Imidazole-substituted analogues of TRH limit behavioral deficits after experimental brain trauma

Treatment with thyrotropin releasing hormone (TRH) or TRH analogues improves outcome after experimental brain or spinal cord trauma. TRH analogues with modifications at the N-terminal position of the tripeptide are effective, whereas analogues with modifications of the C-terminal residue are not. Imidazole-substituted TRH analogues, which modify the middle amino acid (histidine) of the tripeptide, have more recently been developed but have not been evaluated in models of central nervous system (CNS) trauma. In the present studies two imidazole-substituted analogues--4(5)-NO2(Im)TRH and 2,4 diiodo(Im)TRH--are shown to improve behavioral recovery following fluid percussion-induced traumatic brain injury (TBI) in rats. Because 4(5)-NO2(Im)TRH has little endocrine activity and 2,4 diiodo(Im)TRH has minimal cardiovascular effects, these experiments support the hypothesis that the neuroprotective actions of TRH analogues are independent of their endocrine or autonomic actions.