Endothelin and the neurovascular unit in pediatric traumatic brain injury

Abstract

Objective: This study characterized the association between endothelin-1, cerebral hemodynamics, and histopathology after fluid percussion brain injury in the newborn pig.

Methods: Lateral fluid percussion injury was induced in newborn pigs equipped with a closed cranial window. Cerebral blood flow was determined with radiolabeled microspheres and cerebrospinal fluid endothelin-1 was measured by radioimmunoassay.

Results: Cerebrospinal fluid endothelin-1 was increased from 26±4 to 296±37 pg/ml (∼10(-10) M) at 8 hours following fluid percussion injury. Post-injury treatment (30 minutes) with the endothelin-1 antagonist BQ-123 (1 mg/kg, intravenous) blocked pial artery vasoconstriction to topical endothelin-1 (∼10(-10) M) and blunted fluid percussion injury-induced reductions in cerebral blood flow at 8 hours post-insult (56±6 and 26±4 ml/minute versus 57±6 and 40± ml/minute; 100 g for cerebral blood flow before injury and 8 hours post-fluid percussion injury in vehicle and BQ-123 post-treated animals, respectively). Fluid percussion injury resulted in neuronal cell loss and decreased microtubule associated protein 2 immunoreactivity in the parietal cortex, which were blunted by BQ-123.

Discussion: These data indicate that fluid percussion injury-induced changes in cerebral hemodynamics are associated with neuronal damage and that endothelin-1 contributes to fluid percussion injury-induced histopathologic changes.

Figure 1

(A) Influence of fluid percussion injury (fluid percussion injury) on cerebral spinal fluid endothelin-1 (n=5). (B) Influence of endothelin-1 (10⁻¹⁰M) on pial artery diameter before (control) and after fluid percussion injury, and after fluid percussion injury in BQ-123 (1 mg/kg, i.v.) post-treated animals (n=5). (C) Influence of fluid percussion injury on cerebral blood flow (ml/minute, 100 g) in the absence and presence of BQ-123 (n=5). *P<0.05 compared to control value; ⁺P<0.05 compared to vehicle value.

Figure 2

Cerebral cortex stained with either cresyl violet (left panels) or microtubule associated protein 2 (right panels). Conditions are: sham (top panels), fluid percussion injury (middle panels), and fluid percussion injury and BQ-123 (1 mg/kg, i.v.) post-treated (bottom panels).