Effekt einer Palmitoylethanolamid-Prophylaxe auf alte oder neutropenische Mäuse nach intrazerebraler E. coli-Infektion

Abstract

Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old and neutropenic mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 µl vehicle solution (n = 25) or with 250 µl vehicle solution only as controls (n = 25), 12 h and 30 min prior to intracerebral E. coli K1 infection. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts, microglia activation scores as well as meningeal inflammation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen in PEA- and vehicle-treated animals 24 h after infection. Additionally, eight healthy mice were infected and treated with vehicle solution to investigate microglia morphology in healthy old mice. Furthermore, young neutropenic mice were treated with two doses of either 0.1 mg PEA/kg or 1 mg PEA/kg in 250 µl vehicle solution (n = 44) or with 250 µl vehicle solution only as controls (n = 29), 12 h and 30 min prior to intracerebral E. coli K1 infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P =0.042). There was no significant effect of prophylactic PEA in neutropenic mice on the survival time, lethality or bacterial loads. Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.