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Cystamine and ethyl-eicosapentaenoic acid treatment fail to prevent malonate-induced striatal toxicity in mice
Saskia N Sivananthan1, Blair R Leavitt
1Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, University of British Columbia, British Columbia, Vancouver, Canada.
Abstract:
Cystamine has demonstrated neuroprotective activity in a variety of studies, and is currently being evaluated in a human clinical trial in Huntington's disease (HD). Cystamine treatment of various genetic models of HD demonstrated protection against neurodegeneration and/or improvement in behavior. Given the need for a rapid screening tool for HD therapeutics, we assessed the potential therapeutic benefits of cystamine in a short-term acute toxicity murine model of striatal cell death. Cystamine did not provide neuroprotection against bilateral intrastriatal malonate injections in mice as measured by lesion size, loss of striatal volume, or decreased striatal neuronal counts. Similar results were obtained for treatment with another potential therapeutic agent that was protective in genetic mouse models of HD, the essential fatty acid ethyl-eicosapentaenoic acid. Our findings suggest that this toxic model is not reflective or predictive of findings in genetic mouse models, and may not be useful as a preclinical screen for HD therapeutics.
Insights
Cystamine showed no neuroprotection in an acute mouse model of Huntington's disease (HD). This study suggests the acute toxicity model may not accurately predict therapeutic efficacy for HD treatments.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Cystamine exhibits neuroprotective effects in Huntington's disease (HD) models and is in clinical trials.
- Genetic mouse models of HD have shown benefits from cystamine treatment, including reduced neurodegeneration and improved behavior.
Purpose of the Study:
- To evaluate cystamine's therapeutic potential in a short-term acute murine model of striatal cell death.
- To assess the utility of this acute toxicity model as a preclinical screen for HD therapeutics.
Main Methods:
- Administered cystamine to a murine model of acute striatal cell death induced by malonate injections.
- Assessed neuroprotection by measuring lesion size, striatal volume loss, and neuronal counts.
- Compared results with ethyl-eicosapentaenoic acid, another agent protective in genetic HD models.
Main Results:
- Cystamine did not provide neuroprotection against malonate-induced striatal cell death in mice.
- No significant differences were observed in lesion size, striatal volume, or neuronal counts.
- Ethyl-eicosapentaenoic acid also failed to show protection in this acute model.
Conclusions:
- The acute malonate-induced striatal toxicity model is not reflective of findings in genetic HD mouse models.
- This model may not be a reliable preclinical screen for identifying effective HD therapeutics.
