Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

Meneses, Gabriela; Cárdenas, Graciela; Espinosa, Alejandro; Rassy, Dunia; Pérez-Osorio, Ivan Nicolás; Bárcena, Brandon; Fleury, Agnès; Besedovsky, Hugo O.; Fragoso, Gladis; Sciutto, Edda

doi:10.1111/nyas.13985

Cited by 63 publications

(49 citation statements)

References 122 publications

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“…In addition, higher plasma levels of these inflammatory cytokines were observed in the ICU patients, which suggests that a cytokine storm presented in the severe patients [12]. This cytokine storm could induce various neurological symptoms and was previously reported to be able to disrupt the BBB and induce neuroinflammation in the sepsis [27,50,51]. In addition, the neutralizing antibodies (anti-S protein lgG), which are assumed to clear the virus and promote the recovery, can also cause severe secondary injury by altering inflammatory responses.…”

Section: Potential Mechanism Underlying the Neurological Manifestatiomentioning

confidence: 81%

Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis

et al. 2020

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Background Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people. However, clinical research on its neurological manifestations is thus far limited. In this study, we aimed to systematically collect and investigate the clinical manifestations and evidence of neurological involvement in COVID-19. Methods Three medical (Medline, Embase, and Scopus) and two preprints (BioRxiv and MedRxiv) databases were systematically searched for all published articles on neurological involvement in COVID-19 since the outbreak. All included studies were systematically reviewed, and selected clinical data were collected for meta-analysis via random-effects. Results A total of 41 articles were eligible and included in this review, showing a wide spectrum of neurological manifestations in COVID-19. The meta-analysis for unspecific neurological symptoms revealed that the most common manifestations were fatigue (33.2% [23.1-43.3]), anorexia (30.0% [23.2-36.9]), dyspnea/shortness of breath (26.9% [19.2-34.6]), and malaise (26.7% [13.3-40.1]). The common specific neurological symptoms included olfactory (35.7-85.6%) and gustatory (33.3-88.8%) disorders, especially in mild cases. Guillain-Barré syndrome and acute inflammation of the brain, spinal cord, and meninges were repeatedly reported after COVID-19. Laboratory, electrophysiological, radiological, and pathological evidence supported neurologic involvement of COVID-19. Conclusions Neurological manifestations are various and prevalent in COVID-19. Emerging clinical evidence suggests neurological involvement is an important aspect of the disease. The underlying mechanisms can include both direct invasion and maladaptive inflammatory responses. More studies should be conducted to explore the role of neurological manifestations in COVID-19 progression and to verify their underlying mechanisms.

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Section: Potential Mechanism Underlying the Neurological Manifestatiomentioning

confidence: 81%

Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis

et al. 2020

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“…Clinical and experimental evidence link perinatal infection and inflammation to subsequent neurological and developmental sequelae (7). Sepsis can induce neuroinflammation resulting in activation of neurotoxic processes (8). There is increased risk of neurodevelopmental impairment in infants that experience sepsis and a meta-analysis demonstrated that coagulase-negative staphylococci sepsis in very low birth weight infants is associated with a higher incidence of cerebral palsy (9).…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

et al. 2020

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Background: Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice.Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 10 7 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O 2 . White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling.Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro-and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection.Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.

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“…Furthermore, other hypothalamic regions, as the SCN and PVN, are capable of receiving and modulating thermal signals (Lu et al, 2001;Wanner et al, 2013;Guzmán-Ruiz et al, 2015). Immune peripheral signals can reach the central nervous system by humoral or nervous pathways, which in turn can induce glial activation and the secretion of pro-or anti-inflammatory molecules (Meneses et al, 2019). Previous studies have shown neuronal activation in response to LPS (Hare et al, 1995;Marpegán et al, 2005;Paladino et al, 2010Paladino et al, , 2014, but this work provides the first indication of a circadian modulation in hypothalamic responses to high doses of this molecule.…”

Section: Discussionmentioning

confidence: 99%

Differential Thermoregulatory and Inflammatory Patterns in the Circadian Response to LPS-Induced Septic Shock

Fedele

Aiello

Caldart

et al. 2020

Front. Cell. Infect. Microbiol.

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Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

Cited by 63 publications

References 122 publications

Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis

Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

Differential Thermoregulatory and Inflammatory Patterns in the Circadian Response to LPS-Induced Septic Shock

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