title: Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.
abstract: BACKGROUND
  Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein.
  
  
  RESULTS
  Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor.
  
  
  CONCLUSIONS
  A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: Petra M
authors.initials: PM
authors.lastname: Hermann
authors.forename: Deborah
authors.initials: D
authors.lastname: Park
authors.forename: Emily
authors.initials: E
authors.lastname: Beaulieu
authors.forename: Willem C
authors.initials: WC
authors.lastname: Wildering
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005936:Glucans; D006434:Hemocytes / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000633:toxicity; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects; D008195:Lymnaea; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects; D054467:Phospholipases A2 / Q000378:metabolism*; D011134:Polysaccharides / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D005936:Glucans; D000960:Hypolipidemic Agents; D011134:Polysaccharides; C008247:laminaran; D006861:Hydrogen Peroxide; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; D007213:Indomethacin
references.citation: J Exp Biol. 2006 Dec;209(Pt 24):4829-40
references.pmid: 17142672
references.citation: Curr Pharm Des. 2008;14(14):1443-51
references.pmid: 18537667
references.citation: J Neurosci. 2005 Feb 2;25(5):1188-92
references.pmid: 15689555
references.citation: Brain Res Rev. 2006 Sep;52(2):201-43
references.pmid: 16647138
references.citation: J Nutr. 1998 Feb;128(2 Suppl):434S-438S
references.pmid: 9478043
references.citation: Behav Neural Biol. 1982 Dec;36(4):379-90
references.pmid: 7184500
references.citation: J Neurosci. 2002 Feb 15;22(4):1414-25
references.pmid: 11850468
references.citation: Inflammation. 1993 Oct;17(5):573-82
references.pmid: 8225564
references.citation: Mech Ageing Dev. 1988 Mar;42(3):263-74
references.pmid: 3367670
references.citation: Cell Physiol Biochem. 2012;30(3):771-7
references.pmid: 22854271
references.citation: Eur J Pharmacol. 2007 Mar 29;560(1):36-41
references.pmid: 17303115
references.citation: Environ Mol Mutagen. 2013 Jan;54(1):1-7
references.pmid: 23238808
references.citation: J Invertebr Pathol. 1987 May;49(3):321-31
references.pmid: 3035029
references.citation: Proc Natl Acad Sci U S A. 1978 Jun;75(6):2955-8
references.pmid: 275865
references.citation: Biochem Soc Trans. 2007 Nov;35(Pt 5):1127-32
references.pmid: 17956294
references.citation: Cell Tissue Res. 2008 Jul;333(1):147-58
references.pmid: 18431599
references.citation: J Exp Biol. 2008 Feb;211(Pt 4):491-501
references.pmid: 18245625
references.citation: Antioxid Redox Signal. 2011 May 15;14(10):2013-54
references.pmid: 20649473
references.citation: J Neurochem. 2013 Jan;124(1):59-68
references.pmid: 23083210
references.citation: Brain Behav Immun. 2011 Feb;25(2):181-213
references.pmid: 20970492
references.citation: Nat Commun. 2013;4:1578
references.pmid: 23481386
references.citation: Agents Actions. 1994 Mar;41(1-2):111-3
references.pmid: 8079814
references.citation: J Neurosci. 1999 May 15;19(10):3739-51
references.pmid: 10234006
references.citation: J Neuroinflammation. 2012 Jul 02;9:151
references.pmid: 22747753
references.citation: J Physiol. 2007 Dec 15;585(Pt 3):699-704
references.pmid: 17584839
references.citation: Curr Opin Drug Discov Devel. 2009 Jan;12(1):141-8
references.pmid: 19152223
references.citation: Eur J Neurosci. 1995 Jun 1;7(6):1360-5
references.pmid: 7582110
references.citation: Prostaglandins Leukot Essent Fatty Acids. 1995 Oct;53(4):239-54
