AT 1 inhibition mediated neuroprotection after experimental traumatic brain injury is dependent on neutrophils in male mice

Cerebral inflammation with invasion of neutrophils and lymphocytes is a crucial factor in the process of secondary brain damage after traumatic brain injury (TBI). In TBI the intrinsic renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) reduces secondary brain damage and the invasion of neutrophil granulocytes into injured cerebral tissue. The present study investigated the role of immune cells in AT1 inhibition-mediated neuroprotection after experimental TBI. In four different cohorts, male mice were studied to examine effects of neutropenia (anti-Ly6G antibody mediated neutrophil depletion; C57BL/6) or lymphopenia (RAG1 deficiency, RAG1 -/- ) alone, or in combination with candesartan-mediated AT1 inhibition. The present results demonstrate that reduction of neutrophils (neutrophil depletion in wild type mice) and of lymphocytes (RAG1 -/- ) as well as AT1 inhibition in (control antibody treated) wild type and RAG1 -/- mice reduce brain damage and neuroinflammation after TBI compared to control groups, while in neutropenic mice, candesartan had no effect. However, AT1 inhibition was neuroprotective in RAG1 -/- mice, but not in neutropenic mice. Therefore, the results indicate that AT1 inhibition mediated neuroprotection may be exerted by anti-inflammatory effects on neutrophils, with a subsequent reduction of neutrophil invasion.