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Conjugated linoleic acid-enriched butter improved memory and up-regulated phospholipase A2 encoding-genes in rat brain tissue

  • Translational Neurosciences - Original Article
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Abstract

Reduced phospholipase A2 (PLA2) activity has been reported in blood cells and in postmortem brains of patients with Alzheimer disease (AD), and there is evidence that conjugated linoleic acid (CLA) modulates the activity of PLA2 groups in non-brain tissues. As CLA isomers were shown to be actively incorporated and metabolized in the brains of rats, we hypothesized that feeding a diet naturally enriched in CLA would affect the activity and expression of Pla 2 -encoding genes in rat brain tissue, with possible implications for memory. To test this hypothesis, Wistar rats were trained for the inhibitory avoidance task and fed a commercial diet (control) or experimental diets containing either low CLA- or CLA-enriched butter for 4 weeks. After this period, the rats were tested for memory retrieval and killed for tissue collection. Hippocampal expression of 19 Pla 2 genes was evaluated by qPCR, and activities of PLA2 groups (cPLA2, iPLA2, and sPLA2) were determined by radioenzymatic assay. Rats fed the high CLA diet had increased hippocampal mRNA levels for specific PLA2 isoforms (iPla 2 g6γ; cPla 2 g4a, sPla 2 g3, sPla 2 g1b, and sPla 2 g12a) and higher enzymatic activity of all PLA2 groups as compared to those fed the control and the low CLA diet. The increment in PLA2 activities correlated significantly with memory enhancement, as assessed by increased latency in the step-down inhibitory avoidance task after 4 weeks of treatment (r s = 0.69 for iPLA2, P < 0.001; r s = 0.81 for cPLA2, P < 0.001; and r s = 0.69 for sPLA2, P < 0.001). In face of the previous reports showing reduced PLA2 activity in AD brains, the present findings suggest that dairy products enriched in cis-9, trans-11 CLA may be useful in the treatment of this disease.

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Abbreviations

CLA:

Conjugated linoleic acid

PLA2 or Pla 2 :

Phospholipase A2

AD:

Alzheimer disease

sPLA2 :

Secretory Ca2+-dependent PLA2

cPLA2 :

Intracellular cytosolic Ca2+-dependent PLA2

iPLA2 :

Intracellular Ca2+-independent PLA2

PPAR:

Peroxisome proliferator-activated receptors

DHA:

Docosahexaenoic acid

FAME:

Fatty acid methyl esters

AA:

Arachidonic acid

NPD1:

Neuroprotectin D1

SFA:

Saturated fatty acids

LTP:

Long-term potentiation

References

  • AOAC (2000) Official methods of analysis, 17th edn. Association of Official Analytical Chemists, Arlington

    Google Scholar 

  • Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alpérovitch A (2007) Dietary patterns and risk of dementia: the three-city cohort study. Neurology 69:1921–1930

    Article  CAS  PubMed  Google Scholar 

  • Bazan NG, Zorumski CF, Clark GD (1993) The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J Lipid Mediat 6:421–427

    CAS  PubMed  Google Scholar 

  • Bernardo A, Minghetti L (2008) Regulation of glial cell functions by PPAR-gamma natural and synthetic agonists. PPAR Res 2008:1–10. doi:10.1155/2008/864140

    Article  Google Scholar 

  • Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G (2006) Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem 17:789–810

    Article  CAS  PubMed  Google Scholar 

  • Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55:611–622. doi:10.1373/clinchem.2008.112797

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA, Castegna A, Pocernich CB, Drake J, Scapagnini G, Calabrese V (2002) Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutr Biochem 13:444–461. doi:10.1016/S0955-2863(02)00205-X

    Article  CAS  PubMed  Google Scholar 

  • Chalbot S, Zetterberg H, Blennow K, Fladby T, Grundke-Iqbal I, Iqbal K (2010) Cerobrospinal fluid secretory Ca2+-dependent phospholipase A2 activity: a biomarker of blood-cerebrospinal fluid barrier permeability. Neurosci Lett 478:179–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chomczynski P, Sacchi N (1987) Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159. doi:10.1016/0003-2697(87)90021-2

    Article  CAS  PubMed  Google Scholar 

  • Chouinard PY, Corneau L, Barbano DM, Metzger LE, Bauman DE (1999) Conjugated linoleic acids alter milk fatty acid composition and inhibit milk fat secretion in dairy cows. J Nutr 129:1579–1584

