title: Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons.
abstract: OBJECTIVE
  Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons.
  
  
  METHODS
  The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), β-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium.
  
  
  RESULTS
  Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, β-neurexin, and SYP levels, whereas LTG did not.
  
  
  CONCLUSIONS
  These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.
authors.affiliation: Paik Institute for Clinical Research, Inje University, Busan, Korea; Department of Health Science and Technology, Graduate School of Inje University, Busan, Korea.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Jung Goo
authors.initials: JG
authors.lastname: Lee
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Seo
authors.forename: Hye Yeon
authors.initials: HY
authors.lastname: Cho
authors.forename: Chan Hong
authors.initials: CH
authors.lastname: Lee
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Lee
authors.forename: Bong Ju
authors.initials: BJ
authors.lastname: Lee
authors.forename: Jun Hyung
authors.initials: JH
authors.lastname: Baek
authors.forename: Wongi
authors.initials: W
authors.lastname: Seol
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects*; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D000077213:Lamotrigine; D018020:Lithium Compounds / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051381:Rats; D016708:Synaptophysin / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D018020:Lithium Compounds; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D016708:Synaptophysin; C569016:Syp protein, rat; D014227:Triazines; C093438:neuroligin 1; D014635:Valproic Acid; D019869:Phosphatidylinositol 3-Kinases; D000077213:Lamotrigine
keywords: dendritic outgrowth; mood-stabilizing drugs; neural plasticity; signaling; synaptic proteins