title: Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells.
abstract: The mood stabilizing drug lithium is a highly effective treatment for bipolar disorder. Previous studies in our laboratory found that chronic treatment with the mood stabilizing drug valproate in rat brain increased the expression of endoplasmic reticulum (ER) stress proteins GRP78, GRP94 and calreticulin. We report here that in primary cultured rat cerebral cortical cells, expression of GRP78, GRP94 and calreticulin are increased not only by valproate, but also by lithium after chronic treatment for 1 week at therapeutically relevant concentrations. However, two other mood stabilizing drugs carbamazepine and lamotrigine had no effect on expression of GRP78, GRP94 or calreticulin. Chronic treatment with lithium for 1 week increased both mRNA and protein levels of ER stress proteins. In contrast to a classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca2+ -ATPase, chronic treatment with lithium or valproate for 1 week modestly increased GRP78 expression in neuronal cells, had no effect on basal intracellular free Ca2+ concentration and does not induce cell death. These results indicate that lithium and valproate may increase expression of GRP78, GRP94 and calreticulin in primary cultured rat cerebral cortical cells without causing cell damage. These results also suggest that the mechanism of GRP78 increase induced by lithium and valproate may be different from that of thapsigargin.
authors.affiliation: The Vivian Rakoff Mood Disorders Laboratory, Centre for Addiction and Mental Health, 250 College Street, Room 1105, Toronto, Ontario, Canada, M5T 1R8.
authors.forename: Li
authors.initials: L
authors.lastname: Shao
authors.forename: Xiujun
authors.initials: X
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: L Trevor
authors.initials: LT
authors.lastname: Young
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Wang
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003593:Cytoplasm / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics*; D018021:Lithium Chloride / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D018692:Antimanic Agents; D006360:Heat-Shock Proteins; D018021:Lithium Chloride; D018832:Molecular Chaperones; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP