Direct and indirect pathways of glycogen synthase kinase 3B inhibition by lithium in culture of neurons

• Grant number: 16/01302-9
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): May 01, 2016
• Effective date (End): April 30, 2019
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Helena Paula Brentani
• Grantee: Vanessa de Jesus Rodrigues de Paula
• Host 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

Abstract

In recent years we have given special attention to the possible neuroprotective effects of lithium, especially by the discovery of its regulatory effects on protein pro and anti-apoptotic. The lithium substantially increases the expression of cytoprotective proteins in central nervous system either in rat cortex as in human cells of neural origin. Besides neuroprotective effects, it assists in axon regeneration in the central nervous system of mammals. Lithium downregulates the expression and activity of the enzyme glycogen synthase kinase 3b (GSK3B). The GSK3B plays important roles in brain homeostasis by regulating glycogen synthesis under the influence of insulin cascade beyond the remodeling of the cytoskeleton (synaptic plasticity, neurogenesis and tau protein phosphorylation). The inhibition of this enzyme activity by treatment with lithium may be by direct pathway through phosphorylation of its magnesium sites, or indirectly, via protein kinase phosphorylation B (AKT / PKB), and these effects seem to be one of the targets crucial in therapy with lithium salts. The GSK3B is directly related to the regulation of the levels of phosphorylated tau proteins, which are observed in the neurodegeneration in Alzheimer's disease, as well as cytoskeletal denaturation of nerve cell injury by processes that trigger apoptotic cascades. This study aims to identify the main phosphorylation pathway GSK3B (direct or indirect) for chronic and acute treatment with lithium in neurons and explore through the use of bioinformatics tools associated proteins GSK3B in AD. (AU)

Scientific publications

(18)

(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)

MÁRCIA RADANOVIC; CARLOS A. OSHIRO; THIAGO Q. FREITAS; LEDA L. TALIB; ORESTES V. FORLENZA. Correlation between CSF biomarkers of Alzheimer’s disease and global cognition in a psychogeriatric clinic cohort. Revista Brasileira de Psiquiatria, v. 41, n. 6, p. 479-484, 2019-05-30. (14/14211-6, 16/01302-9, 09/52825-8)

STELLA, FLORINDO; PAIS, V, MARCOS; LOUREIRO, JULIA C.; RADANOVIC, MARCIA; FORLENZA, V, ORESTES. Neuropsychiatric symptoms and cerebrovascular risk in non-demented elders: cross-sectional study using the mild behavioural impairment checklist (MBI-C). PSYCHOGERIATRICS, OCT 2021. (16/01302-9, 14/50873-3)

IBARRA, ROMEL; RADANOVIC, MARCIA; PAIS, V, MARCOS; TALIB, LEDA L.; FORLENZA, V, ORESTES. AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State. JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY, AUG 2020. (09/52825-8, 16/01302-9, 14/14211-6)

VACAS, SARA M.; STELLA, FLORINDO; LOUREIRO, JULIA C.; DO COUTO, FREDERICO SIMOES; OLIVEIRA-MAIA, ALBINO J.; FORLENZA, ORESTES V.. Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: A systematic review and meta-analysis. INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, v. 34, n. 9, SI, p. 1336-1344, SEP 2019. (14/14211-6, 09/52825-8, 16/01302-9)

POLHO, GABRIEL B.; CARDILLO, GIANCARLO M.; KERR, DANIEL S.; CHILE, THAIS; GATTAZ, WAGNER F.; FORLENZA, ORESTES V.; BRENTANI, HELENA P.; DE-PAULA, VANESSA J.. ntipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injur. NEURAL REGENERATION RESEARCH, v. 17, n. 5, p. 1156-1160, MAY 2022. (16/01302-9, 14/27129-6)

DE-PAULA, VANESSA J.; DOS SANTOS, CARLA CRISTINE C.; LUQUE, MARIA CAROLINA A.; ALI, TACCYANA M.; KALIL, JORGE E.; FORLENZA, ORESTES V.; CUNHA-NETO, EDECIO. Acute and chronic lithium treatment increases Wnt/beta-catenin transcripts in cortical and hippocampal tissue at therapeutic concentrations in mice. METABOLIC BRAIN DISEASE, v. 36, n. 1, NOV 2020. (14/50890-5, 11/19892-3, 09/52825-8, 16/01302-9)

ROCHA, NICOLE KEMBERLY R.; THEMOTEO, RAFAEL; BRENTANI, HELENA; FORLENZA, ORESTES V.; DE PAULA, VANESSA DE JESUS RODRIGUES. Neuronal-Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer's Disease: Gene Ontology and Lithium Pathways. FRONTIERS IN NEUROSCIENCE, v. 14, DEC 1 2020. (17/14418-8, 11/19892-3, 16/01302-9, 09/52825-8, 18/08621-8, 14/50873-3)

DE-PAULA, V. J.; FORLENZA, V, O.. Lithium modulates multiple tau kinases with distinct effects in cortical and hippocampal neurons according to concentration ranges. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 395, n. 1, NOV 2021. (16/01302-9, 14/50873-3)

