Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury

Donnelly, Dustin J.; Popovich, Phillip G.

doi:10.1016/j.expneurol.2007.06.009

Cited by 851 publications

(796 citation statements)

References 189 publications

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“…these glutamate receptors may lead to progressive neuronal cell death, which is a hallmark of acute and chronic neurological diseases (17). Consequently, NMDA receptor antagonists such as dizocilpine (MK-801) or memantine were developed and revealed neuroprotective effects against ischemia-induced neuronal death in vitro and ischemic brain damage in vivo (18,19).…”

mentioning

confidence: 99%

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Dong

Fischer

Naudé

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

158

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Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF R2 , an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNF R2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

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mentioning

confidence: 99%

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Dong

Fischer

Naudé

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

158

View full text Add to dashboard Cite

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“…The innate immune system is essential for host defence but excessive or prolonged neutrophil‐mediated inflammation is also associated with injury and disease, especially in the brain 2. The above data provide evidence for platelet‐dependent neutrophil infiltration in three different tissue beds.…”

Section: Resultsmentioning

confidence: 75%

“…Neutrophils are the primary cellular response unit during the initial stages of these challenges and are essential for the destruction or removal of inciting stimuli 1. However, prolonged or excessive neutrophil‐mediated inflammation is injurious to adjacent healthy tissue in many situations, and is especially harmful during central nervous system (CNS) inflammation where capacity for repair is limited 2. An interaction with platelets is essential to trigger the tethering and rolling of neutrophils on inflamed venules, before their extravasation 3.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil infiltration to the brain is platelet‐dependent, and is reversed by blockade of platelet GPIbα

et al. 2018

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SummaryNeutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non‐microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue‐specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up‐regulation of CXCL‐1 (2·4‐fold) and CCL5 (1·4‐fold) acting as a compensatory mechanism in platelet‐reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet‐mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.

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“…Both glutamate and ATP lead to calcium overload, which can trigger multiple intracellular pathways leading to cell demise [19,20]. In addition, cytokines such as tumor necrosis factor-α and interleukin (IL)-1β, which are up-regulated within minutes after SCI [21,22], can exacerbate excitotoxicity by impairing glutamate uptake [23].…”

Section: Early Mechanisms Of Ol Lossmentioning

confidence: 99%

“…Infiltrating neutrophils and activated microglia release products that can promote OL loss, including free radicals, pro-inflammatory cytokines, glutamate, and proteases (reviewed by Donnelly and Popovich [22]). Lymphocytes reach peak levels in the rodent spinal cord at~1 week postinjury [24], and can lyse OLs directly [25] and/or induce apoptosis by releasing molecules that activate death receptors via tumor necrosis factor-α, IL-2, and interferon gamma (IFNγ).…”

Section: Early Mechanisms Of Ol Lossmentioning

confidence: 99%

Oligodendrocyte Fate after Spinal Cord Injury

2011

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Summary: Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and apoptosis acutely, with apoptosis continuing at chronic time points. Loss of OLs causes demyelination and impairs axon function and survival. In parallel, a rapid and protracted OL progenitor cell proliferative response occurs, especially at the lesion borders. Proliferating and migrating OL progenitor cells differentiate into myelinating OLs, which remyelinate demyelinated axons starting at 2 weeks postinjury. The progression of OL lineage cells into mature OLs in the adult after injury recapitulates development to some degree, owing to the plethora of factors within the injury milieu. Although robust, this endogenous oligogenic response is insufficient against OL loss and demyelination. First, in this review we analyze the major spatial-temporal mechanisms of OL loss, replacement, and myelination, with the purpose of highlighting potential areas of intervention after SCI. We then discuss studies on OL protection and replacement. Growth factors have been used both to boost the endogenous progenitor response, and in conjunction with progenitor transplantation to facilitate survival and OL fate. Considerable progress has been made with embryonic stem cellderived cells and adult neural progenitor cells. For therapies targeting oligogenesis to be successful, endogenous responses and the effects of the acute and chronic lesion environment on OL lineage cells must be understood in detail, and in relation, the optimal therapeutic window for such strategies must also be determined.

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Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury

Cited by 851 publications

References 189 publications

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Neutrophil infiltration to the brain is platelet‐dependent, and is reversed by blockade of platelet GPIbα

Oligodendrocyte Fate after Spinal Cord Injury

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