Lithium protects against oxidative stress-mediated cell death in α-synuclein-overexpressing in vitro and in vivo models of Parkinson's disease

Buck Institute for Research on Aging, Novato, California 94945, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 10/2011; 89(10):1666-75. DOI: 10.1002/jnr.22700
Source: PubMed

ABSTRACT 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 α-synuclein levels in vitro and in vivo. Specifically, lithium administration was found to protect against cell death in a hydrogen peroxide-treated, stable α-synuclein-enhanced green fluorescent protein (EGFP)-overexpressing dopaminergic N27 cell line. Lithium feeding (0.255% lithium chloride) of 9-month-old pan-neuronal α-synuclein transgenic mice over a 3-month period was also sufficient to prevent accumulation of oxidized/nitrated α-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), striatum, substantia nigra pars compacta (SNpc) and Purkinje cells of the cerebellum. Lithium not only prevented α-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 α-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 therapy for another human disease.

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Available from: Julie Andersen, Sep 28, 2015
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    • "The antidepressants used in this study significantly reduced a-syn protein levels and the number of a-syn-positive cells in the basal ganglia of MBP1-ha-syn tg mice, likely due to an increase in a-syn clearance and/or to a reduction in a-syn accumulation in astrocytes. Antidepressants have been shown to reduce a-syn load in other a-syn tg models; for instance, lithium prevents both a-syn accumulation and neurodegeneration in an animal model of PD (Kim et al., 2011) and it induces the clearance of protein aggregates by autophagy (Sarkar et al., 2005). The reduction of a-syn in the particulate fraction of antidepressant-treated tg mice, together with the reduction in the number of a-syn-positive cells in basal ganglia, suggests that antidepressants might be of use as a-syn-reducing agents. "
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