montirelin and Brain-Injuries

Hemorrhage after traumatic brain injury (TBI) in cats produces significant decreases in cerebral oxygen delivery (DcereO2) and electroencephalographic (EEG) activity. To determine whether effective treatments for the separate insults of TBI and hemorrhagic shock would also prove effective after the clinically relevant combination of the two, we measured the effects of a kappa-opiate antagonist (nalmefene), an inhibitor of lipid peroxidation (tirilazad), a thyrotropin-releasing hormone analog (CG3703), a clinically useful pressor agent (dopamine) or a saline placebo on cerebral blood flow (CBF), and EEG activity after TBI and mild hemorrhagic hypotension. Cats (n = 40, 8 per group) were anesthetized with 1.6% isoflurane in N2O:O2 (70:30) and prepared for fluid-percussion TBI and microsphere measurements of CBF. Cats were randomized to receive nalmefene (1 mg/kg), tirilazad (5 mg/kg), CG3703 (2 mg/kg), dopamine (20 microg x kg(-1) x min[-1]) or a saline placebo (2 ml, 0.9% NaCl). Animals were injured (2.2 atm), hemorrhaged to 70% of preinjury blood volume, treated as just described and resuscitated with a volume of 10% hydroxyethyl starch equal to shed blood. CBF was determined and EEG activity recorded before injury, after hemorrhage, and 0, 60, and 120 min after resuscitation (R0, R60, and R120). CBF increased significantly after resuscitation (R0) in the nalmefene- and CG3703-treated groups. CBF did not differ significantly from baseline in any group at R60 or R120. DcereO2 was significantly less than baseline in the saline-, dopamine-, and tirilazad-treated groups at R60 and in the dopamine-, tirilazad-, and CG3703-treated groups at R120. EEG activity remained unchanged in the nalmefene-treated group but deteriorated significantly at R60 or R120 compared to baseline in the other groups. Nalmefene and CG3703 preserved the hyperemic response to hemodilution (otherwise antagonized by TBI), and nalmefene prevented the deterioration in DcereO2 and EEG activity that occurs after TBI and hemorrhage.

Topics: Animals; Antioxidants; Blood Gas Analysis; Blood Pressure; Brain Injuries; Cats; Cerebral Hemorrhage; Cerebrovascular Circulation; Dopamine; Electroencephalography; Female; Hemoglobins; Male; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Oxygen Consumption; Pregnatrienes; Thyrotropin-Releasing Hormone

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.

Topics: Animals; Blood Pressure; Brain Injuries; Electroencephalography; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Rats; Thyrotropin-Releasing Hormone; Time Factors

Topics: Adenosine Triphosphate; Animals; Brain; Brain Injuries; Energy Metabolism; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Thyrotropin-Releasing Hormone

Treatment with thyrotropin-releasing hormone (TRH) analogs following traumatic injury to the central nervous system (CNS) improves neurological outcome through mechanisms that remain unclear. Previous studies have shown that traumatic brain injury is associated with a profound decline in intracellular free magnesium (Mgf) and in total tissue magnesium (Mgt), the extent of Mgf decline being linearly correlated to the severity of injury and resultant neurological deficit. We have used 31P magnetic resonance spectroscopy and atomic absorption spectrophotometry, respectively, to measure cerebral Mgf concentration and Mgf content in rats following fluid percussion brain trauma and treatment with the TRH analog, CG3703. Treatment at 30 min postinjury with CG3703 significantly improved Mgf when compared to saline-treated controls. There were no significant changes in Mgt, Na+, K+ or water content following CG3703 treatment. Since a decline in intracellular free magnesium may affect cellular bioenergetic status, calcium flux, activity of excitatory amino acids, opiate receptors, and the release of eicosanoids, these results suggest that the beneficial effects of treatment with TRH analogs after CNS trauma may be mediated through magnesium-dependent mechanisms.

Topics: Animals; Body Water; Brain; Brain Injuries; Homeostasis; Hydrogen-Ion Concentration; Magnesium; Magnetic Resonance Spectroscopy; Male; Potassium; Rats; Rats, Inbred Strains; Sodium; Spectrophotometry, Atomic; Thyrotropin-Releasing Hormone