    CAS  PubMed  Google Scholar 

  • Christie WW (1982) A simple procedure for rapid transmethylation of glycerolipids and cholesterol esters. J Lipid Res 23:1072–1075

    CAS  PubMed  Google Scholar 

  • Collomb M, Schmid A, Sieber R, Wechsler D, Ryhanen EL (2006) Conjugated linoleic acids in milk fat: variation and physiological effects. Int Dairy J 16:1347–1361. doi:10.1016/j.idairyj.2006.06.021

    Article  CAS  Google Scholar 

  • Cruz-Hernandez C, Kramer JKG, Kennelly JJ, Glimm DR, Sorensen BM, Okine EK, Goonewardene LA, Weselake RJ (2007) Evaluating the conjugated linoleic acid and trans 18:1 isomers in milk fat of dairy cows fed increasing amounts of sunflower oil and a constant level of fish oil. J Dairy Sci 90:3786–3801. doi:10.3168/jds.2006-698

    Article  CAS  PubMed  Google Scholar 

  • Dangour AD, Uauy R (2011) Reply to FJ Rosales. Am J Clin Nutr 93(2):477

    Article  CAS  Google Scholar 

  • Demar JC Jr, Ma K, Chang L, Bell JM, Rapoport SI (2005) Alpha-linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid. J Neurochem 94:1063–1076

    Article  CAS  PubMed  Google Scholar 

  • Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chemic Rev 111:6130–6185

    Article  CAS  Google Scholar 

  • Eder K, Schleser S, Becker K, Kortling R (2003) Conjugated linoleic acids lower the release of eicosanoids and nitric oxide from human aortic endothelial cells. J Nutr 133:4083–4089

    CAS  PubMed  Google Scholar 

  • Fa M, Diana A, Carta G, Cordeddu L, Melis MP, Murru E, Sogos V, Banni S (2005) Incorporation and metabolism of c9, t11 and t10, c12 conjugated linoleic acid (CLA) isomers in rat brain. Biochim Biophys Acta 1736:61–66. doi:10.1016/j.bbalip.2005.06.010

    CAS  PubMed  Google Scholar 

  • Farooqui AA, Ong WY, Horrocks LA (2006) Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev 58:591–620

    Article  CAS  PubMed  Google Scholar 

  • Fattahi MJ, Mirshafiey A (2014) Positive and negative effects of prostaglandins in Alzheimer’s disease. Psychiatry Clin Neurosci 68(1):50–60

    Article  CAS  PubMed  Google Scholar 

  • Frisardi V, Panza F, Seripa D, Imbimbo BP, Vendemiale AP, Solfrizzi V (2010) Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms. J Alzheimers Dis 22:715–740. doi:10.3233/JAD-2010-100942

    CAS  PubMed  Google Scholar 

  • Fujita S, Ikegaya Y, Nishiyama N, Matsuki N (2000) Ca2+-independent phospholipase A2 inhibitor impairs spatial memory of mice. Jpn J Pharmacol 83:277–278

    Article  CAS  PubMed  Google Scholar 

  • Gattaz WF, Maras A, Cairns NJ, Levy R, Forstl H (1995) Decreased phospholipase A2 activity in Alzheimer brains. Biol Psychiatry 37:13–17. doi:10.1016/0006-3223(94)00123-K

    Article  CAS  PubMed  Google Scholar 

  • 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 246:129–131

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez S, Duncan SE, O’Keefe SF, Sumner SS, Herbein JH (2003) Oxidation and textural characteristics of butter and ice cream with modified fatty acid profiles. J Dairy Sci 86:70–77. doi:10.3168/jds.S0022-0302(03)73585-1

    Article  CAS  PubMed  Google Scholar 

  • Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM (2007) Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci 27:4385–4395. doi:10.1523/JNEUROSCI.0055-07.2007

    Article  CAS  PubMed  Google Scholar 

  • Green JT, Orr SK, Bazinet RP (2008) The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. J Lipid Res 49:939–944. doi:10.1194/jlr.R700017-JLR200

    Article  CAS  PubMed  Google Scholar 

  • Hara A, Radin NS (1978) Lipid extraction of tissues with low-toxicity solvent. Anal Biochem 90:420–426. doi:10.1016/0003-2697(78)90046-5

    Article  CAS  PubMed  Google Scholar 

  • Hunt WT, Kamboj A, Anderson HD, Anderson CM (2010) Protection of cortical neurons from excitotoxicity by conjugated linoleic acid. J Neurochem 115:123–130. doi:10.1111/j.1471-4159.2010.06908.x

