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Abstract Background Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD. Results Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels. Conclusions Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.

Metal phosphides, particularly zinc and aluminum phosphide, occasionally poison horses and other equids following their use as rodenticides and insecticides. Grain-based aluminum phosphide baits are used to control rodents such as prairie dogs. The clinical course in intoxicated horses is short (<24–48 h), and animals may be found dead. Hepatic lesions caused by phosphine poisoning are not well described. Laboratory confirmation depends on detecting phosphine gas in gastric contents. Eight horses and a mule were exposed to zinc phosphide used to control prairie dogs on a Wyoming ranch. Three of 9 exposed equids developed some combination of sweating, ataxia, anxiety, and colic; 2 died acutely, and 1 recovered. A diagnosis of zinc phosphide was made by detecting phosphine in stomach contents from a horse and a mule. The liver was pale and swollen in the affected horse, which died after a clinical course of ~12 h. Other changes were generalized congestion and edema, pulmonary edema, and acute cerebrocortical edema. There was diffuse hepatocellular microvesicular steatosis. Similar histologic lesions were present in 7 equine livers from 2 previously published episodes of metallic phosphide poisoning. Older lesions (>24 h of clinical signs) had centrilobular hepatic necrosis with congestion and a mixture of microvesicular and macrovesicular steatosis. Phosphine poisoning should be considered in horses that die acutely and are found to have steatosis, either with or without hepatocellular necrosis. [ABSTRACT FROM AUTHOR]

Cystamine, a small disulfide-containing chemical, is neuroprotective in a transgenic mouse and a Drosophila model of Huntington's disease (HD) and decreases huntingtin aggregates in an in vitro model of HD. The mechanism of action of cystamine in these models is widely thought to involve inhibition of transglutaminase mediated cross-linking of mutant huntingtin in the process of aggregate formation/stabilization. In this study we show that cystamine, both in vitro and in a transgenic mouse model of HD (R6/2), increases levels of the cellular antioxidant L-cysteine. Several oxidative stress markers increase in HD brain. We provide further evidence of oxidative stress in mouse HD by demonstrating compensatory responses in R6/2 HD brains. We found age-dependent increases in forebrain glutathione (GSH), and increased levels of transcripts coding for proteins involved in GSH synthesis and detoxification pathways, as revealed by quantitative PCR analysis. Given the general importance of oxidative stress as a mediator of neurodegeneration we propose that an increase in brain L-cysteine levels could be protective in HD. Furthermore, cystamine was dramatically protective against 3-nitropropionic acid-induced striatal injury in mice. We suggest that cystamine's neuroprotective effect in HD transgenic mice results from pleiotropic effects that include transglutaminase inhibition and antioxidant activity. [ABSTRACT FROM AUTHOR]

Phenyl saligenin phosphate (PSP) induces a central-peripheral distal axonopathy in domestic fowl that develops 7-21 days after a single exposure. Neurotoxic esterase (NTE) is the initial molecular target for this neurotoxicity. PSP has to covalently bind to NTE and chemically "age" for induction of axonopathy. It was hypothesized that exposure to PSP results in early changes in spinal cord gene expression that do not occur with phenylmethylsulfonyl fluoride, a non-neuropathic compound that also inhibits NTE, or DMSO controls. Targeted display was used to screen approximately 15,000 gel bands. Three candidate genes were identified, but only the transcript designated P1 showed decreased expression following PSP exposure (2 mg/kg i.m.) in subsequent Northern blot and in situ hybridization experiments in samples taken <48 h after exposure. Additional experiments revealed that a approximately 2.5 kb alpha-tubulin transcript had decreased expression at 12-48 h after PSP exposure, with maximum change at 48 h (33%, p = 0.0479). A approximately 4.5 kb alpha-tubulin transcript had increased expression at 12 h (38%, p = 0.0125) and decreased expression at 48 h (28%, p = 0.0576). In situ hybridization on spinal cord revealed neuronal expression of P1 and alpha-tubulin transcripts. Decreased expression of transcripts for P1 and alpha-tubulin was present at 12 and 48 h, respectively. This decrease occurred in all neurons, not just those whose axons degenerate. Results suggest that (1) in PSP-induced OPIDN (organophosphorus-induced delayed neurotoxicity) some gene transcript expression changes are associated with initiation of axonopathy, and (2) PSP modulates spinal cord gene expression in neuronal types that do not undergo axonal degeneration., (Copyright 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:263-271, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10088)