Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
European Archives of Psychiatry and Clinical Neuroscience
Published in: European Archives of Psychiatry and Clinical Neuroscience 7/2016

01-10-2016 | Original Paper

Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease

Authors: Fábio B. Mury, Weber C. da Silva, Nádia R. Barbosa, Camila T. Mendes, Juliana S. Bonini, Jorge Eduardo Souza Sarkis, Martin Cammarota, Ivan Izquierdo, Wagner F. Gattaz, Emmanuel Dias-Neto

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 7/2016

Login to get access

Abstract

Phospholipase A2 (Pla2) is required for memory retrieval, and its inhibition in the hippocampus has been reported to impair memory acquisition in rats. Moreover, cognitive decline and memory deficits showed to be reduced in animal models after lithium treatment, prompting us to evaluate possible links between Pla2, lithium and memory. Here, we evaluated the possible modulation of Pla2 activity by a long-term treatment of rats with low doses of lithium and its impact in memory. Wistar rats were trained for the inhibitory avoidance task, treated with lithium for 100 days and tested for perdurability of long-term memory. Hippocampal samples were used for quantifying the expression of 19 brain-expressed Pla2 genes and for evaluating the enzymatic activity of Pla2 using group-specific radio-enzymatic assays. Our data pointed to a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer’s disease.
Appendix
Available only for authorised users
Literature
1.
Cade JF (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2:349–352PubMed
2.
Manji HK, Moore GJ, Chen G (2000) Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 48:740–754CrossRefPubMed
3.
Shulman KI, Rochon P, Sykora K, Anderson G et al (2003) Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence. BMJ 326:960–961CrossRefPubMedPubMedCentral
4.
Young AH, Newham JI (2006) Lithium in maintenance therapy for bipolar disorder. J Psychopharmacol 20:17–22CrossRefPubMed
5.
Baldessarini RJ (2002) Treatment research in bipolar disorder: issues and recommendations. CNS Drugs 16:721–729CrossRefPubMed
6.
Manji HK, Moore GJ, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46:929–940CrossRefPubMed
7.
De Strooper B, Woodgett J (2003) Alzheimer’s disease: mental plaque removal. Nature 423:392–393CrossRefPubMed
8.
Gould TD, Chen G, Manji HK (2004) In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3. Neuropsychopharmacol 29:32–38CrossRef
9.
Mendes CT, Mury FB, de Sa-Moreira E, Alberto FL et al (2009) Lithium reduces Gsk3b mRNA levels: implications for Alzheimer disease. Eur Arch Psychiatry Clin Neurosci 259:16–22CrossRefPubMed
10.
Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435–439CrossRefPubMed
11.
Li PP, Young LT, Tam YK, Sibony D, Warsh JJ (1993) Effects of chronic lithium and carbamazepine treatment on G-protein subunit expression in rat cerebral cortex. Biol Psychiatry 34:162–170CrossRefPubMed
12.
Manji HK, Potter WZ, Lenox RH (1995) Signal transduction pathways. Molecular targets for lithium’s actions. Arch Gen Psychiatry 52:531–543CrossRefPubMed
13.
Lenox RH, Hahn CG (2000) Overview of the mechanism of action of lithium in the brain: fifty-year update. J Clin Psychiatry 61:5–15PubMed
14.
15.
Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy RN (2008) Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells. Neuroscience 151:1184–1197CrossRefPubMed
16.
Chen HM, De Long CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, O’Shea KS (2014) Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 4:e375CrossRefPubMedPubMedCentral
17.
Pachet AK, Wisniewski AM (2003) The effects of lithium on cognition: an updated review. Psychopharmacology 170:225–234CrossRefPubMed
18.
Rockenstein E, Torrance M, Adame A, Mante M et al (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3 beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27:1981–1991CrossRefPubMed
19.
Yan XB, Hou HL, Wu LM, Liu J, Zhou JN (2007) Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacol 53:487–495CrossRef
20.
