Inflammation which accompanies traumatic brain injury (TBI) can exacerbate neurological deficits. Thus, anti-inflammatory treatments have the potential to improve outcome. Angiotensin II receptor type 1 (ART1) mediates vasoconstriction, and its inhibition has been widely used to treat hypertension. However, recent work has suggested that it may also modulate apoptosis, and neuroinflammation. Thus, treatment with already available ART1 blockers may have additional neuroprotective value. We explore the contribution of ART1 to neuroprotection and brain hemorrhage in a model of TBI. Male, wildtype (Wt) and ART1 knockout (Ko) mice were subjected to TBI using controlled cortical impact (CCI). This model leads to reproducible traumatic brain injury with disruption of motor function and hemorrhage into the area of injury. Sensorimotor function (adhesive removal & elevated body swing tests), brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. To explore the clinical relevance of ART1 in brain injury, we also gave Wt mice an ATR1 inhibitor (candesartan, 0.1mg/kg IP). We found that ATR1 deficient mice were protected from CCI as evidenced by decreased lesion and hemorrhage volumes (decreases of ∼40% in lesion size amongst Ko mice, n=6/group, p<0.05), improved neurobehavioral outcomes (n=6/group, p<0.05) and fewer activated microglia in Ko mice (p<0.05). This was also associated with decreased cytokine expression relative to Wt. Candesartan similarly protected against brain injury and improved neurological outcome out to 14 days post CCI (n=6/group, p<0.05). These data are consistent with the notion that ART1 contributes negatively to traumatic brain injury, and its inhibition or deficiency leads to improved outcomes and decreased immune responses. Considering the clinical availability of ART1 inhibitors, this approach may be a promising novel therapeutic target against TBI and related conditions including stroke.
Intraoperative hypothermia during vascular neurosurgical procedures
