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Title: Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model
Authors: Kemp, KC
Cerminara, N
Hares, K
Redondo, J
Cook, AJ
Haynes, HR
Burton, BR
Pook, M
Apps, R
Scolding, NJ
Wilkins, A
Issue Date: 2016
Citation: Annals of neurology, (2016)
Abstract: Objectives: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuro-protective effects of the cytokines granulocyte-colony stimulating factor and stem cell factor in a humanised murine model of Friedreich's ataxia. Methods: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioural motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for mRNA, protein and histological analysis of the dorsal root ganglion, spinal cord and cerebellum. Results: Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological and behavioural deficits associated with Friedreich's ataxia. Both granulocyte-colony stimulating factor and stem cell factor had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease), and on regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were seen, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. Interpretation: These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying and neuroprotective treatment for Friedreich's ataxia. This article is protected by copyright. All rights reserved.
ISSN: 0364-5134
Appears in Collections:Dept of Life Sciences Research Papers

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