Neural transplantation in animal models of multiple system atrophy: a review

Abstract

Multiple system atrophy of the striatonigral degeneration (MSA-SND) type is increasingly recognized as major cause of neurodegenerative parkinsonism. Due to combined degeneration of substantia nigra pars compacta (SNC) and of striatum, antiparkinsonian therapy based on levodopa substitution eventually fails in more than 90% of patients. Animal models of MSA-SND are urgently required as test-bed for the evaluation of novel therapeutic interventions in this disorder such as neurotrophic factor delivery and neuronal transplantation. A number of well established rodent and primate models of Parkinson's (PD) and Huntington's (HD) disease replicate either nigral ("PD-like") or striatal ("HD-like") pathology and may therefore provide a useful baseline for the development of MSA-SND models. Previous attempts to mimick MSA-SND pathology in rodents have included sequential injections of 6-hydroxydopamine (6OHDA) and quinolinic acid (QA) into medial forebrain bundle and ipsilateral striatum, respectively ("double toxin-double lesion" approach). Preliminary evidence in rodents subjected to such lesions indicates that embryonic transplantation may partially reverse behavioural abnormalities. Intrastriatal injections of mitochondrial toxins such as 3-nitropropionic acid (3NP) and 1-methyl-4-phenylpyridinium (MPP+) in rodents result in (secondary) excitotoxic striatal lesions and subtotal neuronal degeneration of ipsilateral SNC, thus producing MSA-SND-like pathology by a simplified "single toxin-double lesion" approach. Comparative studies of human SND pathology and rodent striatonigral lesions are required in order to determine the rodent model(s) most closely mimicking the human disease process.