Tsaltas E, Kontis D, Boulougouris V, Papakosta VM et al (2007) Enhancing effects of chronic lithium on memory in the rat. Behav Brain Res 177:51–60CrossRefPubMed
21.
Nocjar C, Hammonds MD, Shim SS (2007) Chronic lithium treatment magnifies learning in rats. Neuroscience 150:774–788CrossRefPubMed
22.
Schaeffer EL, Cerulli FG, Souza HO, Catanozi S, Gattaz WF (2014) Synergistic and additive effects of enriched environment and lithium on the generation of new cells in adult mouse hippocampus. J Neural Transm 121:695–706CrossRefPubMed
23.
Su Y, Ryder J, Li B, Wu X et al (2004) Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43:6899–6908CrossRefPubMed
24.
25.
Lund Y, Nissen M, Rafaelsen OJ (1982) Long-term lithium treatment and psychological functions. Acta Psychiatr Scand 65:233–244CrossRefPubMed
26.
Squire LR, Judd LL, Janowsky DS, Huey LY (1980) Effects of lithium carbonate on memory and other cognitive functions. Am J Psychiatry 137:1042–1046CrossRefPubMed
27.
van Gorp WG, Altshuler L, Theberge DC, Wilkins J, Dixon W (1998) Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry 55:41–46CrossRefPubMed
28.
Calil HM, Zwicker AP, Klepacz S (1990) The effects of lithium carbonate on healthy volunteers: mood stabilization? Biol Psychiatry 27:711–722CrossRefPubMed
29.
Weingartner H, Rudorfer MV, Linnoila M (1985) Cognitive effects of lithium treatment in normal volunteers. Psychopharmacology 86:472–474CrossRefPubMed
30.
Nunes PV, Forlenza OV, Gattaz WF (2007) Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 190:359–360CrossRefPubMed
31.
Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF (2011) Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment, randomised controlled trial. Br J Psychiatry 198:351–356CrossRefPubMed
32.
Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L (2014) Mild cognitive impairment: a concept in evolution. J Intern Med 275:214–228CrossRefPubMedPubMedCentral
33.
Bauer M, Alda M, Priller J, Young LT (2003) Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiatry 36:S250–S254CrossRefPubMed
34.
Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK (2000) Enhancement of hippocampal neurogenesis by lithium. J Neurochem 75:1729–1734CrossRefPubMed
35.
Dixon JF, Hokin LE (1998) Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. Proc Natl Acad Sci USA 95:8363–8368CrossRefPubMedPubMedCentral
36.
Son H, Yu IT, Hwang SJ, Kim JS et al (2003) Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus. J Neurochem 85:872–881CrossRefPubMed
37.
Watase K, Gatchel JR, Sun Y, Emamian E et al (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4:836–847CrossRef
38.
Gattaz WF, Maras A, Cairns NJ, Levy R, Forstl H (1995) Decreased phospholipase A2 activity in Alzheimer brains. Biol Psychiatry 37:13–17CrossRefPubMed
39.
Gattaz WF, Cairns NJ, Levy R, Forstl H, Braus DF, Maras A (1996) Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 246:129–131CrossRefPubMed
40.
Gattaz WF, Levy R, Cairns NJ, Forstl H, Braus DF, Maras A (1996) Relevance of metabolism of membrane phospholipids for Alzheimer dementia. Fortschr Neurol Psychiatr 64:8–12CrossRefPubMed
41.
Schaeffer EL, Gattaz WF (2007) Requirement of hippocampal phospholipase A2 activity for long-term memory retrieval in rats. J Neural Transm 114:379–385CrossRefPubMed
42.
Smesny S, Stein S, Willhardt I, Lasch J, Sauer H (2008) Decreased phospholipase A2 activity in cerebrospinal fluid of patients with dementia. J Neural Transm 115:1173–1179CrossRefPubMed
43.
Talib LL, Yassuda MS, Diniz BS, Forlenza OV, Gattaz WF (2008) Cognitive training increases platelet PLA2 activity in healthy elderly subjects. Prostaglandins Leukot Essent Fatty Acids 78:265–269CrossRefPubMed
44.
Olfert ED (1993) Guide to the care and use of experimental animals, 2nd edn. Canadian Council on Animal Care, Ottawa
45.
Bernabeu R, Bevilaqua L, Ardenghi P, Bromberg E et al (1997) Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. Proc Natl Acad Sci USA 94:7041–7046CrossRefPubMedPubMedCentral
46.
Izquierdo LA, Barros DM, Medina JH, Izquierdo I (2003) Exposure to novelty enhances retrieval of very remote memory in rats. Neurobiol Learn Mem 79:51–56CrossRefPubMed
47.
