The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity &amp; Memory Function in Aging

Muscat, Stephanie; Barrientos, Ruth M.

doi:10.3233/bpl-210127

Cited by 17 publications

(9 citation statements)

References 140 publications

(100 reference statements)

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“… 67 Long-term effects are observed in the central nervous system after continuous activation of microglial cells. 68 , 69 Individuals may depend on prolonged vitamin C repletion throughout the recovery period to counteract the oxidative burden and protect against postinjury cognitive decline. Future studies with long-term vitamin C supplementation after sepsis may test this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse models of sepsis suggest that, although vitamin C depletion occurs during the acute illness period, there are distinct phases of the neuroinflammatory response after injury . Long-term effects are observed in the central nervous system after continuous activation of microglial cells . Individuals may depend on prolonged vitamin C repletion throughout the recovery period to counteract the oxidative burden and protect against postinjury cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

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Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

et al. 2023

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ImportanceSepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.ObjectiveTo describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.Design, Setting, and ParticipantsThis prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.InterventionsThe intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.Main Outcomes and MeasuresCognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.ResultsAfter exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.Conclusions and RelevanceIn survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.Trial RegistrationClinicalTrials.gov Identifier: NCT03509350

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

et al. 2023

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“…In the central nervous system, the microglia cells play a key role in neuroinflammatory responses and are the primary innate immune cells of the brain (DiSabato et al 2016;Muscat and Barrientos 2021). Microglia respond to a variety of threats (e.g., invading pathogens) to the brain by producing pro-inflammatory cytokines followed by production of anti-inflammatory cytokines.…”

Section: Msk: Role In the Innate Immune Response And Inflammationmentioning

confidence: 99%

Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states

Sattarifard

Safaei

Khazeeva

et al. 2023

Biochem. Cell Biol.

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The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB, CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host’s innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.

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“…Thus, overproduction of the inflammatory cytokines is not only necessary but also sufficient to induce neuropathic pain. Furthermore, pro-inflammatory cytokines are also critically involved in memory deficits (see 84 , 85 for reviews) and major depression (see 86 , 87 for reviews) in many diseases other than chronic pain. Likewise, the working memory and short-term memory impairments produced by SNI are prevented by genetic deletion of TNFR1 and mimicked by intracerebroventricular or intrahippocampal injection of TNF-α.…”

Section: Cytokine Microenvironment Hypothesis Of Chronic Painmentioning

confidence: 99%

“… 55 , 56 As discussed above, the overproduction of proinflammatory cytokines and glial activation are essential for both hypersensitivity of sensory neurons and the pathological synaptic plasticity in CNS. Previous works show that both proinflammatory cytokines and glial activation are also critically involved in memory deficits (see 84 , 85 for reviews) and major depression (see 86 , 87 for reviews) in many diseases other than chronic pain. Therefore, neuroinflammation might be the common cause for persistent pain and memory/emotional deficits in chronic pain condition.…”

Section: Cytokine Microenvironment Hypothesis Of Chronic Painmentioning

confidence: 99%

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

Liu¹

2022

JIR

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Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg 2+ deficiency is a common feature of chronic pain in animal models and supplement Mg 2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.

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The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Cited by 17 publications

References 140 publications

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors

Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

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