title: A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma.
abstract: We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA₂) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.
authors.affiliation: Department of Integrative Biology and Physiology, University of California, LA, CA 90095, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sharma
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.forename: Fernando
authors.initials: F
authors.lastname: Gomez-Pinilla
mesh_terms: D000447:Aldehydes; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology*; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects
chemical_list: D000447:Aldehydes; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D003474:Curcumin; C027576:4-hydroxy-2-nonenal
references.citation: Neurobiol Aging. 2007 Mar;28(3):424-39
references.pmid: 16500747
references.citation: J Neurosci Res. 2010 Jan;88(1):202-13
references.pmid: 19658197
references.citation: J Biol Chem. 1995 Feb 3;270(5):2213-7
references.pmid: 7836452
references.citation: Biol Pharm Bull. 2003 Jun;26(6):787-93
references.pmid: 12808287
references.citation: J Neurotrauma. 2008 May;25(5):527-37
references.pmid: 18363507
references.citation: Neuroreport. 1995 Mar 27;6(5):730-2
references.pmid: 7541655
references.citation: Free Radic Biol Med. 2008 Aug 15;45(4):443-52
references.pmid: 18501200
references.citation: Eur J Pharmacol. 2007 Mar 29;560(1):36-41
references.pmid: 17303115
references.citation: Biochim Biophys Acta. 1999 Oct 18;1441(1):4-13
references.pmid: 10526223
references.citation: Ann Nutr Metab. 1999;43(5):290-300
references.pmid: 10749029
references.citation: Brain Res. 2008 Sep 10;1229:224-32
references.pmid: 18640105
references.citation: Brain Res. 2010 Jun 23;1341:32-40
references.pmid: 19446534
references.citation: J Neurotrauma. 2004 Oct;21(10):1457-67
references.pmid: 15672635
references.citation: Neuroscience. 1997 Oct;80(3):685-96
references.pmid: 9276486
references.citation: Eur J Neurosci. 2005 Aug;22(3):617-26
references.pmid: 16101743
references.citation: Life Sci. 2004 Jan 9;74(8):969-85
references.pmid: 14672754
references.citation: J Neurochem. 1997 Jul;69(1):273-84
references.pmid: 9202320
references.citation: Biochim Biophys Acta. 2006 Nov;1761(11):1246-59
references.pmid: 16973413
references.citation: Neuroscience. 2003;119(2):365-75
references.pmid: 12770552
references.citation: Brain Res Dev Brain Res. 1994 Mar 18;78(1):81-6
references.pmid: 7911748
references.citation: J Neurochem. 2008 May;105(4):1336-45
references.pmid: 18208543
references.citation: Neurochem Res. 2004 Nov;29(11):1961-77
references.pmid: 15662832
references.citation: J Neurochem. 1999 Jun;72(6):2323-33
references.pmid: 10349841
references.citation: Neuroscience. 2009 Jul 21;161(4):1037-44
references.pmid: 19393301
references.citation: Nat Rev Neurosci. 2004 May;5(5):361-72
references.pmid: 15100719
references.citation: Pharmacol Ther. 2003 Jan;97(1):55-85
references.pmid: 12493535
references.citation: Exp Neurol. 2006 Feb;197(2):309-17
references.pmid: 16364299
references.citation: J Biol Chem. 2007 Nov 30;282(48):34611-22
references.pmid: 17923475
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2007 Jan;76(1):47-55
references.pmid: 17187973
references.citation: J Pharmacol Exp Ther. 2008 Jul;326(1):196-208
references.pmid: 18417733
references.citation: Biochim Biophys Acta. 2000 Oct 31;1488(1-2):1-19
references.pmid: 11080672
references.citation: Clin Exp Pharmacol Physiol. 2006 Oct;33(10):934-9
references.pmid: 17002670
references.citation: FEBS Lett. 1995 Dec 27;377(3):358-62
references.pmid: 8549755
references.citation: Neuroscientist. 2006 Jun;12(3):245-60
references.pmid: 16684969
references.citation: Physiology (Bethesda). 2006 Aug;21:259-68
references.pmid: 16868315
references.citation: Learn Mem. 2009 May 27;16(6):395-405
references.pmid: 19474217
references.citation: Behav Neural Biol. 1994 May;61(3):225-32
references.pmid: 8067978
references.citation: J Neurochem. 1998 Dec;71(6):2322-9
references.pmid: 9832130
references.citation: J Neurochem. 2001 Jul;78(2):413-6
references.pmid: 11461977
references.citation: Mech Ageing Dev. 1998 Mar 16;101(1-2):119-28
references.pmid: 9593318
references.citation: Eur J Neurosci. 2006 Jan;23(2):505-13
references.pmid: 16420457
references.citation: Eur J Neurosci. 2004 Apr;19(7):1699-707
references.pmid: 15078544
references.citation: Brain Res. 2001 Jun 15;904(1):13-9
references.pmid: 11516407
references.citation: Neurobiol Aging. 2010 Apr;31(4):706-9
references.pmid: 18639368
references.citation: J Neurosci. 2001 Nov 1;21(21):8370-7
references.pmid: 11606625
references.citation: Neurosci Lett. 2001 Nov 16;314(3):135-8
references.pmid: 11704302
references.citation: Nature. 2006 Apr 6;440(7085):813-7
references.pmid: 16598260
references.citation: Crit Rev Immunol. 1997;17(3-4):225-83
references.pmid: 9202883
references.citation: Curr Pharm Des. 2004;10(18):2177-83
references.pmid: 15281893
references.citation: J Neurochem. 1997 Jan;68(1):255-64
references.pmid: 8978733
references.citation: J Biol Chem. 2005 Feb 18;280(7):5892-901
references.pmid: 15590663
references.citation: J Neurochem. 1997 Sep;69(3):1161-9
references.pmid: 9282939