A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

Rathbone, Alasdair Timothy Llewelyn; Tharmaradinam, Surejini; Jiang, Shucui; Rathbone, Michel P.; Kumbhare, Dinesh

doi:10.1016/j.bbi.2015.02.009

Cited by 76 publications

(77 citation statements)

References 230 publications

(241 reference statements)

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“…That 82879 was the only positive hit validated out of a total of 104,000 compounds in our apoE phenotypic screen and involves LXR signaling for apoE and ABCA1 induction suggests that LXR engagement may be an obligate step for apoE upregulation, particularly important for regulation of lipidated apoE. Indeed our published data [61] and that of other [75] and ongoing apoE phenotypic screens using different libraries support this observation. Importantly, understanding more about the LXR-independent pathways used by 82879 to stimulate apoE expression may yield new targets by which apoE expression and function can be modulated.…”

Section: Discussionsupporting

confidence: 75%

Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes

et al. 2016

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The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer’s Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 μM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRβ, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 μM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.

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Section: Discussionsupporting

confidence: 75%

Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes

et al. 2016

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“…given this extensive overlap 125 . Perhaps the GBMAx is mechanistically involved in these persistent symptoms following neurotrauma in the subset of patients experiencing PCS.…”

Section: "Bottom-up": Potential Gut-to-brain Signalingmentioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

142

103

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

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“…The chronic problems our patient presented with since childhood, i.e., regulatory disorder of childhood [35] followed by affective disorder, partial epilepsy, RSD pain, and multiple traumatic brain injuries, are known to have neuro-inflammation in common [3][4][5][6]. The use of HBOT, although well documented, is still considered controversial by some.…”

Section: Discussionmentioning

confidence: 97%

“…In particular, pre-existing neuropsychiatric problems can become treatment resistant or intractable when the effects of multiple traumatic brain injuries are superimposed. All of these conditions have been shown to induce variable levels of neuroinflammation [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Effective Stepwise Anti-inflammatory Treatment for Markedly Disabling Neuropsychiatric Comorbidities: A Case Report

Best¹,

Pavel²

2016

J Neurol Neurosci

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Background: This is the first case report of a stepped novel anti-inflammatory treatment plan for a complicated, markedly disabling neuropsychiatric condition with multiple comorbidities. The treatment consisted of 1) hyperbaric oxygen therapy, 2) combination therapy of infused ketamine applied concurrent with transcranial magnetic stimulation, 3) administration of perispinal etanercept, and finally 4) non-invasive transnasal Sphenopalatine Ganglion block.

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A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

Cited by 76 publications

References 230 publications

Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes

Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Effective Stepwise Anti-inflammatory Treatment for Markedly Disabling Neuropsychiatric Comorbidities: A Case Report

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