title: Short-term treatment with tolfenamic acid improves cognitive functions in Alzheimer's disease mice.
abstract: Tolfenamic acid lowers the levels of the amyloid precursor protein (APP) and amyloid beta (Aβ) when administered to C57BL/6 mice by lowering their transcriptional regulator specificity protein 1 (SP1). To determine whether changes upstream in the amyloidogenic pathway that forms Aβ plaques would improve cognitive outcomes, we administered tolfenamic acid for 34 days to hemizygous R1.40 transgenic mice. After the characterization of cognitive deficits in these mice, assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and the Y-maze. These improvements occurred within a shorter period of exposure than that seen with clinically approved drugs. Cognitive enhancement was accompanied by reduction in the levels of the SP1 protein (but not messenger RNA [mRNA]), followed by lowering both the mRNA and the protein levels of APP and subsequent Aβ levels. These findings provide evidence that tolfenamic acid can disrupt the pathologic processes associated with Alzheimer's disease (AD) and are relevant to its scheduled biomarker study in AD patients.
authors: Neurodegeneration Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA.
authors: Gehad M
authors: GM
authors: Subaiea
authors: Lina I
authors: LI
authors: Adwan
authors: Aseef H
authors: AH
authors: Ahmed
authors: Karen E
authors: KE
authors: Stevens
authors: Nasser H
authors: NH
authors: Zawia
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy; D057567:Memory, Long-Term; D008570:Memory, Short-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018697:Nootropic Agents; D016329:Sp1 Transcription Factor; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid
keywords: AD transgenic mouse model; Alzheimer's disease; Learning and memory; Morris water maze; Tolfenamic acid; Y-maze
references: Neurosci Lett. 2006 Apr 10-17;397(1-2):30-4
references: 16378688
references: Neurology. 1997 Mar;48(3):626-32
references: 9065537
references: Curr Alzheimer Res. 2011 Dec;8(8):860-7
references: 21605061
references: Science. 1992 Apr 10;256(5054):184-5
references: 1566067
references: Behav Brain Res. 1999 Sep;103(2):145-62
references: 10513583
references: Lancet. 2011 Mar 19;377(9770):1019-31
references: 21371747
references: Biophys J. 1999 Mar;76(3):1330-4
references: 10049316
references: J Alzheimers Dis. 2008 Feb;13(1):71-80
references: 18334759
references: Arch Neurol. 1993 Apr;50(4):349-58
references: 8460956
references: J Biol Chem. 1996 Sep 20;271(38):23380-8
references: 8798542
references: Drugs. 2011 Oct 22;71(15):2031-65
references: 21985169
references: J Neurosci. 2006 Jul 19;26(29):7555-64
references: 16855083
references: Nature. 2001 Nov 8;414(6860):212-6
references: 11700559
references: Am J Alzheimers Dis Other Demen. 2012 Aug;27(5):296-300
references: 22815077
references: Neurology. 2008 May 6;70(19):1672-7
references: 18458226
references: J Neuropathol Exp Neurol. 2012 May;71(5):362-81
references: 22487856
references: J Alzheimers Dis. 2010;20 Suppl 2:S499-512
references: 20413847
references: Am J Pathol. 2000 Dec;157(6):2093-9
references: 11106581
references: J Natl Cancer Inst. 2006 Jun 21;98(12):855-68
references: 16788159
references: Biochem J. 2004 Oct 15;383(Pt 2):393-9
references: 15242331
references: Science. 2003 Nov 14;302(5648):1215-7
references: 14615541
references: Neurology. 1995 Aug;45(8):1441-5
references: 7644037
references: Neurosci Biobehav Rev. 2002 Jan;26(1):91-104
references: 11835987
references: Am J Pathol. 2010 Feb;176(2):870-80
references: 20042680