IBARRA, ROMEL; RADANOVIC, MARCIA; PAIS, V, MARCOS; TALIB, LEDA L.; FORLENZA, V, ORESTES. AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State. JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY, v. 34, n. 6, SI, p. 659-667, NOV 2021. (09/52825-8, 16/01302-9, 14/14211-6)

MÁRCIA RADANOVIC; CARLOS A. OSHIRO; THIAGO Q. FREITAS; LEDA L. TALIB; ORESTES V. FORLENZA. Correlation between CSF biomarkers of Alzheimer’s disease and global cognition in a psychogeriatric clinic cohort. Revista Brasileira de Psiquiatria, n. ahead, p. -, 2019. (09/52825-8, 16/01302-9, 14/14211-6)

DE-PAULA, VANESSA DE J. R.; FORLENZA, ANDREA S.; FORLENZA, ORESTES V.. Relevance of gutmicrobiota in cognition, behaviour and Alzheimer's disease. PHARMACOLOGICAL RESEARCH, v. 136, p. 29-34, OCT 2018. (09/52825-8, 16/01302-9, 13/20695-3)

DE OLIVEIRA, ALEXANDRA MARTINI; RADANOVIC, MARCIA; HOMEM DE MELLO, PATRICIA COTTING; BUCHAIN, PATRICIA CARDOSO; VIZZOTTO, ADRIANA DIAS; HARDER, JANAINA; STELLA, FLORINDO; PIERSOL, CATHERINE VERRIER; GITLIN, LAURA N.; FORLENZA, ORESTES VICENTE. An intervention to reduce neuropsychiatric symptoms and caregiver burden in dementia: Preliminary results from a randomized trial of the tailored activity program-outpatient version. INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, v. 34, n. 9, SI, p. 1301-1307, SEP 2019. (14/14211-6, 09/52825-8, 16/01302-9)

SAJATOVIC, MARTHA; DOLS, ANNEMIEK; REJ, SOHAM; ALMEIDA, OSVALDO P.; BEUNDERS, ALEXANDRA J. M.; BLUMBERG, HILARY P.; BRIGGS, FARREN B. S.; FORESTER, BRENT P.; PATRICK, REGAN E.; FORLENZA, V, ORESTES; et al. Bipolar symptoms, somatic burden, and functioning in older-age bipolar disorder: Analyses from the Global Aging & Geriatric Experiments in Bipolar Disorder Database project. BIPOLAR DISORDERS, AUG 2021. (16/01302-9, 14/50873-3)

OLIVEIRA, ALEXANDRA MARTINI; RADANOVIC, MARCIA; HOMEM DE MELLO, PATRICIA COTTING; BUCHAIN, PATRICIA CARDOSO; BARBOSA VIZZOTTO, ADRIANA DIAS; HARDER, JANAINA; STELLA, FLORINDO; GITLIN, LAURA N.; PIERSOL, CATHERINE VERRIER; VALIENGO, LEANDRO L. C.; et al. Adjunctive Therapy to Manage Neuropsychiatric Symptoms in Moderate and Severe Dementia: Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program. JOURNAL OF ALZHEIMER'S DISEASE, v. 83, n. 1, p. 475-486, 2021. (14/14211-6, 16/01302-9, 09/52825-8)

CARDILLO, GIANCARLO DE MATTOS; RODRIGUES DE-PAULA, VANESSA DE JESUS; IKENAGA, ELIZA HIROMI; COSTA, LUCIANA RODRIGUES; CATANOZI, SERGIO; SCHAEFFER, EVELIN LISETE; GATTAZ, WAGNER FARID; KERR, DANIEL SHIKANAI; FORLENZA, ORESTES VICENTE. Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice. JOURNAL OF ALZHEIMER'S DISEASE, v. 63, n. 1, p. 93-101, 2018. (14/14211-6, 09/52825-8, 16/01302-9)

RADANOVIC, MARCIA; OSHIRO, CARLOS A.; FREITAS, THIAGO Q.; TALIB, LEDA L.; FORLENZA, ORESTES V.. Correlation between CSF biomarkers of Alzheimer's disease and global cognition in a psychogeriatric clinic cohort. Revista Brasileira de Psiquiatria, v. 41, n. 6, p. 479-484, NOV-DEC 2019. (09/52825-8, 16/01302-9, 14/14211-6)

MAZIERO, MARIA PAULA; RIBEIRO BELAN, ARIELLA FORNACHARI; DE ARRUDA CAMARGO, MARINA VON ZUBEN; SILAGI, MARCELA LIMA; FORLENZA, ORESTES VICENTE; RADANOVIC, MARCIA. Textual Inference Comprehension in Mild Cognitive Impairment: The Influence of Semantic Processing and Verbal Episodic Memory. FRONTIERS IN AGING NEUROSCIENCE, v. 13, OCT 4 2021. (16/01302-9)

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. (09/52825-8, 11/19892-3, 16/01302-9)