Da Silva WC, Bonini JS, Bevilaqua LRM, Izquierdo I, Cammarota M (2006) Histamine enhances inhibitory avoidance memory consolidation through a H2 receptor-dependent mechanism. Neurobiol Learn Mem 86:100–106CrossRefPubMed
48.
Izquierdo LA, Barros DM, Vianna MR, Coitinho A et al (2002) Molecular pharmacological dissection of short- and long-term memory. Cell Mol Neurobiol 22:269–287CrossRefPubMed
49.
Barros DM, Izquierdo LA, e Souza TM, Ardenghi PG et al (2000) Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats. Behav Brain Res 114:183–192CrossRefPubMed
50.
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167CrossRefPubMed
51.
Chomczynsky P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
52.
Bustin SA, Benes V, Garson JA, Hellemans J et al (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55:611–622CrossRefPubMed
53.
Vandesompele J, De Preter K, Pattyn F, Poppe B et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:1–12CrossRef
54.
Forlenza OV, Schaeffer EL, Gattaz WF (2002) Phospholipase A2 activity in rat embryonic brain and in primary cultures of cortical neurons. J Neural Transm 109:623–631CrossRefPubMed
55.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275PubMed
56.
Farooqui AA, Horrocks LA (2004) Brain phospholipases A2, a perspective on the history. Prostaglandins Leukot Essent Fatty Acids 71:161–169CrossRefPubMed
57.
Farooqui AA, Yang HC, Horrocks L (1997) Involvement of phospholipase A2 in neurodegeneration. Neurochem Int 30:517–522CrossRefPubMed
58.
Flesch I, Schmidt B, Ferber E (1985) Acyl chain specificity and kinetic properties of phospholipase A1 and A2 of bone marrow-derived macrophages. Z Naturforsch C 40:356–363PubMed
59.
Noponen M, Sanfilipo M, Samanich K, Ryer H et al (1993) Elevated PLA2 activity in schizophrenics and other psychiatric patients. Biol Psychiatry 34:641–649CrossRefPubMed
60.
Ross BM, Moszczynska A, Erlich J, Kish SJ (1998) Phospholipid-metabolizing enzymes in Alzheimer’s disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity. J Neurochem 70:786–793CrossRefPubMed
61.
Chalecka-Franaszek E, Chuang DM (1999) Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 96:8745–8750CrossRefPubMedPubMedCentral
62.
63.
64.
Zhang X, Heng X, Li T, Li L, Yang D, Zhang X, Du Y, Doody RS, Le W (2011) Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer’s disease transgenic mouse model. J Alzheimer’s Dis 24:739–749
65.
Kessing LV, Forman JL, Andersen PK (2010) Does lithium protect against dementia? Bipolar Disord 12:87–94CrossRefPubMed
66.
Forlenza OV, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF (2012) Does lithium prevent Alzheimer’s disease? Drugs Aging 29:335–342CrossRefPubMed
67.
Aprahamian I, Santos FS, Dos Santos B, Talib L, Diniz BS, Radanovic M, Gattaz WF, Forlenza OV (2014) Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry 75:e672–e678CrossRefPubMed
68.
de Sousa RT, Zanetti MV, Busatto GF, Mouro MG, Zarate CA Jr, Gattaz WF, Higa EM, Machado-Vieira R (2014) Lithium increases nitric oxide levels in subjects with bipolar disorder during depressive episodes. J Psychiatr Res 55:96–100CrossRefPubMedPubMedCentral
69.
Talbot K, Young RA, Jolly-Tornetta C, Lee VM, Trojanowski JQ, Wolf BA (2000) A frontal variant of Alzheimer’s disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex. Neurochem Int 37:17–31CrossRefPubMed
70.
Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, Bottino CM (2004) Platelet phospholipase A(2) activity in Alzheimer’s disease and mild cognitive impairment. J Neural Transm 111:591–601CrossRefPubMed
71.
Smith LA, Cornelius V, Warnock A, Bell A, Young AH (2007) Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord 9:394–412CrossRefPubMed
72.
Chuang DM (2004) Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol 16:83–90CrossRefPubMed
73.
Gattaz WF, Talib LL, Schaeffer EL, Diniz BS, Forlenza OV (2014) Low platelet iPLA2 activity predicts conversion from mild cognitive impairment to Alzheimer’s disease, a 4-year follow-up study. J Neural Transm 121:193–200CrossRefPubMed
74.
Schmitt C, Furet Y, Perrotin D, Paintaud G (2009) Acute lithium intoxications, review of the literature and cases study. Therapie 64:55–63CrossRefPubMed
