Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis

Lee, Dong Hoon; Rötger, Caroline; Appeldoorn, Chantal C.M.; Reijerkerk, Arie; Gladdines, Werner; Gaillard, Pieter J.; Linker, Ralf A.

doi:10.1016/j.jneuroim.2014.06.025

Cited by 41 publications

(23 citation statements)

References 24 publications

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“…The severity of inflammation initiated after SCI is of a higher intensity and longer duration than is observed in trauma in an extra-neural soft tissue. This is related to the large quantity of damaged myelin, a potently immunogenic, pro-inflammatory material in the white matter injury in models of neurotrauma [40][41][42] and of multiple sclerosis [43] and to a potential mechanism of a vicious cycle sustaining severe inflammation. A large amount of damaged myelin is associated with the initiation of chemotaxis of numerous macrophages into the necrotic site starting at day 3 post-SCI.…”

Section: Discussionmentioning

confidence: 99%

“…In parallel with myelin-phagocytizing, activated macrophages high levels of pro-inflammatory factors were released in the spinal cord including pro-inflammatory cytokines; IFN-gamma, TNF-alpha, IL1-beta, IL-6 ( Fig 6), chemokines (CC and CXC), and reactive oxygen species [2]. The additional supply of damaged myelin likely sustained further macrophage chemotaxis [40,43]. Given the mechanism proposed here for the vicious cycle of The COI apparently expands during the long Inflammatory Phase and is surrounded and thus limited by gradually growing in the density wall of reactive astrogliosis while the severity of macrophage infiltration declines in the Resolution Phase.…”

Section: Discussionmentioning

confidence: 99%

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Prolonged inflammation leads to ongoing damage after spinal cord injury

et al. 2020

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The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68 + /CD163macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other proinflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prolonged inflammation leads to ongoing damage after spinal cord injury

et al. 2020

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“…This nanoplatform has also been exploited for the delivery of methylprednisolone (2B3-201), enhancing its transport up to 6.5-fold. 142 2B3-201 is capable of reducing neuroinflammation in rats with encephalomyelitis, and reached Phase I clinical trials for multiple sclerosis 55 (ClinicalTrials.gov identifier: NCT02048358). Even more remarkable is the selective increase in brain delivery of single domain antibodies against amyloid plaques in APP/PS1 mice.…”

Section: Gsh: a Highly Specialized Shuttlementioning

confidence: 99%

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

et al. 2016

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Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins.

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“…6), chemokines (CC and CXC), and reactive oxygen species [1]. The additional supply of damaged myelin likely sustained further macrophage chemotaxis [38, 41]. Given the mechanism proposed here for the vicious cycle of damage and inflammation, the extraordinary duration of the inflammation, beyond 16 weeks post-SCI can be explained.…”

Section: Discussionmentioning

confidence: 99%

Prolonged inflammation leads to ongoing damage after spinal cord injury

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et al. 2019

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27The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains 28 limited. Emerging evidence indicates the severity of post-SCI inflammation and an ongoing 29 controversy in the roles of astrocytes with studies identifying astrocytes as associated both with 30 ongoing inflammation and damage as well as potentially having a protective role. We have 31 completed an extensive systematic study with MRI, histopathology, proteomics and ELISA 32 analyses designed to further define the severe protracted and damaging inflammation after SCI in 33 a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting 34 day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68 + /CD163 -35 macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) 36 when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous 37 tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163macrophage 38 numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present 39 at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by 40 a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord 41 edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around 42 the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. 43Acutely increased levels of TNF-, IL-1, IFN- and other pro-inflammatory cytokines, 44 chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In 45 this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have 46 demonstrated a close association between progressive astrogliosis and reduction in the severity of 47 inflammation. 48 4 49 50 KEYWORDS 51 Neurotrauma inflammation, cavity of injury, arachnoiditis, M1 macrophage, astrogliosis. 5 52 53Spinal cord injury (SCI) is a leading cause of long term morbidity after motor vehicle 54 accidents or trauma in combat, with no clinically standardized or substantially effective treatment. 55Effective therapeutics have remained limited due to an incomplete understanding of the 56 pathogenesis of SCI and thus identified effective therapeutic targets while the underlying and 57 persistent inflammatory damage after SCI remains poorly characterized. The role of invasive 58 inflammatory cells and specifically astrogliosis in the ongoing damage after SCI is not fully 59 defined with studies supporting both a role in SCI damage [1,2] as well as a proposed potential 60 protective role for astrocytes [3]. We have completed an extensive analysis with MRI, 61 histochemistry, proteomics and ELISA in a rat model of SCI in order to further define the 62 pathological changes that occur after SCI. 63 SCI initiates hemorrhage and ischemia, free radical release, severe inflammation,...

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Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis

Cited by 41 publications

References 24 publications

Prolonged inflammation leads to ongoing damage after spinal cord injury

Prolonged inflammation leads to ongoing damage after spinal cord injury

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

Prolonged inflammation leads to ongoing damage after spinal cord injury

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