references: Hum Mol Genet. 1997 Sep;6(9):1535-41
references: 9285791
references: Science. 2006 Nov 3;314(5800):781-4
references: 17082448
references: Trends Genet. 2001 Oct;17(10):S7-12
references: 11585670
references: Nat Protoc. 2006;1(2):848-58
references: 17406317
references: Neurobiol Dis. 2001 Dec;8(6):982-92
references: 11741394
references: Nat Neurosci. 1999 Aug;2(8):695-7
references: 10412057
references: Mol Cell Biol. 2004 Jan;24(2):865-74
references: 14701757
references: Neurobiol Aging. 2003 Sep;24(5):645-53
references: 12885572
references: Br J Pharmacol. 2012 Mar;165(5):1246-59
references: 22044248
references: J Neurochem. 2000 Oct;75(4):1408-18
references: 10987820
references: Curr Alzheimer Res. 2011 Jun;8(4):385-92
references: 21557719
references: N Engl J Med. 2010 Jan 28;362(4):329-44
references: 20107219
references: Nat Rev Immunol. 2002 Oct;2(10):748-59
references: 12360213
references: J Neurosci. 2003 Oct 29;23(30):9796-804
references: 14586007
references: N Engl J Med. 2001 Nov 22;345(21):1515-21
references: 11794217
references: JAMA. 2000 Mar 22-29;283(12):1571-7
references: 10735393
references: Nat Neurosci. 2001 Mar;4(3):233-4
references: 11224536
references: Brain Res. 2008 May 1;1207:225-36
references: 18374906
references: Science. 1992 Oct 2;258(5079):126-9
references: 1439760
references: BMJ. 2003 Jul 19;327(7407):128
references: 12869452
references: Curr Aging Sci. 2009 Dec;2(3):205-13
references: 20021415
references: Neurodegener Dis. 2007;4(1):13-27
references: 17429215
references: Neurobiol Aging. 1997 Jul-Aug;18(4):351-7
references: 9330961
references: Neurology. 1996 Aug;47(2):425-32
references: 8757015
references: J Neuroimmunol. 1996 Dec;71(1-2):81-6
references: 8982106
references: J Biol Chem. 1997 Feb 7;272(6):3406-10
references: 9013583
references: J Neurosci. 2005 Jan 26;25(4):823-9
references: 15673661
references: Physiol Rev. 2001 Apr;81(2):741-66
references: 11274343
references: Neuroimaging Clin N Am. 2012 Feb;22(1):11-22, vii
references: 22284730
references: J Neurosci Res. 2008 Aug 15;86(11):2499-504
references: 18449948
references: J Neurochem. 2012 Jan;120 Suppl 1:9-21
references: 22122372
references: J Biol Chem. 2009 Apr 17;284(16):10453-61
references: 19218241
references: Curr Neuropharmacol. 2011 Dec;9(4):643-50
references: 22654722
references: Ann Neurol. 1999 Dec;46(6):860-6
references: 10589538
references: J Neurosci. 2008 Jan 2;28(1):3-9
references: 18171917
references: Nat Rev Neurosci. 2005 Feb;6(2):119-30
references: 15685217
references: Psychopharmacology (Berl). 2008 Mar;197(1):37-43
references: 18008065
references: Invest New Drugs. 2011 Feb;29(1):41-51
references: 19851711
references: Alzheimers Dement. 2012 May;8(3):219-26
references: 22546354
references: Am J Epidemiol. 2002 Sep 1;156(5):445-53
references: 12196314
references: Mol Cancer Ther. 2009 Mar;8(3):533-42
references: 19258429
references: Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):443-8
references: 16407166
references: Neurology. 2002 Sep 24;59(6):880-6
references: 12297571
references: Behav Brain Res. 2009 Jan 23;196(2):220-7
references: 18831990
references: Nat Genet. 1993 Sep;5(1):22-30
references: 8220418
references: J Biol Chem. 2012 Oct 5;287(41):34786-800
references: 22891248
references: J Neurosci. 2000 Jan 15;20(2):558-67
references: 10632585
references: J Neurosci. 2012 Jul 25;32(30):10117-28
references: 22836247
references: Brief Funct Genomic Proteomic. 2004 Apr;3(1):47-59
references: 15163359
references: Gynecol Oncol. 2011 Jul;122(1):163-70
references: 21496890
references: Behav Brain Res. 2009 Sep 14;202(2):252-9
references: 19463709