Mechanism of Action of Natural Compounds in Peripheral Multiorgan Dysfunction and Hippocampal Neuroinflammation Induced by Sepsis

Abstract

Bacterial sepsis induces the production of excessive pro-inflammatory cytokines and oxidative stress, resulting in tissue injury and hyperinflammation. Patients recovering from sepsis have increased rates of central nervous system (CNS) morbidities, which are linked to long-term cognitive impairment, such as neurodegenerative pathologies. This paper focuses on the tissue injury and hyperinflammation observed in the acute phase of sepsis and on the development of long-term neuroinflammation associated with septicemia. Here we evaluate the effects of Coriolus versicolor administration as a novel approach to treat polymicrobial sepsis. Rats underwent cecal ligation and perforation (CLP), and Coriolus versicolor (200 mg/kg in saline) was administered daily by gavage. Survival was monitored, and tissues from vital organs that easily succumb to infection were harvested after 72 h to evaluate the histological changes. Twenty-eight days after CLP, behavioral analyses were performed, and serum and brain (hippocampus) samples were harvested at four weeks from surgery. Coriolus versicolor increased survival and reduced acute tissue injury. Indeed, it reduced the release of pro-inflammatory cytokines in the bloodstream, leading to a reduced chronic inflammation. In the hippocampus, Coriolus versicolor administration restored tight junction expressions, reduce cytokines accumulation and glia activation. It also reduced toll-like receptor 4 (TLR4) and neuronal nitric oxide synthase (nNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome components expression. Coriolus versicolor showed antioxidant activities, restoring glutathione (GSH) levels and catalase and superoxide dismutase (SOD) activities and reducing lipid peroxidation, nitrite and reactive oxygen species (ROS) levels. Importantly, Coriolus versicolor reduced amyloid precursor protein (APP), phosphorylated-Tau (p-Tau), pathologically phosphorylated tau (PHF1), phosphorylated tau (Ser202 and Thr205) (AT8), interferon-induced transmembrane protein 3 (IFITM3) expression, and β-amyloid accumulation induced by CLP. Indeed, Coriolus versicolor restored synaptic dysfunction and behavioral alterations. This research shows the effects of Coriolus versicolor administration on the long-term development of neuroinflammation and brain dysfunction induced by sepsis. Overall, our results demonstrated that Coriolus versicolor administration was able to counteract the degenerative process triggered by sepsis.

Modulation of TLR4/NFκB Pathways in Autoimmune Myocarditis

“…The route and dose of the Coriolus versicolor were based on previous studies conducted in our [ 23 , 24 , 26 ] and other laboratories [ 29 ]. In previous studies, we already tested the effects of Coriolus versicolor (200 mg/Kg) in different inflammatory models, showing its beneficial effects.…”

“…In previous studies, we already tested the effects of Coriolus versicolor (200 mg/Kg) in different inflammatory models, showing its beneficial effects. In particular, no toxicity was observed, even with prolonged exposure to this compound [ 23 ].…”

“…Several studies, in fact, have reported the antioxidant and immunomodulatory effects of Coriolus versicolor and the anti-inflammatory properties as well. Previous studies conducted in our laboratories showed the ability of Coriolus versicolor to modulate the TLR4/NF-κB and oxidative pathways in colitis and peripheral multiorgan dysfunction [ 23 , 24 ]. Based on these data, in this paper we evaluated the modulation of this pathway in autoimmune myocarditis.…”

Peripheral inflammation triggering central anxiety through the hippocampal glutamate metabolized receptor 1

“…As an important part of the limbic system, the hippocampus is essential in responding to systemic inflammation and regulating cognitive functions and mood, such as anxiety and depression 14–16 . A large amount of data from different peripheral inflammatory models demonstrate the causal role of rising levels of hippocampal inflammation, neurogenesis inhibition, excitability, and inhibitory imbalance in inducing anxiety‐related symptoms 17–19 . However, aspects of the molecular cascade linking peripheral inflammation, hippocampal dysfunction, and anxiety‐like behavior in colitis still need to be clarified, particularly which pathway or molecule directly mediates the occurrence of anxiety behavior in mice with colitis.…”

“…[14][15][16] A large amount of data from different peripheral inflammatory models demonstrate the causal role of rising levels of hippocampal inflammation, neurogenesis inhibition, excitability, and inhibitory imbalance in inducing anxiety-related symptoms. [17][18][19] However, aspects of the molecular cascade linking peripheral inflammation, hippocampal dysfunction, and anxiety-like behavior in colitis still need to be clarified, particularly which pathway or molecule directly mediates the occurrence of anxiety behavior in mice with colitis. A detailed understanding of these pathways may provide vital information for developing new strategies to combat UC comorbidities.…”