title: Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss.
abstract: This study was undertaken to examine the bioactivity, specificity, and reversibility of lithium's action on the growth, survival, proliferation, and differentiation of cultured Schwann cells (SCs). In isolated SCs, lithium promoted a state of cell cycle arrest that featured extensive cell enlargement and c-Jun downregulation in the absence of increased expression of myelin-associated markers. In addition, lithium effectively prevented mitogen-induced S-phase entry without impairing cell viability. When lithium was administered together with differentiating concentrations of cyclic adenosine monophosphate (cAMP) analogs, a dramatic inhibition of the expression of the master regulator of myelination Krox-20 was observed. Likewise, lithium antagonized the cAMP-dependent expression of various myelin markers such as protein zero, periaxin, and galactocerebroside and allowed SCs to maintain high levels of expression of immature SC markers even in the presence of high levels of cAMP and low levels of c-Jun. Most importantly, the inhibitory action of lithium on SC proliferation and differentiation was shown to be dose dependent, specific, and reversible upon removal of lithium compounds. In SC-neuron cultures, lithium suppressed myelin sheath formation while preserving axonal integrity, SC-axon contact, and basal lamina formation. Lithium was unique in its ability to prevent the onset of myelination without promoting myelin degradation or SC dedifferentiation. To conclude, our results underscored an unexpected antagonistic action of lithium on SC mitogenesis and myelin gene expression. We suggest that lithium represents an attractive pharmacological agent to safely and reversibly suppress the onset of SC proliferation, differentiation, and myelination while maintaining the integrity of pre-existing myelinated fibers.
authors.affiliation: The Miami Project to Cure Paralysis and the Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.|Universidad de Buenos Aires. CONICET, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Buenos Aires, Argentina.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Piñero
authors.affiliation: The Miami Project to Cure Paralysis and the Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Berg
authors.affiliation: The Miami Project to Cure Paralysis and the Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Natalia Denise
authors.initials: ND
authors.lastname: Andersen
authors.affiliation: Universidad de Buenos Aires. CONICET, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Buenos Aires, Argentina.
authors.forename: Patricia
authors.initials: P
authors.lastname: Setton-Avruj
authors.affiliation: The Miami Project to Cure Paralysis and the Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. pmonje@miami.edu.
authors.forename: Paula Virginia
authors.identifier: http://orcid.org/0000-0001-8510-9598
authors.initials: PV
authors.lastname: Monje
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018692:Antimanic Agents; D018021:Lithium Chloride
keywords: Dedifferentiation; Krox-20; Lithium chloride; Myelination; Schwann cells; cAMP