Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches

Gu, Ming; Mei, Xianglin; Zhao, Yanan

doi:10.1007/s12640-020-00270-5

Cited by 113 publications

(75 citation statements)

References 113 publications

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“…Pathophysiological mechanisms for delirium in COVID-19 are many. Inflammatory response to systemic infections alters the blood-brain barrier, allowing a central inflammatory response leading to neuronal dysfunction of cholinergic circuits, among other alterations (32). Pulmonary, cardiac, and renal insufficiency reduce CNS mitochondrial oxidation, increase CNS dopamine, and decrease acetylcholine production (33).…”

Section: Discussionmentioning

confidence: 99%

Etiologies of Delirium in Consecutive COVID-19 Inpatients and the Relationship Between Severity of Delirium and COVID-19 in a Prospective Study With Follow-Up

Velásquez-Tirado

Trzepacz

Vásquez

2021

JNP

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The investigators aimed to describe delirium etiologies and clinical characteristics, as well as the relationship between COVID-19 and delirium severities, at baseline and follow-up after delirium improvement among patients with SARS-CoV-2 infection.Methods: A longitudinal study of 20 consecutive critically ill, delirious COVID-19 inpatients, assessed with the Charlson Comorbidity Index-Short Form (CCI-SF), COVID-19 Clinical Severity Scale (CCSS), Delirium Etiology Checklist, Delirium Motor Subtype Scale-4, and Delirium Diagnostic Tool-Provisional (DDT-Pro), was conducted. Correlational analysis of delirium severity (DDT-Pro) with each measure of clinical severity (CCI-SF and CCSS) and comparison of baseline DDT-Pro scores between patients who were living and those who were deceased at follow-up were conducted.Results: Participants were 50-90 years old (male, 75%; hypertension, 60%). The prevalence of preexisting medical comorbidities (CCI-SF) was low and not correlated with delirium severity (p50.193). Eighteen patients were on mechanical or high-flow noninvasive ventilation at baseline in the intensive care unit (ICU; CCSS scores 2-4). Delirium severity (DDT-Pro scores 0-6) correlated with COVID-19 severity (0.459, p50.021). Delirium motor subtype was hyperactive in 75% of patients. There were three to four etiologies for delirium in each patient, most commonly organ insufficiency (100%), systemic infection (100%), and metabolic and endocrine disturbances (95%). The baseline DDT-Pro score was #4 for five (25%) patients who died before the final assessment, with a trend of being lower than that for survivors (x 2 53.398, p50.065).Conclusions: Among inpatients with COVID-19, at least three different etiological categories were identified for delirium. ICU staff treating patients with severe cases of COVID-19 should anticipate a greater severity of delirium. Although multivariate analyses with larger study samples are needed, more severe delirium may herald greater risk of death among COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Etiologies of Delirium in Consecutive COVID-19 Inpatients and the Relationship Between Severity of Delirium and COVID-19 in a Prospective Study With Follow-Up

Velásquez-Tirado

Trzepacz

Vásquez

2021

JNP

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“…However, a clear relationship between dementia and infectious alterations of normal physiology is difficult to establish for several reasons. Sepsis, on the other hand, a grave condition which can be caused by several pathogens, is known to produce severe BBB dysfunction (Barichello et al, 2021 ), microglial activation (Li et al, 2020 ), acute neuroinflammation, brain injury and cerebral dysfunction (Meneses et al, 2019 ; Gu et al, 2021 ), and long-term cognitive and functional impairments (Brown, 2019 ; Rengel et al, 2019 ). This is also true for bacterial meningitis, especially in the case of neonates (Heath et al, 2011 ) and young infants (Hsu et al, 2018 ).…”

Section: Infection Burden and The Epidemiology Of Dementiamentioning

confidence: 99%

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

Farmen

Tofiño-Vian

Iovino

2021

Front. Cell. Neurosci.