    Article  CAS  PubMed  Google Scholar 

  • Ip C, Banni S, Angioni E, Carta G, McGinley J, Thompson HJ, Barbano D, Bauman D (1999) Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats. J Nutr 129:2135–2142

    CAS  PubMed  Google Scholar 

  • Izquierdo LA, Barros DM, Medina JH, Izquierdo I (2003) Exposure to novelty enhances retrieval of very remote memory in rats. Neurobiol Learn Mem 79:51–56

    Article  PubMed  Google Scholar 

  • Kummer MP, Heneka MT (2008) PPARs in Alzheimer’s disease. PPAR Res. 2008:1–8. doi:10.1155/2008/403896

    Article  Google Scholar 

  • Lautens LL, Chiou XG, Sharp JD, Young WS 3rd, Sprague DL, Ross LS, Felder CC (1998) Cytosolic phospholipase A2 (cPLA2) distribution in murine brain and functional studies indicate that cPLA2 does not participate in muscarinic receptor-mediated signaling in neurons. Brain Res 809:18–30

    Article  CAS  PubMed  Google Scholar 

  • Lawson RE, Moss AR, Givens DI (2001) The role of dairy products in supplying CLA to man’s diet: a review. Nutr Res Rev 14:153–172. doi:10.1079/NRR200121

    Article  CAS  PubMed  Google Scholar 

  • Lock AL, Horne CAM, Bauman DE, Salter AM (2005) Butter naturally enriched in CLA and vaccenic acid alters tissue fatty acids and improves the plasma lipoprotein profile in cholesterol-fed hamsters. J Nutr 135:1934–1939

    CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin-phenol reagents. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Luchsinger JA, Mayeux R (2004) Dietary factors and Alzheimer’s disease. Lancet Neurol 3:579–587. doi:10.1016/S1474-4422(04)00878-6

    Article  PubMed  Google Scholar 

  • Lukiw WJ, Bazan NG (2010) Inflammatory, apoptotic, and survival gene signaling in Alzheimer’s disease. A review on the bioactivity of neuroprotectin D1 and apoptosis. Mol Neurobiol 42:10–16. doi:10.1007/s12035-010-8126-4

    Article  CAS  PubMed  Google Scholar 

  • Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60:940–946. doi:10.1001/archneur.60.7.940

    Article  PubMed  Google Scholar 

  • Nakanishi T, Koutoku T, Kawahara S, Murai A, Furuse M (2003) Dietary conjugated linoleic acid reduces cerebral prostaglandin E2 in mice. Neurosci Lett 341:135–138. doi:10.1016/S0304-3940(03)00189-7

    Article  CAS  PubMed  Google Scholar 

  • 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 254:446–449

    Article  CAS  PubMed  Google Scholar 

  • O’Shea M, Bassaganya-Riera J, Mohede ICM (2004) Immunomodulatory properties of conjugated linoleic acid. Am J Clin Nutr 79:1199S–1206S

    PubMed  Google Scholar 

  • Pariza MW (2004) Perspective on the safety and effectiveness of conjugated linoleic acid. Am J Clin Nutr 79:1132S–1136S

    CAS  PubMed  Google Scholar 

  • Piomelli D (1993) Arachidonic acid in cell signaling. Curr Opin Cell Biol 5:274–280

    Article  CAS  PubMed  Google Scholar 

  • Qu BX, Gong Y, Sinclair D, Fu M, Perl D, Diaz-Arrastia R (2013) cPLA2α knockout mice exhibit abnormalities in the architecture and synapses of cortical neurons. Brain Res 1497:101–105. doi:10.1016/j.brainres.2012.12.018

    Article  CAS  PubMed  Google Scholar 

  • Reynolds CM, Roche HM (2010) Conjugated linoleic acid and inflammatory cell signaling. Prostaglandins Leukot Essent Fatty Acids 82:199–204. doi:10.1016/j.plefa.2010.02.021

    Article  CAS  PubMed  Google Scholar 

  • 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 70:786–793. doi:10.1046/j.1471-4159.1998.70020786.x

    Article  CAS  PubMed  Google Scholar 

  • Rossato JI, Bevilaqua LR, Lima RH, Medina JH, Izquierdo I, Cammarota M (2006) On the participation of hippocampal p38 mitogen-activated protein kinase in extinction and reacquisition of inhibitory avoidance memory. Neuroscience 143:15–23. doi:10.1016/j.neuroscience.2006.07.025

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Mejia RO, Newman JW, Toh S, Yu GC, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, Mucke L (2008) Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nat Neurosci 11:1311–1318

