Effects of Nalmefene, CG3703, Tirilazad, or Dopamine on Cerebral Blood Flow, Oxygen Delivery, and Electroencephalographic Activity After Traumatic Brain Injury and Hemorrhage

Abstract

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.

Multifunctional Drugs for Head Injury

“…191 Early experimental studies demonstrating that TRH and the early TRH analogs, such as CG3703 and YM-14673, improve motor outcome 192 attributed some of this improvement to physiological and metabolic actions of the compounds, including improving magnesium status 193 or bioenergetic state, 193 and promoting recovery in cerebral blood flow following brain trauma. 194 However, physiological actions of these compounds, including autonomic, analeptic, and endocrine effects, were considered undesirable from a clinical point of view. Aside from their potential use in recovery from disturbances of consciousness, 195 they were accordingly not vigorously pursued as neuroprotectants.…”

Pathobiology of dynorphins in trauma and disease

“…Some of the effects of dynorphin which result in neural dysfunction in vivo can be attenuated by broad acting (MOR, DOR, and KOR) antagonists such as naloxone or selective KOR antagonists such as nor-binaltorphimine (21,40,42,(47)(48)(49)(50)(51)(52). Similarly, opioid antagonists are reported to be beneficial in experimental models of spinal cord injury (SCI) or traumatic brain injury (TBI) suggesting that endogenous dynorphins (or potentially other endogenous opioid peptides) are disrupted and contribute to secondary CNS injury (47,(53)(54)(55)(56)(57). The components of dynorphin-induced secondary injury or neuropathic pain attributable to opioid receptor activation are complex and somewhat more controversial than the nonopioid mediated neuropathologic effects of dynorphins.…”

“…Highlighting the complexity of these issues within the whole animal, rats receiving drugs with generally opposing effects, i.e., either a KOR agonist (U54,488H) or the opioid antagonist nalmefene, had improved open field behavior after SCI (53). Some of the detrimental effects of dynorphin may stem from KOR-mediated alterations in vascular function subsequent to injury [see (55,58,76,81,82)] or local disruptions in the concentrations of excitatory amino acids including glutamate (33,49,83,84). Circumstantial evidence suggests that dynorphin-induced KOR activation may concurrently protect against the non-opioid, neurotoxic effects of dynorphin (38).…”

Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats

“… 24–27 Impact TBI also was associated with impaired cerebral vascular compensatory responses to changes in the partial pressures of carbon dioxide, 28–30 oxygen, 31 and hematocrit. 32 Like impact TBI, bTBI resulted in some degree of cerebral vascular injury with recent evidence of level-dependent reductions in relative blood flow in the cortex and hippocampus of rats exposed to several shock-wave intensities in an air-driven shock tube. 33 Both single and repeated blast overpressures resulted in impaired cerebral vascular endothelium-dependent dilation, a vascular pathology associated with extracellular matrix alterations and an increase in inflammatory cytokines for sustained periods post-blast.…”