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

BackgroundThe 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.MethodMinocycline, 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.ResultsMinocycline 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.ConclusionOral 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.

Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration

“…The above findings suggest that inhibition of neuroinflammation is not sufficient enough to prevent neuron loss. However, since only one dose of minocycline was used to treat the mouse model (this study) or the sheep model 15 , we can not rule out the possibility that higher doses of the drug may show protective effects.…”

“…The selection of this starting point for the drug treatment is important. First, in a recent treatment study, minocycline was administered to a sheep model of ND at a stage where neuroinflammation had already started 15 . Neither neuron loss nor neuroinflammation was suppressed 15 .…”

“…First, in a recent treatment study, minocycline was administered to a sheep model of ND at a stage where neuroinflammation had already started 15 . Neither neuron loss nor neuroinflammation was suppressed 15 . Second, no improvement on plaque pathology was observed when the drug was given to APP Tg mice at a post-neuroinflammation stage 20 .…”

“…Accumulating evidence has indicated that anti-inflammatory agents are protective for AD 13 . Neuroinflammation was reported to take place prior to overt neuron loss in various animal models displaying age-related neuron loss 14 15 16 . Therefore, neuroinflammation is an early event of neurodegeneration and may play a critical role in the disease progression.…”

Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses

“…Neuroinflammation is a hallmark of many NCLs. The efficacy of the antibiotic minocycline to suppress neuroinflammation and neurodegeneration has been analyzed in a naturally occurring CLN6 sheep model [ 21 ]. Oral administration of minocycline to pre-symptomatic lambs did not alter neuroinflammation and neurodegeneration.…”