75.
Chuang DM (2005) The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 1053:195–204CrossRefPubMed
76.
Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097CrossRefPubMed
77.
Schaeffer EL, Gattaz WF (2005) Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory. Psychopharmacology 181:392–400CrossRefPubMed
78.
Schaeffer EL, Bassi F Jr, Gattaz WF (2005) Inhibition of phospholipase A2 activity reduces membrane fluidity in rat hippocampus. J Neurotransm 112:641–647
79.
Rosenberger TA, Villacreses NE, Contreras MA, Bonventre JV, Rapoport SI (2003) Brain lipid metabolism in the cPLA2 knockout mouse. J Lipid Res 44:109–117CrossRefPubMed
80.
Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, Matsuki N (2001) Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A(2) inhibitor in rat hippocampal slices. Br J Pharmacol 132:1417–1422CrossRefPubMedPubMedCentral
81.
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39CrossRefPubMed
82.
Nishizaki T, Nomura T, Matsuoka T, Tsujishita Y (1999) Arachidonic acid as a messenger for the expression of long-term potentiation. Biochem Biophys Res Commun 254:446–449CrossRefPubMed
83.
Schaeffer EL, Forlenza OV, Gattaz WF (2009) Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease. Psychopharmacology 202:37–51CrossRefPubMed
84.
Gama MA, Raposo NR, Mury FB, Lopes FC, Dias-Neto E, Talib LL, Gattaz WF (2015) Conjugated linoleic acid-enriched butter improved memory and up-regulated phospholipase A2 encoding-genes in rat brain tissue. J Neural Transm 122:1371–1380CrossRefPubMed
85.
Vakhapova V, Cohen T, Richter Y, Herzog Y, Kam Y, Korczyn AD (2014) Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study. Dement Geriatr Cogn Disord 38:39–45CrossRefPubMed
86.
Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T (2006) Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56:159–164CrossRefPubMed
87.
Eckert GP, Schaeffer EL, Schmitt A, Maras A, Gattaz WF (2011) Increased brain membrane fluidity in schizophrenia. Pharmacopsychiatry 44:161–162CrossRefPubMed
88.
Barbosa NR, Junqueira RM, Vallada HP, Gattaz WF (2007) Association between BanI genotype and increased phospholipase A2 activity in schizophrenia. Eur Arch Psychiatry Clin Neurosci 257:340–343CrossRefPubMed
89.
Tavares H, Yacubian J, Talib LL, Barbosa NR, Gattaz WF (2003) Increased phospholipase A2 activity in schizophrenia with absent response to niacin. Schizophr Res 61:1–6CrossRefPubMed
90.
Gattaz WF, Schmitt A, Maras A (1995) Increased platelet phospholipase A2 activity in schizophrenia. Schizophr Res 16:1–6CrossRefPubMed
91.
Ting C, Rajji TK, Ismail Z, Tang-Wai DF, Apanasiewicz N, Miranda D, Mamo D, Mulsant BH (2010) Differentiating the cognitive profile of schizophrenia from that of Alzheimer disease and depression in late life. Plos One 5:e10151CrossRefPubMedPubMedCentral
Metadata
Title
Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease
Authors
Fábio B. Mury
Weber C. da Silva
Nádia R. Barbosa
Camila T. Mendes
Juliana S. Bonini
Jorge Eduardo Souza Sarkis
Martin Cammarota
Ivan Izquierdo
Wagner F. Gattaz
Emmanuel Dias-Neto
Publication date
01-10-2016
Publisher
Springer Berlin Heidelberg
Published in
European Archives of Psychiatry and Clinical Neuroscience / Issue 7/2016
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI
https://doi.org/10.1007/s00406-015-0665-2

Other articles of this Issue 7/2016

European Archives of Psychiatry and Clinical Neuroscience 7/2016 Go to the issue

Original Paper

Using the cognitive assessment interview to screen cognitive impairment in psychosis

Short Communication

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain

Original Paper

Diagnosis and neurocognitive profiles in first-episode non-affective psychosis patients

Editorial

Searching biomarkers for mental disorders—lessons from Alzheimer’s disease

Original Paper

General and social cognition in remitted first-episode schizophrenia patients: a comparative study

Original Paper

Problem solving, impulse control and planning in patients with early- and late-stage Huntington’s disease