Motor neurone disease in molybdenum‐deficient sheep fed the endogenous purine xanthosine: possible mechanism for <i>Tribulus</i> staggers

Ca, Bourke

doi:10.1111/j.1751-0813.2012.00947.x

Cited by 10 publications

(26 citation statements)

References 15 publications

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“…The differential regulation of the purines xanthine, hypoxanthine, inosine and AMP under lithium treatment is consistent with the hypothesis of a central role for this pathway in depression [38]. Xanthosine, the corresponding nucleoside of xanthine, has been linked to stagger in sheep, thus associating purine to motor neuron disease [39]. Further, recent studies have shown that ascorbate levels act on the purine metabolism pathway, which suggests that the effect of lithium on ascorbate and purine metabolites that was observed in this study could be linked [40].…”

Section: Discussionsupporting

confidence: 83%

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

et al. 2013

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We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1154Q/+). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1154Q/+ mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1154Q/+ mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1154Q/+ mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.

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Section: Discussionsupporting

confidence: 83%

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

et al. 2013

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“…In a previous study, xanthosine ingestion by Mo‐deprived sheep was found to be the likely cause of T. terrestris MNS. Unusually, the altered neurotransmission that developed was associated with astrocyte degeneration, not neuronal cell body degeneration.…”

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confidence: 90%

“…Pasture molybdenum values in the northern hemisphere are typically between 0.9 and 2.6 ppm dry matter, but values as high as 60 ppm have been recorded . In Australia, plant Mo values as low as <0.01 ppm have been associated with outbreaks of a Tribulus terrestris ‐associated motor neurone syndrome (MNS) in sheep . Livestock have physiological mechanisms that prevent dietary sources of these purines from reaching the central nervous system (CNS), because they can exert neuromodulatory effects via an astrocyte‐dependent process that controls the uptake and release of the neurotransmitter glutamate .…”

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confidence: 99%

“…Species vary in their xanthine oxidase‐dehydrogenase activity. In most, it is high in liver, intestine, lung and blood, but low in the brain; however, in sheep it is only moderate in liver and very low in intestine, lung, blood and brain, which places them at great risk of excessive purine salvage should they ingest significant purine loads for extended periods while concurrently Mo‐deprived.…”

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confidence: 99%

“…Astrocytic dysfunction as a primary cause of altered neurotransmission is a relatively new concept . In the report of the xanthosine study, the term ‘motor neurone disease’ was used, but the term MNS would have been more appropriate. Motor neurone disease conventionally implies the presence of neuronal degeneration, in particular degeneration of the ventral horn motor neurones in the spinal cord, and although the ventral horn astrocytes that modulate these neurones were degenerate in the xanthosine syndrome, the neuronal cell bodies themselves were not.…”

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confidence: 99%

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Molybdenum deprivation, purine ingestion and an astrocyte‐associated motor neurone syndrome in sheep: assumed clinical effects of inosine

Ca¹

2015

Aust Veterinary J

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These findings suggest that purinergic neuromodulation of respiration, vocalisation and swallowing is different to that of limb movement. The syndrome produced, and assumed to be caused by the treatment given, has not been reported in livestock. A similar syndrome is seen in human motor neurone disease, but not in equine motor neurone disease, and this is consistent with it being an upper, not a lower, motor neurone effect.

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