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Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression

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Show simple item record Kay, Graham W. en Palmer, David N. en 2016-05-09T01:36:37Z 2013-07-30 en
dc.identifier.issn 1742-2094 en
dc.description.abstract Background: The neuronal ceroid lipofuscinoses (NCLs; or Batten disease) are fatal inherited human neurodegenerative diseases affecting an estimated 1:12,500 live births worldwide. They are caused by mutations in at least 11 different genes. Currently, there are no effective treatments. Progress into understanding pathogenesis and possible therapies depends on studying animal models. The most studied animals are the CLN6 South Hampshire sheep, in which the course of neuropathology closely follows that in affected children. Neurodegeneration, a hallmark of the disease, has been linked to neuroinflammation and is consequent to it. Activation of astrocytes and microglia begins prenatally, starting from specific foci associated with the later development of progressive cortical atrophy and the development of clinical symptoms, including the occipital cortex and blindness. Both neurodegeneration and neuroinflammation generalize and become more severe with increasing age and increasing clinical severity. The purpose of this study was to determine if chronic administration of an anti-inflammatory drug, minocycline, from an early age would halt or reverse the development of disease. Method: Minocycline, a tetracycline family antibiotic with activity against neuroinflammation, was tested by chronic oral administration of 25 mg minocycline/kg/day to presymptomatic lambs affected with CLN6 NCL at 3 months of age to 14 months of age, when clinical symptoms are obvious, to determine if this would suppress neuroinflammation or disease progression. Results: Minocycline was absorbed without significant rumen biotransformation to maintain pharmacological concentrations of 1 μM in plasma and 400 nM in cerebrospinal fluid, but these did not result in inhibition of microglial activation or astrocytosis and did not change the neuronal loss or clinical course of the disease. Conclusion: Oral administration is an effective route for drug delivery to the central nervous system in large animals, and model studies in these animals should precede highly speculative procedures in humans. Minocycline does not inhibit a critical step in the neuroinflammatory cascade in this form of Batten disease. Identification of the critical steps in the neuroinflammatory cascade in neurodegenerative diseases, and targeting of specific drugs to them, will greatly increase the likelihood of success. en
dc.format.extent 97-105 en
dc.language.iso en en
dc.publisher Springer en
dc.relation The original publication is available from - Springer - en
dc.relation.uri en
dc.rights © 2013 Kay and Palmer; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. en
dc.rights.uri en
dc.subject CLN6 en
dc.subject Anti-inflammatory drugs en
dc.subject Batten disease en
dc.subject Cerebrospinal fluid en
dc.subject Cortical atrophy en
dc.subject CSF en
dc.subject HPLC en
dc.subject NCL en
dc.subject Neurodegeneration en
dc.subject Neuroinflammation en
dc.subject Ovine model en
dc.subject Neurology & Neurosurgery en
dc.subject.mesh Brain en
dc.subject.mesh Neuroglia en
dc.subject.mesh Animals en
dc.subject.mesh Sheep en
dc.subject.mesh Neurodegenerative Diseases en
dc.subject.mesh Atrophy en
dc.subject.mesh Disease Progression en
dc.subject.mesh Inflammation en
dc.subject.mesh Minocycline en
dc.subject.mesh Glial Fibrillary Acidic Protein en
dc.subject.mesh Anti-Bacterial Agents en
dc.subject.mesh Liver Function Tests en
dc.subject.mesh Chromatography, High Pressure Liquid en
dc.subject.mesh Macrophage Activation en
dc.subject.mesh Growth en
dc.subject.mesh Image Processing, Computer-Assisted en
dc.subject.mesh Female en
dc.subject.mesh Male en
dc.subject.mesh Neuronal Ceroid-Lipofuscinoses en
dc.title Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression en
dc.type Journal Article
lu.contributor.unit Lincoln University en
lu.contributor.unit Faculty of Agriculture and Life Sciences en
lu.contributor.unit Department of Wine, Food and Molecular Biosciences en
lu.contributor.unit Research Management Office en
lu.contributor.unit /LU/Research Management Office/2018 PBRF Staff group en
dc.identifier.doi en
dc.subject.anzsrc 1103 Clinical Sciences en
dc.subject.anzsrc 1109 Neurosciences en
dc.subject.anzsrc 1107 Immunology en
dc.relation.isPartOf Journal of Neuroinflammation en
pubs.organisational-group /LU
pubs.organisational-group /LU/Agriculture and Life Sciences
pubs.organisational-group /LU/Agriculture and Life Sciences/WFMB
pubs.organisational-group /LU/Research Management Office
pubs.organisational-group /LU/Research Management Office/2018 PBRF Staff group
pubs.publication-status Published en
pubs.volume 10 en
dc.rights.licence Attribution en

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