Article

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.

Download full-text

Full-text

Available from: Julie Andersen
    • "α-synuclein plays a key role in maintaining synaptic vesicles in presynaptic terminals and regulating the release of dopamine (Sidhu et al., 2004). One effect of lithium is to prevent the effects of elevated α-synuclein on oxidatively driven cell death (Kim et al., 2011). The inhibitory effect of α-synuclein on complex I seems to be dose-dependent and affects certain regions of the brain, suggesting that α-synuclein may be a potential factor underlying decreased neuronal densities observed in BD (Liu et al., 2009, Savitz et al., 2014, Gigante et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.
    No preview · Article · Dec 2015
  • Source
    • "Similarly, lithium was found to be protective against oxidative stress in rat dopaminergic N27 cells which over-express A53T alpha-synuclein. In the brains of alpha-synuclein A53T over-expressing transgenic mice, lithium prevents/degrades paraquat/maneb-induced alphasynuclein protein aggregation (Kim et al., 2011). Chronic lithium treatment in vivo and in vitro in the absence of either neurotoxin showed significant increases in tyrosine hydroxylase in the frontal cortex, hippocampus, and striatum of rats and mice as well as in human neuroblastoma SH-SY5Y and rat dopaminergic N27 cells (Chen et al., 1998; Lieu et al., 2014; Lazzara et al., 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lithium, the long-standing hallmark treatment for bipolar disorder, has recently been identified as a potential neuroprotective agent in neurodegeneration. Here we focus on introducing numerous in vitro and in vivo studies that have shown lithium treatment to be efficacious in reducing oxidative stress and inflammation, increasing autophagy, inhibiting apoptosis, and decreasing the accumulation of α-synulcein, with an emphasis on Parkinson's disease. A number of biological pathways have been shown to be involved in causing these neuroprotective effects. The inhibition of GSK-3β has been the mechanism most studied; however, other modes of action include the regulation of apoptotic proteins and glutamate excitotoxicity as well as down-regulation of calpain. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side-effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases.
    Full-text · Article · Oct 2015 · Frontiers in Neuroscience
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the pathological accumulation of alpha-synuclein (α-syn) within oligodendroglial cells. This accumulation is accompanied by neuroinflammation with astrogliosis and microgliosis, that leads to neuronal death and subsequent parkinsonism and dysautonomia. Antidepressants have been explored as neuroprotective agents as they normalize neurotrophic factor levels, increase neurogenesis and reduce neurodegeneration, but their anti-inflammatory properties have not been fully characterized. We analyzed the anti-inflammatory profiles of three different antidepressants (fluoxetine, olanzapine and amitriptyline) in the MBP1-hα-syn transgenic (tg) mouse model of MSA. We observed that antidepressant treatment decreased the number of α-syn-positive cells in the basal ganglia of 11-month-old tg animals. This reduction was accompanied with a similar decrease in the colocalization of α-syn with astrocyte markers in this brain structure. Consistent with these results, antidepressants reduced astrogliosis in the hippocampus and basal ganglia of the MBP1-hα-syn tg mice, and modulated the expression levels of key cytokines that were dysregulated in the tg mouse model, such as IL-1β. In vitro experiments in the astroglial cell line C6 confirmed that antidepressants inhibited NF-κB translocation to the nucleus and reduced IL-1β protein levels. We conclude that the anti-inflammatory properties of antidepressants in the MBP1-hα-syn tg mouse model of MSA might be related to their ability to inhibit α-syn propagation from oligodendrocytes to astroglia and to regulate transcription factors involved in cytokine expression. Our results suggest that antidepressants might be of interest as anti-inflammatory and α-syn-reducing agents for MSA and other α-synucleinopathies. GLIA 2013.
    Full-text · Article · Feb 2014 · Glia
Show more