No quiet surrender: molecular guardians in multiple sclerosis brain

Steinman, Lawrence

doi:10.1172/jci74255

Cited by 20 publications

(9 citation statements)

References 99 publications

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“…Exogenously administered agents require a high permeability through the BBB and a persisting bioavailability to ensure longlasting therapeutic effects (279). Only a limited number of small molecules has shown beneficial "protective" effects on glial cells following acute CNS insult so far, which is best documented during neuroinflammation (92, [280][281][282][283][284][285][286]. Thus, there is a dire need for novel strategies that mediate recovery after acute CNS insult and lead to long-term regeneration in chronic inflammatory and degenerative diseases.…”

Section: Therapeutic Outlook and Discussionmentioning

confidence: 99%

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

2020

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Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system.

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Section: Therapeutic Outlook and Discussionmentioning

confidence: 99%

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

2020

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“…Like the rockets designed by those famous Brocket scientists^, proteins can be designed by Bprotein engineers^without some of the undesired features, to make a new generation of guardian molecules [11]. It appears that EPO and activated protein C are 2 proteins that can be designed to provide anti-inflammatory benefit, without unwanted side effects.…”

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confidence: 99%

Parsing Physiological Functions of Erythropoietin One Domain at a Time

Steinman

2015

Neurotherapeutics

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A domain of erythropoietin (EPO), separate from the domain involved in red blood cell development, has been identified. This region of EPO has anti-inflammatory and neuroprotective effects. Use of a peptide sequence from this region provides the potential for an effective therapeutic without effects on erythropoiesis.Keywords Erythropoietin . Neuroprotection . Multiple sclerosis . Experimental autoimmune encephalomyelitis Although erythropoietin (EPO) is best known for its role in hematopoiesis, there are other functions that are instigated via this protein. EPO is effective as a neuroprotective molecule in various animal models of neuroinflammation and ischemia, including experimental autoimmune encephalomyelitis (EAE), brain trauma, and stroke [1][2][3][4][5][6]. Fortunately, proteins are often divided into discrete domains with different functional activities residing in different regions of the molecule. In this issue of Neurotherapeutics, Yuan et al. [7] discuss how they were able to dissociate a domain of EPO with antiinflammatory and neuroprotective effects from the regions of the molecule responsible for erythropoiesis. The ability to isolate the neuroprotective and anti-inflammatory effects of the molecule from its effects on red blood cell (RBC) development might enable the design of potent guardian molecules for unmet neurologic needs, without the potential side effect of EPO causing polycythemia, hypertension, and stroke.Yuan et al.[7] devised a successful strategy to parse the domains of EPO that might be free of its effect on RBC mass, while still retaining its neuroprotective effects. They made a library of peptides of lengths ranging from 7 to 25 amino acids, containing 1-2 cysteines. A 19-mer peptide containing 2 cysteines, termed JM-4, gave the strongest results, with antiinflammatory and protective properties dissociated from effects on RBC mass. The JM-4 peptide is derived from the AB loop of EPO. Shorter linear peptides, and peptides without the cysteines, were far less effective. For example, a 17-mer peptide from the same region was far less effective [7].The diligence and persistence of Yuan et al. [7] were worthwhile: they learned that while the 19-mer JM-4 was effective in 2 models of EAE, they also discovered that a shorter 17-mer containing only 1 cysteine residue was far less effective in these models. Apparently, length mattered considerably in this case: incorporation of the second cysteine was critical for these protective effects. Further understanding of the structure/function relationships stemming from this observation is likely to be interesting and will illuminate how EPO interacts with its receptor to attenuate inflammation.Yuan et al. [7] were able to demonstrate the reversal of paralytic disease at the onset of symptoms without effects on RBC mass. Proinflammatory cytokine production was reduced. JM-4 protected against demyelination and axonal loss [7]. In addition, they showed that JM-4 protected from amyloid β-induced toxicity in an in vitro model, indicating t...

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“…Remarkably, a component of the myelin sheath had evolved not only to serve as an insulator for the electrical response along axons, but may have coevolved to provide protection against inflammation in the brain (71). This result would exemplify how lipid components of the central nervous system have guardian properties to attenuate inflammation (5).…”

Section: Translational Research At Stanford Over the Past 20 Yearsmentioning

confidence: 99%

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

Steinman

2016

Mol Med

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Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by Lawrence Steinman, MD, of Stanford University in California. A visionary in the field of neurology, this is the story of Dr. Steinman's scientific journey.

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No quiet surrender: molecular guardians in multiple sclerosis brain

Cited by 20 publications

References 99 publications

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

Parsing Physiological Functions of Erythropoietin One Domain at a Time

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

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