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.

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.

• Authors: Graham W Kay, David N Palmer
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 10 Pg. 97 (Jul 30 2013) ISSN: 1742-2094 [Electronic] England
• PMID: 23899308 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Glial Fibrillary Acidic Protein
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (cerebrospinal fluid, pharmacokinetics, pharmacology)
• Atrophy
• Brain (metabolism, pathology)
• Chromatography, High Pressure Liquid
• Disease Progression
• Female
• Glial Fibrillary Acidic Protein (biosynthesis, genetics)
• Growth (drug effects)
• Image Processing, Computer-Assisted
• Inflammation (chemically induced, pathology)
• Liver Function Tests
• Macrophage Activation (drug effects)
• Male
• Minocycline (cerebrospinal fluid, pharmacokinetics, pharmacology)
• Neurodegenerative Diseases (pathology)
• Neuroglia (drug effects)
• Neuronal Ceroid-Lipofuscinoses (metabolism, pathology)
• Sheep