Lithium protects against oxidative stress-mediated cell death in alpha-synuclein over-expressing in vitro and in vivo models of Parkinson’s disease

摘要

Lithium has recently been suggested to have neuroprotective properties in relation to several neurodegenerative diseases. In this study, we examined the potential cytoprotective effect of lithium in preventing oxidative stress-induced protein accumulation and neuronal cell death in the presence of increased alpha-synuclein levels in vitro and in vivo. Specifically, lithium administration was found to protect against cell death in a hydrogen peroxide treated, stable alpha-synuclein-EGFP over-expressing dopaminergic N27 cell line. Lithium feeding (0.255% lithium chloride) of 9 month old pan-neuronal alpha-synuclein transgenic mice over a 3 month period was also sufficient in preventing accumulation of oxidizeditrated alpha-synuclein as a consequence of chronic paraquat/maneb administration in multiple brain regions including the glomerular layer, mitral cells, and the granule cell layer of the olfactory bulb (OB), the striatum, substantia nigra pars compacta (SNpc), and Purkinje cells of the cerebellum. Lithium not only prevented alpha-synuclein mediated protein accumulation/aggregation in these brain regions but also protected neuronal cells including mitral cells and dopaminergic SNpc neurons against oxidative stress-induced neurodegeneration. These results suggest that lithium can prevent both alpha-synuclein accumulation and neurodegeneration in an animal model of PD, suggesting that this drug, already FDA-approved for use in bipolar disorder, may constitute a novel therapeutic for this other human disease.