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Effects of lithium on the expression and activity of the enzymes Phospholipase A2 and glycogen synthase kinase 3B and its relation to the phosphorylation state of Tau protein

Grant number: 11/19892-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Orestes Vicente Forlenza
Grantee:Vanessa de Jesus Rodrigues de Paula
Home Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:09/52825-8 - Neurobiology of Alzheimer's disease: risk markers, prognosis and therapeutic response, AP.TEM

Abstract

The therapeutic action of lithium occurs, in part, by inhibition of glutamatergic response via receptors N-methyl-d-aspartate (NMDA). The binding of glutamate or NMDA to these receptors in the synaptic membrane allows calcium influx and subsequent activation of cation-dependent enzymes, such as calcium-calmodulin protein kinase II (CaMKII), PKC, phospholipase C gamma and some subtypes of PLA2. Exposure of neurons in different brain regions to NMDA leads to activation of the cytosolic PLA2 (cPLA2) by influx of calcium in micromolar concentrations. The main product of cleavage of phosphatidylcholine by cPLA2 is arachidonic acid (AA), an important second-messenger cell signaling. AA regulates the conductance of ion channels, the release of neurotransmitters, the phosphorylation of substrates by the action of kinases and the synthesis of transcriptional factors, with effects on neuronal polarity, synaptic plasticity and long-term potentiation (LTP). Studies show that lithium inhibits the activity and expression of cPLA2, the latter effect observed in the transcriptional level (reduction in mRNA) and protein concentration. Other subtypes of PLA2, such as secretory PLA2 (sPLA2) and cytosolic PLA2 independent of calcium (iPLA2) are not affected by lithium. Lithium inhibits calcium-dependent PKC by reducing the expression of AP-2 (activating protein-2), which in turn regulates the transcription of cPLA2. If, on the one hand, the inhibition of cPLA2 by lithium is consistent with its therapeutic action in mood disorders, this effect may hinder the formation and consolidation of memory, which are processes dependent on the integrity of this pathway and the release of AA. In addition, by inhibiting cPLA2, lithium can, in theory, exacerbate the deficit in the activity of this enzyme is already observed in patients with AD. Glycogen synthase kinase 3² (GSK3²) is another important neuronal enzyme whose activity is inhibited by lithium. The GSK3² plays important roles in brain homeostasis, regulating the synthesis of glycogen under the influence of insulin cascade, remodeling of the cytoskeleton (synaptic plasticity, neurogenesis and phosphorylation of tau) and neuronal response to injury (apoptosis and gene regulation). Recent studies have shown the involvement of this enzyme in the pathophysiology of some neuropsychiatric disorders such as AD, schizophrenia and mood disorders. In bipolar disorder, the indirect inhibition of GSK3² by lithium, which leads to phosphorylation of the Ser9 residue (pGSK3²), was associated with therapeutic response. In AD, where the hyperactivity of GSK3² contributes to the production of Ab and the hyperphosphorylation of tau, inhibition of this enzyme by lithium is seen as a therapeutic approach that will mitigate the amiloidogênese and changes in the cytoskeleton. In conclusion, GSK3² and PLA2 enzymes are essential for neuronal homeostasis, both being involved in the pathophysiology of AD and mood disorders. However, we observed that the action of lithium may result in responses in two apparently antagonistic enzymes, considering the pathophysiological cascade of AD. Therefore it is necessary to clarify the effect of lithium in different subtypes of PLA2, and then discusses its implications in neurodegenerative and inflammatory processes. The study aims to investigate the effects of lithium on the activity of GSK3² and PLA2 subtypes in primary cultures of cortical and hippocampal neurons. Establish dose-response curves and treatment time for the expected inhibitory effects on enzymes above. To investigate downstream effects of the treatment of neuronal cultures with lithium, determining the concentrations of arachidonic acid, neurotrophins (BDNF, NGF), markers of apoptosis (Bcl-2, Bax and Bad), inflammatory cytokines (IL-1 and IL-6 ), kinases (PKA, AKT, CAMKII, PKC), tau phosphorylation (Ser 199, Ser 393, Ser 214, Ser 202, C terminus) and analysis of samples by microarray. (AU)

Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE-PAULA, VANESSA J.; GATTAZ, WAGNER F.; FORLENZA, ORESTES V. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations. BIPOLAR DISORDERS, v. 18, n. 8, p. 692-695, DEC 2016. Web of Science Citations: 7.
DE-PAULA, VANESSA J.; KERR, DANIEL S.; SCOLA, GUSTAVO; GATTAZ, WAGNER F.; FORLENZA, ORESTES V. Lithium Distinctly Modulates the Secretion of Pro- and Anti-Inflammatory Interleukins in Co-Cultures of Neurons and Glial Cells at Therapeutic and Sub-Therapeutic Concentrations. Current Alzheimer Research, v. 13, n. 8, p. 848-852, 2016. Web of Science Citations: 6.
LANE VALIENGO, LEANDRO DA COSTA; STELLA, FLORINDO; FORLENZA, ORESTES VICENTE. Mood disorders in the elderly: prevalence, functional impact, and management challenges. NEUROPSYCHIATRIC DISEASE AND TREATMENT, v. 12, p. 2105-2114, 2016. Web of Science Citations: 20.
DE-PAULA, VANESSA DE JESUS; KERR, DANIEL SHIKANAI; FABIANO DE CARVALHO, MARILIA PALMA; SCHAEFFER, EVELIN LISETE; TALIB, LEDA LEME; GATTAZ, WAGNER FARID; FORLENZA, ORESTES VICENTE. Long-Term Lithium Treatment Increases cPLA(2) and iPLA(2) Activity in Cultured Cortical and Hippocampal Neurons. Molecules, v. 20, n. 11, p. 19878-19885, NOV 2015. Web of Science Citations: 6.

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