Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury

Xu, Xin; Gao, Weiwei; Cheng, Shiqi; Yin, Dongpei; Li, Fēi; Wu, Yingang; Sun, Dongdong; Zhou, Shuai; Wang, Dong; Zhang, Yongqiang; Jiang, Rongcai; Zhang, Jianning

doi:10.1186/s12974-017-0934-2

Cited by 172 publications

(118 citation statements)

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“…Our method for inducing TBI in mice was described previously [37]. We anesthetized animals with intravenous chloral hydrate (5%, 0.1 ml/10 g) and then fixed them in a stereotactic frame (Kopf Instruments, Tujunga, CA, USA).…”

Section: Modelmentioning

confidence: 99%

“…shown that microglia can be activated after trauma, resulting in increased intracellular caspase-1 and pyroptosis [47], and TBI can also promote microglia polarization [37]. To determine whether VX765 treatment affected microglia polarization and intracellular pyroptosis, changes in relevant markers were detected by immunofluorescence.…”

Section: Microglial Changes After Trauma Previous Studies Havementioning

confidence: 99%

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VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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Section: Modelmentioning

confidence: 99%

Section: Microglial Changes After Trauma Previous Studies Havementioning

confidence: 99%

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…In one study delivering recombinant IL-4 after stroke in IL-4 knockout mice, repeated measures were not accounted for and wild-type mice were not tested (52). A variety of other approaches to TBI that promote an M2-like response have also observed improvement in behavioral outcomes (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (31)(32)(33)(34)(35)(36). However, in many of these studies, behavior is not (or could not be) assessed prior to treatment to ensure the absence of accidental bias.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Enam

Kader

Bodkin

et al. 2020

Preprint

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Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity. There already exists clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as Interleukin-4 (IL-4). To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs to transiently express IL-4 via synthetic IL-4 mRNA. We observed that these IL-4 expressing MSCs indeed induce a robust M2like macrophage phenotype and promote anti-inflammatory gene expression in a modified TBI model of closed head injury. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes. This suggests that an acute enrichment of M2like macrophages cannot solely orchestrate the neurogenesis, axonal regeneration, and improved WMI after diffuse TBI. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists in spite of acute enrichment of M2-like macrophages in the brain. Last, we comment on our modified TBI model, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

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“…Specific forms of Alzheimer's pathology in which APOE4 is not a risk factor, such as PPA (primary progressive aphasia) with relative sparing of the hippocampal cortex, may be attributable to either localized, repeated trauma (or infection, vascular injury, and so on) to the affected lateral neocortex or to genetic risk factors that are preferentially expressed in affected cells rather than due to effects on amyloid metabolism. Likewise, potential protective factors, such as the use of statins in the context of head trauma, may function by their effects on the microvasculature or glial cells, either of which may operate through mitigation of cell damage, cell division, and cell senescence.…”

Section: Part 3: Addressing Key Questionsmentioning

confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury

Cited by 172 publications

References 59 publications

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

A unified model of dementias and age‐related neurodegeneration

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