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Bacterial meningitis is an inflammation of the meninges which covers and protects the brain and the spinal cord. Such inflammation is mostly caused by blood-borne bacteria that cross the blood-brain barrier (BBB) and finally invade the brain parenchyma. Pathogens such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the main etiological causes of bacterial meningitis. After trafficking across the BBB, bacterial pathogens in the brain interact with neurons, the fundamental units of Central Nervous System, and other types of glial cells. Although the specific molecular mechanism behind the interaction between such pathogens with neurons is still under investigation, it is clear that bacterial interaction with neurons and neuroinflammatory responses within the brain leads to neuronal cell death. Furthermore, clinical studies have shown indications of meningitis-caused dementia; and a variety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are characterized by the loss of neurons, which, unlike many other eukaryotic cells, once dead or damaged, they are seldom replaced. The aim of this review article is to provide an overview of the knowledge on how bacterial pathogens in the brain damage neurons through direct and indirect interactions, and how the neuronal damage caused by bacterial pathogen can, in the long-term, influence the onset of neurodegenerative disorders.

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“…After ischemic stroke, pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α can induce changes in the integrity of the BBB, which increases permeability ( 29 ). This pro-inflammatory environment can lead to a more robust release of other inflammatory mediators, such as the chemokine MCP-1( 30 ). Due to the excessive stimulation of immune cells, large quantities of leukocyte adhesion to endothelial cells occurs, resulting in the excessive activation of the anti-infection response ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

4‑Methoxybenzylalcohol protects brain microvascular endothelial cells against oxygen‑glucose deprivation/reperfusion‑induced injury via activation of the PI3K/AKT signaling pathway

et al. 2021

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Damage to the blood-brain barrier (BBB) during the process of cerebral ischemic injury is a key factor that affects the treatment of this condition. The present study aimed to assess the potential effects of 4-methoxybenzyl alcohol (4-MA) on brain microvascular endothelial cells (bEnd.3) against oxygen-glucose deprivation/reperfusion (OGD/Rep) using an in vitro model that mimics in vivo ischemia/reperfusion injury. In addition, the present study aimed to explore whether this underlying mechanism was associated with the inhibition of pro-inflammatory factors and the activation status of the PI3K/Akt signaling pathway. bEnd.3 cells were subjected to OGD/Rep-induced injury before being treated with 4-MA, following which cell viability, lactate dehydrogenase (LDH) release and levels of nitric oxidase (NO) were detected by colorimetry, pro-inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were detected by ELISA. The expression levels of occluding and claudin-5were evaluated by immunofluorescence staining. The expression levels of AKT, phosphorylated (p)-Akt, endothelial nitric oxide synthase (eNOS) and p-eNOS were also measured by western blot analysis. After bEnd.3 cells were subjected to OGD/Rep-induced injury, cell viability and NO levels were significantly decreased, whilst LDH leakage and inflammatory factor (TNF-α, IL-1β and IL-6) levels were significantly increased. Treatment with 4-MA significantly ameliorated cell viability, LDH release and the levels of NO and pro-inflammatory factors TNF-α, IL-1β and IL-6 as a result of OGD/Rep. Furthermore, treatment with 4-MA upregulated the expression of occludin, claudin-5, Akt and eNOS, in addition to increasing eNOS and AKT phosphorylation in bEnd.3 cells. These results suggest that 4-MA can alleviate OGD/Rep-induced injury in bEnd.3 cells by inhibiting inflammation and by activating the PI3K/AKT signaling pathway as a possible mechanism. Therefore, 4-MA can serve as a potential candidate for treating OGD/Rep-induced injury.

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Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches

Cited by 113 publications

References 113 publications

Etiologies of Delirium in Consecutive COVID-19 Inpatients and the Relationship Between Severity of Delirium and COVID-19 in a Prospective Study With Follow-Up

Etiologies of Delirium in Consecutive COVID-19 Inpatients and the Relationship Between Severity of Delirium and COVID-19 in a Prospective Study With Follow-Up

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

4‑Methoxybenzylalcohol protects brain microvascular endothelial cells against oxygen‑glucose deprivation/reperfusion‑induced injury via activation of the PI3K/AKT signaling pathway

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