Neurological disability correlates with spinal cord axonal loss and reduced N‐acetyl aspartate in chronic multiple sclerosis patients

Bjartmar, Carl; Kidd, Grahame J.; Mörk, Sverre; Rudick, Richard A.; Trapp, Bruce D.

doi:10.1002/1531-8249(200012)48:6<893::aid-ana10>3.3.co;2-2

Cited by 204 publications

(294 citation statements)

References 20 publications

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“…However, Met-RAN-TES modestly reduced neurological disability during the chronic-plateau phase of EAE. 81 As described previously, CXCR3 is present on virtually all perivascular lymphocytes in MS lesions, suggesting an important role for this chemokine receptor in directing T lymphocytes to sites of neuroinflammation. CXCR3 appeared to represent an exciting therapeutic target for MS disease, whose blockade might restrict the infiltration of pathogenic leukocytes into the CNS.…”

Section: Multiple Sclerosis: a Jumble Of Chemokines And Chemokine Recmentioning

confidence: 58%

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Savarin-Vuaillat¹,

Ransohoff²

2007

Neurotherapeutics

156

126

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Summary:Chemokines and chemokine receptors comprise a large number of molecules implicated in a wide range of physiological and pathological functions. Numerous studies have demonstrated the roles of chemokines and chemokine receptors: 1) during development, by regulating hematopoiesis, cardiogenesis, and vascular and cerebellar development; 2) during tumor biology, by controlling cell proliferation, angiogenesis, and metastasis; and 3), especially during leukocyte migration, by acting on firm adhesion, locomotion, diapedesis, and chemotaxis. This review focuses on chemokine and chemokine receptor involvement in diverse neurological diseases and their therapeutic potentials. Because of its induction or upregulation during CNS pathologies, members of the chemokine system can be used as biological markers. CXCR4 and CXCL12, by the correlation between their expression and the glioblastoma tumor progression, could be a marker to grade this type of CNS tumor. CCR1, by virtue of specific expression in A␤ plaques, may be a marker for Alzheimer pathology. Downregulation of CCL2 in cerebrospinal fluid may be a candidate to characterize multiple sclerosis (MS), but needs additional investigation. Moreover, chemokines and chemokine receptors represent interesting therapeutic targets. Using chemokine receptor antagonists, several studies provided exciting findings for potential neurological disease treatment. Chemokine receptor antagonists reduce disease severity in animal models of MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed an inhibition of tumor growth. Inhibition of chemokine receptor signaling is not the only therapeutic strategy: for example, CXCR4 -CXCL12 has anti-inflammatory properties and CX3CL1-CX3CR1 controls neurotoxicity. Thus, chemokine biology suggests several approaches for treating neurological disease.

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Section: Multiple Sclerosis: a Jumble Of Chemokines And Chemokine Recmentioning

confidence: 58%

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Savarin-Vuaillat¹,

Ransohoff²

2007

Neurotherapeutics

156

126

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“…Moreover, remyelination is typically incomplete and ultimately fails in the setting of recurrent episodes contributing to the progressive demyelination, gliosis, axonal damage, and neurodegeneration typically noted in MS [66,67]. Several studies have indicated that axonal pathology is the best correlate of chronic neurological impairment in MS and its animal model, experimental autoimmune encephalomyelitis (EAE) [68][69][70][71][72][73].…”

Section: Myelin Regeneration Fails In Msmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…Remyelination becomes less efficient in the later stage of MS in part due to a failure of OPC differentiation (Franklin and ffrench‐Constant, 2008; Kuhlmann et al, 2008; Wolswijk, 1998). Failure of remyelination is a major contributor to the accumulation of axonal and neuronal degeneration that characterizes the progressive stage of the disease in which clinical deficits accumulate over time (Bjartmar et al, 2000; De Stefano et al, 2001). The axonal degeneration observed after toxin‐induced demyelination in mice depleted of OPCs is prevented by the transplantation of exogenous OPCs that restore remyelination capacity (Irvine and Blakemore, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Neurological disability correlates with spinal cord axonal loss and reduced N‐acetyl aspartate in chronic multiple sclerosis patients

Cited by 204 publications

References 20 publications

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Cell Therapy for Multiple Sclerosis

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

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