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schaeffer EL, Gattaz WF (2005) Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory. Psychopharmacology 181:392–400

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EL, Gattaz WF (2007) Requirement of hippocampal phospholipase A2 activity for long-term memory retrieval in rats. J Neural Transm 114:379–385

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EL, Zorron PuL, Gagliotti DA, Gattaz WF (2009) Conditioning training and retrieval increase phospholipase A(2) activity in the cerebral cortex of rats. J Neural Transm 116:41–50

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EL, da Silva ER, de A Novaes B, Skaf HD, Gattaz WF (2010) Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 34:1381–1389. doi:10.1016/j.pnpbp.2010.08.019

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EL, Skaf HD, Novaes Bde A, da Silva ER, Martins BA, Joaquim HD, Gattaz WF (2011) Inhibition of phospholipase A2 in rat brain modifies different membrane fluidity parameters in opposite ways. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1612–1617

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (2003) Aging, amyloid, and Alzheimer’s disease: a perspective in honor of Carl Cotman. Neurochem Res 28:1705–1713

    Article  CAS  PubMed  Google Scholar 

  • Sergeeva MG, Aleshin SE, Grabeklis S, Reiser G (2010) PPAR activation has dichotomous control on the expression levels of cytosolic and secretory phospholipase A2 in astrocytes; inhibition in naïve, untreated cells and enhancement in LPS-stimulated cells. J Neurochem 115:399–410. doi:10.1111/j.1471-4159.2010.06931.x

    Article  CAS  PubMed  Google Scholar 

  • 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 115:1173–1179. doi:10.1007/s00702-008-0081-0

    Article  CAS  PubMed  Google Scholar 

  • Stachowska E, Dziedziejko V, Safranow K, Gutowska I, Adler G, Ciechanowicz A, Machalinski B, Chlubek D (2007) Inhibition of phospholipase A2 activity by conjugated linoleic acids in human macrophages. Eur J Nutr 46:28–33

    Article  CAS  PubMed  Google Scholar 

  • 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 37:17–31

    Article  CAS  PubMed  Google Scholar 

  • Van Soest PJ, Robertson JB, Lewis BA (1991) Methods for dietary fiber, neutral detergent fiber, and nonstarch polysaccharides in relation to animal nutrition. J Dairy Sci 74:3583–3597. doi:10.3168/jds.S0022-0302(91)78551-2

    Article  PubMed  Google Scholar 

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:research0034.1–research0034.11. doi:10.1186/gb-2002-3-7-research0034

    Article  Google Scholar 

  • Williard DE, Harmon SD, Kaduce TL, Preuss M, Moore SA, Robbins ME, Spector AA (2001) Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in differentiated rat brain astrocytes. J Lipid Res 42:1368–1376

    CAS  PubMed  Google Scholar 

  • Xu J, Drew PD (2007) Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia. J Immunol 178:1904–1913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Marlice Teixeira Ribeiro and Carlos Gustavo Santos Ribeiro for technical assistance with butter production. The Laboratory of neuroscience receives important financial support from the Associação Beneficente Alzira Denise Hertzog da Silva and from the JNK Empreendimentos Ltda. This project has been funded by EMBRAPA/AGROFUTURO, FAPEMIG, NANOBIOMG, FAPESP, Associação Beneficente Alzira Denise Hertzog da Silva and JNK Empreendimentos Ltda.

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Authors and Affiliations

  1. Embrapa Dairy Cattle, Brazilian Agricultural Research Corporation, Juiz de Fora, Minas Gerais, Brazil

    Marco A. S. Gama & Fernando C. F. Lopes

  2. Laboratory of Neurosciences-LIM27, Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    Fábio B. Mury, Emmanuel Dias-Neto, Leda L. Talib & Wagner F. Gattaz

  3. Faculty of Pharmacy, Research Center for Innovative Health Sciences, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil

    Nádia R. B. Raposo

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  1. Marco A. S. Gama
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Correspondence to Wagner F. Gattaz.

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702_2015_1401_MOESM1_ESM.docx

Supplemental Table 1. Oligonucleotide primers used for PCR amplication of Pla 2 genes and endogenous controls from rat cDNA (DOCX 17 kb)

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Gama, M.A.S., Raposo, N.R.B., Mury, F.B. et al. Conjugated linoleic acid-enriched butter improved memory and up-regulated phospholipase A2 encoding-genes in rat brain tissue. J Neural Transm 122, 1371–1380 (2015). https://doi.org/10.1007/s00702-015-1401-9

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