title: Long-Term Lithium Treatment Increases cPLA₂ and iPLA₂ Activity in Cultured Cortical and Hippocampal Neurons.
abstract: BACKGROUND
  Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis.
  
  
  OBJECTIVE
  To investigate the effect of lithium on cytosolic phospholipase A₂ (PLA₂) activity, a key player on membrane phospholipid turnover which has been found to be reduced in blood and brain tissue of patients with Alzheimer's disease (AD).
  
  
  METHODS
  Primary cultures of cortical and hippocampal neurons were treated for 7 days with different concentrations of lithium chloride (0.02 mM, 0.2 mM and 2 mM). A radio-enzymatic assay was used to determine the total activity of PLA₂ and two PLA₂ subtypes: cytosolic calcium-dependent (cPLA₂); and calcium-independent (iPLA₂).
  
  
  RESULTS
  cPLA₂ activity increased by 82% (0.02 mM; p = 0.05) and 26% (0.2 mM; p = 0.04) in cortical neurons and by 61% (0.2 mM; p = 0.03) and 57% (2 mM; p = 0.04) in hippocampal neurons. iPLA₂ activity was increased by 7% (0.2 mM; p = 0.04) and 13% (2 mM; p = 0.05) in cortical neurons and by 141% (0.02 mM; p = 0.0198) in hippocampal neurons.
  
  
  CONCLUSIONS
  long-term lithium treatment increases membrane phospholipid metabolism in neurons through the activation of total, c- and iPLA₂. This effect is more prominent at sub-therapeutic concentrations of lithium, and the activation of distinct cytosolic PLA₂ subtypes is tissue specific, i.e., iPLA₂ in hippocampal neurons, and cPLA₂ in cortical neurons. Because PLA₂ activities are reported to be reduced in Alzheimer's disease (AD) and bipolar disorder (BD), the present findings provide a possible mechanism by which long-term lithium treatment may be useful in the prevention of the disease.
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil.
authors.forename: Vanessa de Jesus
authors.initials: Vde J
authors.lastname: De-Paula
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. dskerr@gmail.com.
authors.forename: Daniel Shikanai
authors.initials: DS
authors.lastname: Kerr
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. mariliapalmafc@gmail.com.
authors.forename: Marília Palma Fabiano
authors.initials: MP
authors.lastname: de Carvalho
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. schaeffer@usp.br.
authors.forename: Evelin Lisete
authors.initials: EL
authors.lastname: Schaeffer
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. leda.talib@gmail.com.
authors.forename: Leda Leme
authors.initials: LL
authors.lastname: Talib
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. gattaz@usp.br.
authors.forename: Wagner Farid
authors.initials: WF
authors.lastname: Gattaz
authors.affiliation: Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, São Paulo 05403-010, Brazil. forlenza@usp.br.
authors.forename: Orestes Vicente
authors.initials: OV
authors.lastname: Forlenza
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism*; D011247:Pregnancy; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats
chemical_list: D008094:Lithium; D054467:Phospholipases A2
keywords: cPLA2 activity; iPLA2 activity; lithium; neuronal cell culture