Blood‐brain barrier leakage and cerebral edema in an impact‐acceleration model of traumatic brain injury in mice

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI often occurs as closed head injury without apparent focal injury, accompanied by diffuse neuronal damage and brain edema. The Marmarou impact‐acceleration (I‐A) weight‐drop model is the most widely used animal model of diffuse TBI, in rats. In order to study molecular mechanisms using transgenic animals, we modified the I‐A model of TBI for C57/black 6 mice. Drop height and weight combinations were optimized to induce maximal injury without skull fracture, to induce moderate or severe TBI. Moderate TBI caused seizures, apnea, 5–15 minutes of unconsciousness, and reversible neurological deficit. In contrast, severe TBI induced a vegetative state requiring ventilation for 30 min, followed by seizures and death. Vascular leakage was assessed by brain uptake of large‐ (Evans Blue (EB)‐albumin) or small‐ (Na + fluorescein (FL)) molecules by intra‐aortic perfusion, or by i.v. injection of EB (80mg/Kg) prior to injury. Moderate TBI increased brain FL, but not EB uptake at 1 h, 6 h or 24 h after injury with no evidence of increased brain water uptake measured by wet – dry tissue weight or by MRI (ADC or T2 map). In contrast, severe TBI significantly increased brain water content (78.3 % versus 77.4%; n≥3 each, p < 0.05), accompanied by increased brain uptake of EB at 30 minutes, demonstrating cerebral edema and vascular leakage. This work is supported by NIH R01 HL61507, HL70753, HL96640 and HL84852.