Protective effects of TRH and its stable analogue, RGH-2202, on kainate-induced seizures and neurotoxicity in rodents.
Thyrotropin-releasing hormone (TRH) has been postulated to be involved in the regulation of seizures and neural degeneration. We examined the effects of TRH and its stable analogue, RGH-2202, on the kainate-induced seizures and excitotoxicity in mice - a model of a drug-resistant temporal lobe epilepsy. We found that TRH (2.0 and 5.0 mg/kg) and RGH-2202 (2.5 and 5 mg/kg) elevated the ED(50) for kainate-induced convulsions and tended to decrease mortality. A histological analysis showed that kainate caused a neuronal loss of CA(1) and CA(3) hippocampal fields. TRH (10, 20 and 50 mg/kg) and RGH-2202 (2.5, 7.5 and 10.0 mg/kg) markedly reduced the excitotoxic effect of kainate. Further studies showed that TRH (1-100 microM) and RGH-2202 (100 microM) significantly attenuated the kainate (150 microM)-induced lactate dehydrogenase release in a primary cortical cell culture from rat embryos. In conclusion, the present study showed that TRH and RGH-2202 attenuated the kainate-induced seizures and inhibited the kainate-evoked neurotoxicity in vivo and in vitro. These results support the hypothesis of a potential utility of TRH and its analogues in the treatment of seizures and some neurodegenerative diseases.
Jaworska-Feil
L
L
Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St., 31-343, Kraków, Poland.
Kajta
M
M
Budziszewska
B
B
Leśkiewicz
M
M
Lasoń
W
W
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007608:Kainic Acid / Q000506:poisoning* / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D009498:Neurotoxins; D013973:Thyrotropin-Releasing Hormone; C055448:posatirelin; D007770:L-Lactate Dehydrogenase; D007608:Kainic Acid