HMGB1 Mediates Cognitive Impairment in Sepsis Survivors

Abstract

Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments. We observed that serum levels of high mobility group box 1 (HMGB1), a critical mediator of acute sepsis pathophysiology, are increased in sepsis survivors. Significantly, these levels remain elevated for at least 4 wks after CLP . Sepsis survivors develop significant, persistent impairments in learning and memory, and anatomic changes in the hippocampus associated with a loss of synaptic plasticity. Administration of neutralizing anti-HMGB1 antibody to survivors, beginning 1 wk after onset of peritonitis, significantly improved memory impairments and brain pathology. Administration of recombinant HMGB1 to naïve mice recapitulated the memory impairments. Together, these findings indicate that elevated HMGB1 levels mediate cognitive decline in sepsis survivors, and suggest that it may be possible to prevent or reverse cognitive impairments in sepsis survivors by administration of anti-HMGB1 antibodies.

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

“…Accumulating evidence has demonstrated the involvement of oxidative stress and inflammation as a major step in the development of SAE and long-term cognitive impairments [21][22][23]. Oxidative stress plays a key role in the development of cognitive impairments during sepsis.…”

Imaging in sepsis-associated encephalopathy—insights and opportunities

“…11,12 These findings are supported by work in mice that demonstrated hippocampal abnormalities and deficits in cognition after caecal ligation and puncture. 39 Encouragingly, these deficits were ameliorated following administration of a neutral izing antibody to high mobility group box 1, a cytokine that was found to have a role in sepsis. 39 It is important to emphasize that the relationship between SAE and long-term cognitive decline remains unproven.…”

“…39 Encouragingly, these deficits were ameliorated following administration of a neutral izing antibody to high mobility group box 1, a cytokine that was found to have a role in sepsis. 39 It is important to emphasize that the relationship between SAE and long-term cognitive decline remains unproven. However, given the potential clinical importance of such a phenomenon, it is critical that we undertake studies that seek to establish or refute this hypothesis.…”

TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

“…This finding is concordant with previous studies that demonstrated long term memory impairment after sepsis in rodents. For example, Chavan et al (2012) studied memory deficits in mice 1 and 4 months after CLP, finding significant impairment in spatial memory. Tuon et al (2008) also described impairment in the novel object recognition memory test 10 days after CLP in rats, but not at later stages.…”