Heparanase contributes to sepsis‐associated encephalopathy and neurovascular glycocalyx degradation

While there has been increasing recognition of long‐term neurocognitive dysfunction in survivors of sepsis (termed sepsis‐associated encephalopathy, SAE), little is known about its underlying pathogenesis. We developed a mouse model of septic neurocognitive dysfunction by investigating the effects of sepsis on synaptic plasticity in the hippocampus (an area important in learning and memory). As heparan sulfate (HS) is known to contribute to the regulation of hippocampal synaptic plasticity, we sought to determine the role of SAE with heparanase, a HS‐specific glucuronidase that contributes to the pathogenesis of septic lung and kidney injury. In wild‐type mice, cecal ligation and puncture (CLP) induced physical signs (piloerection, lethargy, and weight loss) of sepsis that peaked by 24–48 h; these signs abated before 7 days. Despite this apparent resolution of septicemia, CLP significantly impaired hippocampal long‐term potentiation 7 days after injury, indicative of SAE. Similar findings were noted with intraperitoneal lipopolysaccharide (LPS, 20 μg/g), a non‐infectious model of sepsis. Consistent with our previous observations in septic lung and kidney injury, CLP increased brain heparanase expression at 48 h, with induction of both proheparanase and active heparanase. Pharmacologically blocking heparanase expression attenuated the loss of hippocampal long‐term potentiation 7 days after CLP or LPS administration. Interestingly, in vivo brain microscopy revealed that endotoxemia was associated with heparanase‐mediated loss of neurovascular glycocalyx thickness, suggesting a potential vascular‐specific mechanism by which septic heparanase induction may induce SAE. In conclusion, CLP induces neurocognitive dysfunction that persists after overt sepsis resolution; this dysfunction was attenuated by heparanase inhibition. These findings identify a potential animal model of SAE as well as possible pathophysiologic mechanisms underlying its development. Support or Funding Information K08 HL105538