Lithium improves cell viability in psychosine‐treated MO3.13 human oligodendrocyte cell line via autophagy activation

Abstract

Globoid cell leukodystrophy (GLD) is a rare, rapidly progressing childhood leukodystrophy triggered by deficit of the lysosomal enzyme galactosylceramidase (GALC) and characterized by the accumulation of galactosylsphingosine (psychosine; PSY) in the nervous system. PSY is a cytotoxic sphingolipid, which leads to widespread degeneration of oligodendrocytes and Schwann cells, causing demyelination. Here we report on autophagy in the human oligodendrocyte cell line MO3.13 treated with PSY and exploitation of Li as an autophagy modulator to rescue cell viability. We demonstrate that PSY causes upregulation of the autophagic flux at the level of autophagosome and autolysosome formation and LC3-II expression. We show that pretreatment with Li, a drug clinically used to treat bipolar disorders, can further stimulate autophagy, improving cell tolerance to PSY. This Li protective effect is found not to be linked to reduction of PSY-induced oxidative stress and might not stem from a reduction of PSY accumulation. These data provide novel information on the intracellular pathways activated during PSY-induced toxicity and suggest the autophagy pathway as a promising novel therapeutic target for ameliorating the GLD phenotype. © 2016 Wiley Periodicals, Inc.

Lithium prevents cell apoptosis through autophagy induction

“…Autophagosomes bind to lysosomes and create an autolysosome and its contents are degraded by lysosomal hydrolysis. In accordance with our study, also previous studies showed the protective effects of lithium in autophagy induction (29) in oligodendrocytes (30), microglia (31), endothelial cells (32), dopaminergic neurons (33), cerebel- lar cells (34), and PC12 cells (9). In addition, lithium also plays a protective role in autophagy induction in many diseases such as: spinal cord injury (35), amyotrophic lateral sclerosis, prion, Parkinson's disease and colorectal cancer (36).…”

A Novel Neuroprotective Mechanism for Lithium That Prevents Association of the p75NTR-Sortilin Receptor Complex and Attenuates proNGF-Induced Neuronal DeathIn VitroandIn Vivo

“…Among the most well-established functions of lithium ion is the phosphorylation and inhibition of GSK3β and as well as upregulating levels of BDNF and stimulating anti-apoptotic signaling ( Rowe and Chuang, 2004 ; Wada et al, 2005 ; Young, 2009 ; Pasquali et al, 2010 ). Additionally, lithium ion can promote autophagy, which can be neuroprotective, although this was observed at millimolar doses in vitro ( Motoi et al, 2014 ; Del Grosso et al, 2016 ; Liu et al, 2017 ), and at 50 mg/kg in vivo ( Liu et al, 2017 ), doses much higher than those used here. Lithium ion has also been shown to delay disease progression of amyotrophic lateral sclerosis (ALS) in humans and in the mouse G93A model of the disease ( Fornai et al, 2008 ).…”

“…Recently, we performed a drug screen to identify compounds that block the binding of proNGF to cells expressing sortilin and p75 NTR , and lithium citrate was among these compounds. Lithium ion can inhibit apoptosis by a variety of different mechanisms ( Wada et al, 2005 ), including increasing Akt activity, by phosphorylating and inactivating GSK3β ( Tajes et al, 2009 ; Pasquali et al, 2010 ), and promoting autophagy ( Motoi et al, 2014 ; Del Grosso et al, 2016 ; Liu et al, 2017 ). Chronic treatment with lithium has also been shown to upregulate BDNF expression in the brain ( Fukumoto et al, 2001 ) and retina ( Wu et al, 2014 ), which provides another potential neuroprotective mechanism for lithium ion.…”

Development of methods for detecting the fate of mesenchymal stem cells regulated by bone bioactive materials

“…In general, in vivo biological evaluation will be carried out after in vitro biological evaluation is qualified, and finally clinical research could be carried out. MSCs viability test can evaluate the cytocompatibility of materials by evaluating the viability of MSCs on bioactive materials [ [42] , [43] , [44] , [45] ]. MSCs proliferation could be regulated by bioactive materials.…”