An analogue of thyrotropin-releasing hormone improves outcome after brain injury: 31P-NMR studies

Abstract

The effects of a long-acting, centrally active thyrotropin-releasing hormone (TRH) analogue, CG3703, on neurological outcome, survival, and intracellular metabolism were evaluated after experimental fluid-percussion (FP) brain injury (2.0-2.4 atm) in the rat. In control (saline-treated) animals, FP brain injury caused a fall in mean arterial pressure (MAP) and resulted in a 58% mortality rate. Surviving control animals showed a pronounced neurological deficit over the following 4-wk period. Administration of CG3703 at 30 min posttrauma significantly increased MAP (mean increase, 21 mmHg). All animals treated with CG3703 survived and demonstrated significantly improved chronic neurological scores compared with saline-treated controls. In a subpopulation of injured animals, phosphorus magnetic resonance spectroscopy (31P-MRS) was used to evaluate changes in brain intracellular metabolism after trauma in control and CG3703-treated animals. A fall in phosphocreatine-to-inorganic phosphate ratio (PCr/Pi) was observed in all animals after FP injury. The PCr/Pi ratio failed to recover in saline controls but demonstrated significant recovery in CG3703-treated animals. Furthermore, an increased phosphomonoester peak was observed after CG3703 but not after saline administration. These results suggest that the centrally active TRH analogue CG3703 can improve neurological outcome and survival after brain injury, perhaps through direct effects on cerebral metabolism.