Distinct post-sepsis induced neurochemical alterations in two mouse strains

Abstract

Sepsis associated encephalopathy, occurs in 70% of severe septic cases, following which survivors exhibit long-term cognitive impairment or global loss of cognitive function. Currently there is no clearly defined neurochemical basis of septic encephalopathy. Moreover, the lingering neurological complications associated with the severe acute respiratory syndrome CoV 2 (SARS-CoV-2) and the significant worsening in outcomes for those individuals with SARS-Cov-2 following sepsis underscore the need to define factors underlying the susceptibility to acute toxic encephalitis. In this study, differential neurochemical sequelae in response to sepsis (lipopolysaccharide (LPS)-induced endotoxemia and caecal ligation and puncture (CLP)), were evaluated in two inbred mouse strains, known to differ in behaviour, immune profile, and neurotransmitter levels, namely BALB/c and C57BL/6J. It was hypothesized that these strains would differ in sepsis severity, cytokine profile, peripheral tryptophan metabolism and central monoamine turnover. BALB/c mice exhibited more pronounced sickness behavioural scores, hypothermia, and significant upregulation of cytokines in the LPS model relative to C57BL/6J mice. Increased plasma kynurenine/tryptophan ratio, hippocampal serotonin and brainstem dopamine turnover were evident in both strains, but the magnitude was greater in BALB/c mice. In addition, CLP significantly enhanced kynurenine levels and hippocampal serotonergic and dopaminergic neurotransmission in C57BL/6J mice. Overall, these studies depict consistent changes in kynurenine, serotonin, and dopamine post sepsis. Further evaluation of these monoamines in the context of septic encephalopathy and cognitive decline is warranted. Moreover, these data suggest the continued evaluation of altered peripheral kynurenine metabolism as a potential blood-based biomarker of sepsis.