Abstract
BackgroundAccurately assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models. With the development of transgenic mice, the rapid adaptation of a 6-OHDA mouse model of Parkinson’s disease that was originally described for the use in rats has come with a lack of a comprehensive characterization of lesion progression. In this study we therefore first characterised the time course of neurodegeneration in the substantia nigra pars compacta and striatum over a 4 week period following 6-OHDA injection into the medial forebrain bundle of mice. We then utilised the model to assess the anti-dyskinetic efficacy of recombinant activin A, a putative neuroprotectant and anti-inflammatory that is endogenously upregulated during the course of Parkinson’s disease.ResultsWe found that degeneration of fibers in the striatum was fully established within 1 week following 6-OHDA administration, but that the loss of neurons continued to progress over time, becoming fully established 3 weeks after the 6-OHDA injection. In assessing the anti-dyskinetic efficacy of activin A using this model we found that treatment with activin A did not significantly reduce the severity, or delay the time-of-onset, of dyskinesia.ConclusionFirst, the current study concludes that a 3 week duration is required to establish a complete lesion of the nigrostriatal tract following 6-OHDA injection into the medial forebrain bundle of mice. Second, we found that activin A was not anti-dyskinetic in this model.
Highlights
Assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models
Improvement in mortality rates is observed in the 6-OHDA mouse model when the injection location is shifted from the medial forebrain bundle (MFB) to either intrastriatal or intranigral, but this comes at the cost of reduced and more variable l-Dopa induced dyskinesia (LID) expression [10]
In order to establish the progression of lesion development, mice were unilaterally injected with 6-OHDA or ascorbic acid into the MFB and nigrostriatal degeneration was assessed over 4 weeks
Summary
Assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a reduction in dopamine availability in the striatum. This manifests as motor dysfunction, including tremors, rigidity and bradykinesia [1]. Improvement in mortality rates is observed in the 6-OHDA mouse model when the injection location is shifted from the medial forebrain bundle (MFB) to either intrastriatal or intranigral, but this comes at the cost of reduced and more variable LID expression [10]. We first aimed to investigate the progression of neuron loss in the SNpc and terminal loss in the striatum over a 4 week period
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