17 research outputs found
Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway
Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1β increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1β increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9−/− mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety
The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial
Postnatal LPS Challenge Impacts Escape Learning and Expression of Plasticity Factors Mmp9 and Timp1 in Rats: Effects of Repeated Training
Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline
Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline
Late Anxiety-Like Behavior and Neuroinflammation in Mice Subjected to Sublethal Polymicrobial Sepsis
Current Concepts in the Diagnosis, Pathophysiology, and Treatment of Delirium: A European Perspective
Delirium is a complex syndrome defined as an acute, fluctuating syndrome of altered attention, awareness, and cognition. Delirium is common in the elderly, but unfortunately underdiagnosed. The consequences could be significant such as an increase in mortality, hospitalization, loss of autonomy, and increased risk to be institutionalized. The predisposing and precipitating factors are well known, but the pathogenesis is not yet identified clearly. However, evidence that delirium is a neurotoxic factor which develops due primarily to neurotransmitter (cholinergic insufficiency) and inflammatory (increase in stress response/neuroinflammation) mechanisms is increasing each passing day. Delirium is associated with serious complications, but can also be treatable if diagnosed early and managed properly. It is important to develop primary and secondary prevention and therefore close contact with the patient, ensuring adequate vision, hearing, nutrition, hydration, and sleep; informing the caregivers about delirium for recognizing early symptoms of delirium, mobilizing the patient as early as possible, and managing the pain are strongly recommended. Besides, clinicians must identify the real underlying medical conditions. If non-pharmacologic interventions are insufficient, pharmacologic therapy should be implemented