Hemopressin, a cannabinoid peptide, protects against cognitive impairments of sepsis-associated encephalopathy in mice

Sepsis can be described as an organ dysfunction mediated by a dysregulated host inflammatory response to an infection condition. Even with substantial mortality rates, survivors show a series of long-term impairments such as immunosuppression, cognitive impairments, and other complications. Despite the rich literature about sepsis physiopathology, there isn’t an effective treatment that can modulate the acute inflammation and protect survivors against late impairments. In our previous studies, we saw that hemopressin (HP), a cannabinoid peptide inverse agonist of CB1, attenuates the early inflammatory response and improves immunosuppression and cognitive late impairments in mice. Therefore, the aim of this study is to evaluate the HP mechanism and protective effects in sepsis-associated encephalopathy (SAE). Our in vivo sepsis model was cecal ligation and puncture (CLP) with 9 punctures, 21G needle, in C57BL/6 mice. The treatment was performed in the timepoints of 5, 24, 48, and 72 hours after CLP and consists of the antibiotic ertapenem (75 mg/kg) and HP (250 nmol/kg) or vehicle. In the in vitro model we use Bv2 cells stimulated with LPS (100 ng/mL) and treated with HP in 1, 3, and 10 µM concentrations. Firstly, in the in vivo approach, HP shows an improvement in sepsis synaptic impairments through the reversion of synaptophysin decrease in the mouse prefrontal cortex. Interestingly, HP also indicates the capability to modulate CB2, but not CB1, expression in mice brains during SAE. In addition, HP also modulates the inflammatory ambient decreasing the production of cytokines and chemokines like IL-12p70, MCP1, and IL6, and also increasing IL-10. Furthermore, in our in vitro approach HP restored impaired CB1 and CB2 microglial expression after stimulus, but did not show an effect on TNF and NO realease. Therefore, our early data shows that HP seems to modulate the cannabinoid system expression in microglia and it may act by regulating inflammation in SAE.