Angiotensin II Receptor 1 Blockage Limits Brain Damage and Improves Functional Outcome After Brain Injury in Aged Animals Despite Age-Dependent Reduction in AT1 Expression.

Ralph Timaru-Kast,Regina Hummel,Michael K E Schäfer,Clara Luh,Changsheng Huang,Serge C Thal,Philipp Gotthardt

doi:10.3389/fnagi.2019.00063

Abstract

Traumatic brain injury (TBI) is a frequent pathology associated with poor neurological outcome in the aged population. We recently observed accelerated cerebral inflammation in aged mice in response to TBI. Candesartan is a potent specific inhibitor of angiotensin II receptor type 1 (AT1) which limits cerebral inflammation and brain damage in juvenile animals after experimental TBI. In the present study, we show significantly lower posttraumatic AT1 mRNA levels in aged (21 months) compared to young (2 months) mice. Despite low cerebral At1 expression, pharmacologic blockade by treatment with candesartan [daily, beginning 30 min after experimental TBI by controlled cortical impact (CCI)] was highly effective in both young and aged animals and reduced histological brain damage by −20% after 5 days. In young mice, neurological improvement was enhanced by AT1 inhibition 5 days after CCI. In older animals, candesartan treatment reduced functional impairment already on day 3 after TBI and post-traumatic body weight (BW) loss was attenuated. Candesartan reduced microglia activation (−40%) in young and aged animals, and neutrophil infiltration (−40% to 50%) in aged mice, whereas T-cell infiltration was not changed in either age group. In young animals, markers of anti-inflammatory microglia M2a polarization [arginase 1 (Arg1), chitinase3-like 3 (Ym1)] were increased by candesartan at days 1 and 5 after insult. In older mice 5 days after insult, expression of Arg1 was significantly higher independently of the treatment, whereas Ym1 gene expression was further enhanced by AT1 inhibition. Despite age-dependent posttraumatic differences in At1 expression levels, inhibition of AT1 was highly effective in a posttreatment paradigm. Targeting inflammation with candesartan is, therefore, a promising therapeutic strategy to limit secondary brain damage independent of the age.

Highlights

Traumatic brain injury (TBI) is the most common cause for trauma-related death and severe disability in industrialized countries (Langlois et al, 2006)
Our results demonstrate that posttraumatic angiotensin II receptor type 1 (AT1) inhibition improves neurological recovery, reduces histological brain damage and limits immune response in both age groups
A recent study showed that an early acute increase in tumor necrosis factor α (TNFα) levels is followed by a decrease in the days to control values (Borrajo et al, 2014a), whereas we recently showed an early and long-lasting cerebral inflammation up to 3 days after insult (Timaru-Kast et al, 2012a)

Summary

Introduction

Traumatic brain injury (TBI) is the most common cause for trauma-related death and severe disability in industrialized countries (Langlois et al, 2006). As a result, advanced age is associated with poor outcome following TBI (Stocchetti et al, 2012) and is characterized by elevated brain tissue and blood serum inflammatory cytokines levels (Hazeldine et al, 2015) and enhanced immune response (Csiszar et al, 2003). Aging rodents show an early and long-lasting posttraumatic cytokine release (Sandhir et al, 2004), pronounced and prolonged microglia activation (Sandhir et al, 2008), and immune cell infiltration (Neumann, 2001). We recently demonstrated an enhanced cerebral inflammatory response, brain edema formation and functional deficits after experimental TBI in 21- compared to 2-months-old mice (Timaru-Kast et al, 2012a). The data suggest that early onset and long duration of inflammation may be important for poor functional recovery in older animals

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