiliation: Department of Pediatrics, Taipei Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan.|Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Shi-Bing
authors.initials: SB
authors.lastname: Wong
authors.affiliation: Neuroscience Program in Academia Sinica, Taipei, Taiwan.|Institute of Biomedical Sciences; Academia Sinica, Taipei, Taiwan.
authors.forename: Sin-Jhong
authors.initials: SJ
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Taipei Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan.
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wang-Tso
authors.initials: WT
authors.lastname: Lee
authors.affiliation: Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Min
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D008867:Microtomy; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D012640:Seizures / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D003470:Culture Media; D018696:Neuroprotective Agents; D047495:PPAR gamma; D016194:Receptors, N-Methyl-D-Aspartate; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D018698:Glutamic Acid; D008274:Magnesium