Motor evoked potentials in a mouse model of chronic multiple sclerosis

Amadio, Stefano; Pluchino, ﻿Stefano; Brini, Elena; Morana, Paolo; Guerriero, R.; Boneschi, Filippo Martinelli; Comı, Gıancarlo; Zaratin, Paola; Muzio, Valeria; Carro, Ubaldo Del

doi:10.1002/mus.20463

Cited by 25 publications

(22 citation statements)

References 32 publications

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“…Both immunohistological and cortical motor evoked potential studies have suggested there is a substantial diminution in corticospinal axon numbers in mice with long-standing MOG peptide EAE (Black et al, 2006; Amadio et al, 2006). Enumeration of specifically labeled corticospinal axons would be desirable to strengthen this conclusion.…”

Section: Resultsmentioning

confidence: 99%

Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Soulika¹,

Lee²,

McCauley³

et al. 2009

J. Neurosci.

129

131

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Axonal loss is the principal cause of chronic disability in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). In C57BL/6 mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide 35-55, the first evidences of axonal damage in spinal cord were in acute subpial and perivascular foci of infiltrating neutrophils and lymphocytes and included intra-axonal accumulations of the endovesicular Toll-like receptor TLR8, and the inflammasome protein NAcht leucine-rich repeat protein 1 (NALP1). Later in the course of this illness, focal inflammatory infiltrates disappeared from the spinal cord, but there was persistent activation of spinal cord innate immunity and progressive, bilaterally symmetric loss of small-diameter corticospinal tract axons. These results support the hypothesis that both contact-dependent and paracrine interactions of systemic inflammatory cells with axons and an innate immune-mediated neurodegenerative process contribute to axonal loss in this multiple sclerosis model.

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Section: Resultsmentioning

confidence: 99%

Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Soulika¹,

Lee²,

McCauley³

et al. 2009

J. Neurosci.

129

131

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“…Mice were anesthetized with trichloroethanol, 0.02 ml/g of body weight, and placed under a heating lamp to avoid hypothermia. Neurophysiological studies were performed as described (14,32). An unpaired Student's t test (2-tailed distribution, 2 samples with equal variance, α = 0.05) was performed for statistical evaluation of the data.…”

Section: Methodsmentioning

confidence: 99%

Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice

Biffi¹,

Capotondo²,

Fasano³

et al. 2006

J. Clin. Invest.

Self Cite

217

183

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Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSAoverexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients.

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“…Treatment with Ad-G/IL4 significantly improved also the neurophysiological parameters. Motor-evoked potentials (MEP)-used as a functional measure of corticospinal tract integrity 14 -were measured in C-EAE mice at 75 days post-immunization. MEP was recordable in 10/11 (91%) of the Ad-G/IL4-treated mice but in only 5/10 (50%) of the control, Ad-Gtreated mice (Po0.05, w 2 ).…”

Section: Intracisternal Delivery Of Ad-g/il4 Induces Clinical and Funmentioning

confidence: 99%

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

et al. 2008

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Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity.Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4 + CD69 À CD25 + Foxp3 + ) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

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Motor evoked potentials in a mouse model of chronic multiple sclerosis

Cited by 25 publications

References 32 publications

Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

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