Experimental sepsis-associated encephalopathy is accompanied by altered cerebral blood perfusion and water diffusion and related to changes in cyclooxygenase-2 expression and glial cell morphology but not to blood-brain barrier breakdown
Graphical abstract
Introduction
Sepsis-associated encephalopathy (SAE) refers to brain dysfunction ranging from mild delirium to deep coma that occurs in up to 70% of patients with severe systemic infection (Gofton and Young, 2012, Jones and Griffiths, 2013, Lamar et al., 2011, Young, 2013). In addition to acute mental dysregulation in the form of delirium, sepsis also has long-term detrimental effects on mental health. Indeed, clinical sepsis is associated with the development of post-traumatic stress disorders (PTSD) months later (Boer et al., 2008, Rosendahl et al., 2013, Schelling et al., 2001, Wintermann et al., 2015).
In spite of its impact on mental and cognitive health, the mechanisms underlying SAE are poorly understood (Chaudhry and Duggal, 2014). SAE, including delirium, has been proposed to be related to reduced cerebral blood flow (CBF) and oxygen extraction, blood–brain barrier breakdown (BBB), brain inflammation and edema (Chaudhry and Duggal, 2014, Papadopoulos et al., 2000, Tsuruta and Oda, 2016). Indeed, baseline CBF has been shown to be reduced during SAE (Bowton et al., 1989, Maekawa et al., 1991, Pfister et al., 2008, Pierrakos et al., 2013, Pierrakos et al., 2014, Smith et al., 1998, Yokota et al., 2003). Furthermore, systematic assessment of middle cerebral artery (MCA) blood velocity to variations in arterial blood pressure indicates that impaired cerebral autoregulation is associated with sepsis-associated delirium (Pfister et al., 2008, Schramm et al., 2012). Of note, some authors have also suggested that loss of cerebral autoregulation sepsis-associated contributes to edema during sepsis (Piazza et al., 2009).
Interestingly, and concomitantly with vasospasms in the MCA of patients with sepsis and brain dysfunction, T2- and diffusion-weighted Magnetic Resonance Imaging (MRI) have indicated white matter vasogenic edema (Bartynski et al., 2006, Sharshar et al., 2007). Moreover, in patients who died of sepsis, dilation of the perivascular space accompanied by dissociation of myelinated and white matter microglial activation have been observed (Lemstra et al., 2007, Sharshar et al., 2007, Zrzavy et al., 2019). Finally, delirium has been found to be associated with disruption of white matter organization at hospital discharge and 3 months later, which, in turn, was associated with long-term cognitive impairment (Morandi et al., 2012). So among the proposed underlying mechanisms, clinical SAE has been shown to be associated with reduced CBF, signs of edema formation and white matter changes. However, the relationships between these phenomena and the occurrence and role of BBB breakdown as well as glial activation remain to be determined.
Experimental models allowing to systematically vary factors of interest have the potential to unravel the pathophysiological mechanisms underlying SAE. Intravenous administration of bacterial lipopolysaccharide (LPS) fragments in human volunteers is sufficient to reduce global CBF (Moller et al., 2002, Pollard et al., 1997). However, after systemic administration of LPS in animals, some studies have also observed rapidly decreased global or incoming CBF (Bryan and Emerson, 1977, Christenson et al., 1986, Ekstrom-Jodal et al., 1982, Tempel et al., 1986, Villega et al., 2017, Wyler et al., 1969, Wyler et al., 1972), whereas others studies have shown increased CBF in cortical MCA territories, but dose-dependent impaired autoregulation of CBF (Rosengarten et al., 2007, Rosengarten et al., 2008). And although peripheral LPS administration in rodents induces microglial activation in different brain structures (Hoogland et al., 2015), no study so far seems to have assessed white matter.
Cecal ligation and puncture (CLP) is a more clinically-relevant sepsis model than systemic LPS administration in that it involves live bacteria and mimics the different hemodynamic phases observed in clinical sepsis. Interestingly, during the first 24 h after CLP, CBF has been shown to be preserved (Hinkelbein et al., 2007) while increased T2-weighted contrast at the base of the brain suggested vasogenic edema and decreased apparent diffusion coefficient (ADC) indicated cytotoxic edema in the cortex and hippocampus (Bozza et al., 2010).
The aim of the present work was to establish temporal and spatial relationships between CNS hemodynamic, metabolic and structural changes during experimental sepsis using imaging and histological approaches on brains of the same animals. We studied CBF and brain microstructure using Arterial Spin Labeling (ASL) and Diffusion-weighted Magnetic Resonance Imaging (dMRI), respectively, in animals with SAE 24 h after CLP. In addition, we also detected the vasoactive prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2), which is upregulated under inflammatory response, the presence of perivascular immunoglobulins G (IgG) as a measure of BBB integrity, and modifications of glia cell morphology in the brains of the same animals.
Section snippets
Animals
Twenty-one male 3.5 month old Wistar rats (Charles River, l'Abresle, France) weighing 340.3 ± 3.6 g were used. Animals were treated according to European recommendations on animal research (European Council Directive of 24 November 1986 (86/609/EEC) and European Parliament and Council Directive of 22 September 2010 (2010/63/UE)), housed 2 per cage in a temperature-controlled room (22.0 ± 1.0 °C) with lights on from 8 AM to 8 PM with free access to water and food. After arrival rats were left
CLP reduced food intake and induced encephalopathy
Within the 23 h following the end of surgery, no mortality was observed in the sham-operated group (One animal did die however at the induction of anesthesia for imaging) while CLP resulted in 12.5% mortality. One-way ANOVAs on food consumption relative to body weight during the 24 h before surgery did not reveal any differences between animals to be allocated to treatment groups. However, a Mann-Whitney U test on food consumption relative to body weight during the 24 h after the start of
Discussion
The main findings of the present work were that CLP induced sepsis-associated CNS dysfunction resulted in higher T2-weighted contrast intensities in the cortex, striatum and at the base of the brain, decreased blood perfusion distribution to the cortex and increased axial water diffusion in the corpus callosum and fractional anisotropy in the ventral striatum compared to sham surgery. In these animals, CLP induced perivascular COX-2 expression, decreased cortical COX-2 and AQP4 expression and
Acknowledgements
This work was supported by public grants from the French Agence Nationale de la Recherche within the context of the Investments for the Future program referenced ANR-10-LABX-57 named TRAIL (project HR-dMRI).
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