Abstract
Lithium is a mood stabilizing agent commonly used for the treatment of bipolar disorder. Here, we investigated the potential neuroprotective effect of lithium against paraquat toxicity and its underlying mechanisms in vitro. SH-SY5Y human neuroblastoma cells were treated with paraquat (PQ) 0.5 mM concentration after lithium pretreatment to test lithium's capability in preventing cell toxicity. Cell death was evaluated by LDH, WST-8, and tryphan blue assays. Apoptosis was analyzed using DNA fragmentation, Annexin V immunostaining, Sub G1 cell cycle analysis, and caspase-3 activity assays. BCL2, BAX, and NRF2 protein expression were evaluated by Western-blotting and the BDNF protein level was determined with ELISA. mRNA levels of BCL2, BAX, BDNF, and NRF2 target genes (HO-1, GCS, NQO1), as well as miR-34a expression were analyzed by qPCR assay. Functional experiments were done via transfection with NRF2 siRNA and miR-34a mimic. Lithium treatment prevented paraquat induced cell death and apoptosis. Lithium treated cells showed increased anti-apoptotic protein BCL2 and decreased pro-apoptotic protein BAX expression. Lithium exerted a neurotrophic effect by increasing BDNF protein expression. It also diminished reactive oxygen species production and activated the redox sensitive transcription factor NRF2 and increased its target genes expression. Knockdown of NRF2 abolished neuroprotective, anti-apoptotic, and anti-oxidant effects of lithium. Furthermore, lithium significantly decreased both basal and PQ-induced expression of miR-34a. Transfection of miR-34a specific mimic reversed neuroprotective, anti-apoptotic, and anti-oxidant effects of lithium against PQ-toxicity. Our results revealed two novel mechanisms of lithium neuroprotection, namely NRF2 activation and miR-34a suppression.
Highlights
Lithium is a mood-stabilizing agent widely used for treatment of acute episodes as well as for long-term relapse prevention in patients with bipolar disorder (BD), an illness with evident abnormalities in brain pointing at a neurodegenerational process or represent disturbed neuronal development (Cousins and Grunze, 2012; Diniz et al, 2013; Malhi et al, 2013)
We examined the effect of lithium on mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and NRF2 -regulated genes including Heme-oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase (NQO1), glucosylceramide synthase (GCS)
The neuroprotective effect of lithium on PQ toxicity was evaluated in SH-SY5Y cells
Summary
Lithium is a mood-stabilizing agent widely used for treatment of acute episodes as well as for long-term relapse prevention in patients with bipolar disorder (BD), an illness with evident abnormalities in brain pointing at a neurodegenerational process or represent disturbed neuronal development (Cousins and Grunze, 2012; Diniz et al, 2013; Malhi et al, 2013). Apart from mood stabilization, neuroprotective and neurotrophic effects of lithium have been identified in clinical, preclinical, and in vitro studies (Forlenza et al, 2014). A wide variety of in vivo and in vitro studies confirmed neuroprotective effect of lithium against various insults (Pasquali et al, 2010; Diniz et al, 2013), rendering a potential for lithium in treatment of chronic neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease (PD), Amyotrophic lateral sclerosis, and Huntington’s disease. Inhibition of glycogen synthase kinase 3beta (GSK-3β) and inositol monophosphatase (IMPase), decreased the expression of the pro-apoptotic protein BAX and increased the expression of the anti-apoptotic protein BCL-2, activation of the cell survival kinases and increased expression of such neurotrophic factors brain-derived neurotrophic factor (BDNF) are wellknown effects of lithium (Forlenza et al, 2014)
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