references.pmid: 8577777
references.citation: Dev Comp Immunol. 1991 Winter;15(1-2):17-26
references.pmid: 1646736
references.citation: Dev Comp Immunol. 2007;31(4):321-31
references.pmid: 16926049
references.citation: Biol Cell. 2006 May;98(5):265-78
references.pmid: 16293103
references.citation: Behav Neural Biol. 1982 Dec;36(4):391-402
references.pmid: 7184501
references.citation: Neurobiol Aging. 2013 Feb;34(2):610-20
references.pmid: 22459601
references.citation: Int Rev Neurobiol. 2004;59:297-326
references.pmid: 15006493
references.citation: Crit Rev Neurobiol. 1994;8(1-2):65-83
references.pmid: 8124731
references.citation: Eur J Neurosci. 2003 Jun;17(11):2438-46
references.pmid: 12814375
references.citation: Biochim Biophys Acta. 2005 Jun 15;1735(1):68-78
references.pmid: 15950537
references.citation: J Biol Chem. 2003 May 23;278(21):19453-62
references.pmid: 12609991
references.citation: Mol Neurobiol. 2009 Aug;40(1):15-32
references.pmid: 19365736
references.citation: FEBS Lett. 1992 Sep 7;309(2):190-2
references.pmid: 1505682
references.citation: Nat Neurosci. 2008 Nov;11(11):1311-8
references.pmid: 18931664
references.citation: BMB Rep. 2008 Aug 31;41(8):560-7
references.pmid: 18755070
references.citation: Behav Neurosci. 2007 Dec;121(6):1400-14
references.pmid: 18085894
references.citation: Pharmacol Res. 2001 Dec;44(6):437-50
references.pmid: 11735348
references.citation: Br J Pharmacol. 2008 Sep;155(1):4-16
references.pmid: 18552881
references.citation: Cleve Clin J Med. 2011 Aug;78 Suppl 1:S47-9
references.pmid: 21972331
references.citation: BMC Neurosci. 2012 Aug 17;13:103
references.pmid: 22898271
references.citation: Free Radic Biol Med. 2007 Jan 15;42(2):153-64
references.pmid: 17189821
references.citation: Learn Mem. 2000 May-Jun;7(3):124-31
references.pmid: 10837501
references.citation: Eur J Neurosci. 1997 Dec;9(12):2624-33
references.pmid: 9517468
references.citation: Mech Ageing Dev. 1988 Mar;42(3):275-90
references.pmid: 3367671
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):924-9
references.pmid: 20176130
references.citation: Biochimie. 2011 Jan;93(1):46-51
references.pmid: 20868723
references.citation: Toxicon. 1987;25(9):939-46
references.pmid: 3433305
references.citation: Z Zellforsch Mikrosk Anat. 1972;130(4):497-526
references.pmid: 4117131
references.citation: J Exp Biol. 2009 Oct 1;212(19):3164-73
references.pmid: 19749110
references.citation: J Neuropathol Exp Neurol. 2004 Sep;63(9):901-10
references.pmid: 15453089
references.citation: J Biol Chem. 2003 Apr 25;278(17):15319-25
references.pmid: 12588866
references.citation: Learn Mem. 2002 Jan-Feb;9(1):41-7
references.pmid: 11917005
references.citation: Curr Biol. 2006 Jul 11;16(13):1269-79
references.pmid: 16824916
references.citation: Eur J Neurosci. 2011 Jan;33(1):143-52
references.pmid: 21070389
references.citation: Trends Pharmacol Sci. 2009 Apr;30(4):174-81
references.pmid: 19269697
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):784-90
references.pmid: 20553961
references.citation: Neuromolecular Med. 2010 Jun;12(2):133-48
references.pmid: 19855947
references.citation: J Psychopharmacol. 2007 Sep;21(7):757-67
references.pmid: 17606472
references.citation: Biochem J. 1980 Feb 15;186(2):633-6
references.pmid: 7378071
references.citation: Ageing Res Rev. 2004 Nov;3(4):431-43
references.pmid: 15541710
references.citation: Anal Bioanal Chem. 2008 Jul;391(5):1545-54
references.pmid: 18427788
references.citation: Neurobiol Aging. 2012 Jan;33(1):149-61
references.pmid: 20153084