MSA is a variant of PD characterized by a combination of clinical symptoms involving cerebellar, extra-pyramidal, and autonomic systems. The predominant subtype of MSA is striatonigral degeneration (SND), a form of levodopa unresponsive parkin-sonism. Neuropathological changes of SND include degeneration of the nigrostri-atal pathway, medium spiny striatal GABAergic projection pathways (putamen greater then caudate), as well as other regions of the brainstem, cerebellum, and spinal cord. Inclusion-like aggregates that immuno-stain for ubiquitin and alpha-synuclein are seen in oligodendrocytes and neurons.
The basis for developing an animal model for SND emerged from established animal models for both parkinsonism having SNpc pathology and Huntington's disease (HD) with striatal pathology. For example, rodent models for SND have been generated through sequential stereotaxic injections of 6-OHDA and quinolinic acid (QA) into the medial forebrain bundle and striatum or striatal injections of MPP+ and 3-nitropropionic acid (3-NP) (220-222). These double-lesioning models are characterized morphologically by neuronal degeneration in the SNpc and ipsilateral striatum. The order of neurotoxic lesioning may influence the degree of nigral or striatal pathology. For example, animals receiving 6-OHDA prior to QA exhibit predominantly nigral pathology, whereas animals receiving QA prior to 6-OHDA show predominantly striatal pathology. This may be due to QA-induced terminal damage or other complex interactions after lesioning that reduce the terminal uptake of 6-OHDA. Glial inclusions have not been reported in any of these models, indicating a significant difference compared with the human condition.
Motor deficits in models for MSA and SND are assessed by ipsilateral and contralateral motor tasks (including stepping response, impaired paw reaching, and balance) and drug-induced circling behavior. As described earlier, characteristic drug-induced circling behavior occurs after 6-OHDA lesioning, resulting in ipsilat-eral rotation in response to amphetamine and contralateral rotation in response to apomorphine. The subsequent striatal lesioning with QA diminishes or has no affect on amphetamine-induced ipsilateral rotation and reduces or abolishes apomorphine-induced contralateral rotation. This observation may be mediated by dopamine release on the intact side in response to amphetamine and/or the loss of dopamine receptor activation on the lesioned side in response to apomorphine. The lack of response to apomorphine has been shown to correlate with the volume of the striatal lesion and is analogous to the diminished efficacy of levodopa therapy observed in the majority of SND patients.
A nonhuman primate (Macaca fasicularis) model of SND has been generated through the sequential systemic administration of MPTP and 3-NP (220,223). The parkinsonian features after MPTP-lesioning are levodopa responsive; however, subsequent administration of 3-NP worsens motor symptoms and nearly eliminates the levodopa response. Levodopa occasionally induces facial dyskinesia as sometimes seen in human MSA. Similar to SND, morphological changes include cell loss in the SNpc (typical of MPTP-lesioning) and severe circumscribed degeneration of striatal GABAergic projection neurons (typical of 3-NP lesioning). Despite the similarities with the human condition, the MSA model is characterized by an equal degree of lesioning in the putamen and caudate nucleus, whereas in human SND, the putamen is more affected. In addition, inclusion bodies that may underlie the pathogenesis of SND have not been reported in the nonhuman primate model.
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