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 t he regulation of seizures and neural degeneration. We examined the effects of TRH and its stable analogue, RGH-2202, on the kainate-induced seizures a nd excitotoxicity in mice - a model of a drug-resistant temporal lobe epile psy. We found that TRH (2.0 and 5.0 mg/kg) and RGH-2202 (2.5 and 5 mg/kg) e levated the ED50 for kainate-induced convulsions and tended to decrease mor tality. A histological analysis showed that kainate caused a neuronal loss of CA, and CA, 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 muM) and RGH-2202 (100 muM) signif icantly attenuated the kainate (150 muM)-induced lactate dehydrogenase rele ase 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 vitr o. These results support the hypothesis of a potential utility of TRH and i ts analogues in the treatment of seizures and some neurodegenerative diseas es. (C) 2001 Elsevier Science B.V. All rights reserved.