title: Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model.
abstract: Alzheimer's disease (AD), the most prevalent dementia in the elderly, is characterized by progressive synaptic and neuronal loss. Mitochondrial dysfunctions have been consistently reported as an early event in AD and appear before Aβ deposition and memory decline. In order to define a new neuroprotectant strategy in AD targeting mitochondrial alterations, we develop tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (ANAVEX2-73, AE37), a mixed muscarinic receptor ligand and a sigma-1 receptor (σ1R) agonist. We previously reported that ANAVEX2-73 shows anti-amnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-β25-35 peptide (Aβ25-35). The σ1R is present at mitochondria-associated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator of ER stress responses and local Ca(2+) exchanges with the mitochondria. We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference σ1R agonist, on preservation of mitochondrial integrity in Aβ25-35-injected mice. In isolated mitochondria from hippocampus preparations of Aβ25-35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Aβ25-35 injection, mitochondrial respiration in mouse hippocampus was altered. ANAVEX2-73 (0.01-1 mg/kg IP) restored normal respiration and PRE-084 (0.5-1 mg/kg IP) increased respiration rates. Both compounds prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, all indicators of increased toxicity. ANAVEX2-73 and PRE-084 efficiently prevented the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptosis. The σ1R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.
authors: Inserm U 710, University of Montpellier 2 Montpellier, France ; Amylgen, Montferrier-sur-Lez France.
authors: Valentine
authors: V
authors: Lahmy
authors: Inserm U 955, Team 03, Créteil France ; Faculty of Medicine, Université Paris-Est, Unité Mixte de Recherche S955, Université Paris-Est Créteil Val-de-Marne Créteil, France.
authors: Romain
authors: R
authors: Long
authors: Inserm U 955, Team 03, Créteil France ; Faculty of Medicine, Université Paris-Est, Unité Mixte de Recherche S955, Université Paris-Est Créteil Val-de-Marne Créteil, France.
authors: Didier
authors: D
authors: Morin
authors: Amylgen, Montferrier-sur-Lez France.
authors: Vanessa
authors: V
authors: Villard
authors: Inserm U 710, University of Montpellier 2 Montpellier, France ; Amylgen, Montferrier-sur-Lez France.
authors: Tangui
authors: T
authors: Maurice
keywords: ANAVEX2-73; Alzheimer’s disease; cytoprotection; mitochondrial damages; sigma-1 receptor
references: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
references: 19897719
references: Science. 1997 Feb 21;275(5303):1129-32
references: 9027314
references: Eur J Pharmacol. 1997 Jan 14;319(1):1-4
references: 9030890
references: Cell. 1996 Jul 12;86(1):147-57
references: 8689682
references: Ann N Y Acad Sci. 2008 Dec;1147:180-95
references: 19076441
references: J Neurochem. 2006 Oct;99(1):226-36
references: 16987248
references: FEBS Lett. 1999 Aug 20;457(1):131-4
references: 10486579
references: J Pineal Res. 2010 Mar;48(2):117-25
references: 20041986
references: FEBS Lett. 2005 May 23;579(13):2913-8
references: 15890345
references: Am J Pathol. 2011 Jul;179(1):315-34
references: 21703413
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18670-5
references: 20937894
references: Cell. 2007 Nov 2;131(3):596-610
references: 17981125
references: Biochim Biophys Acta. 2013 Apr;1830(4):3082-94
references: 23298811
references: FEBS Lett. 1998 Mar 13;424(3):155-8
references: 9539141
references: Neurobiol Aging. 2000 May-Jun;21(3):455-62
references: 10858595
references: Br J Pharmacol. 2002 Apr;135(7):1607-15
references: 11934800
references: PLoS One. 2007 Jun 20;2(6):e536
references: 17579710
references: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14681-6
references: 9843949
references: Br J Pharmacol. 2006 Dec;149(8):998-1012
references: 17057756
references: J Cell Biochem. 2011 May;112(5):1450-7
references: 21321998
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4997-5002
references: 9560217
references: FASEB J. 2005 Dec;19(14):2040-1
references: 16210396
references: J Neurochem. 2002 Jan;80(1):91-100
references: 11796747
references: PLoS One. 2012;7(8):e42344
references: 22927926
references: Hum Mol Genet. 2006 May 1;15(9):1437-49
references: 16551656
references: Mitochondrion. 2013 Jul;13(4):298-311
references: 23562762
references: Br J Pharmacol. 2007 Sep;152(2):267-79
references: 17641675
references: Nature. 1996 Jul 11;382(6587):120-1
references: 8700201
references: Neuron. 2005 Aug 4;47(3):365-78
references: 16055061
references: Hum Mol Genet. 2010 Apr 15;19(R1):R12-20
references: 20413653
references: Nat Med. 2000 May;6(5):513-9
references: 10802706
references: J Biol Chem. 1992 Sep 5;267(25):18210-7
references: 1517249
references: Science. 2004 Apr 16;304(5669):448-52
references: 15087549
references: Science. 1998 Sep 25;281(5385):2027-31
references: 9748162
references: J Bioenerg Biomembr. 2005 Aug;37(4):207-25
references: 16167177
references: Life Sci. 2005 Aug 19;77(14):1612-24
references: 16002098
references: J Biol Chem. 1995 May 19;270(20):11962-9
references: 7744846
references: Eur J Pharmacol. 2012 May 5;682(1-3):12-20
references: 22381068
references: Neuron. 2008 Dec 10;60(5):748-66
references: 19081372
references: Mol Neurobiol. 2010 Jun;41(2-3):107-14
references: 20217279
references: Curr Top Microbiol Immunol. 1995;194:331-8
references: 7895506
references: Neuropsychopharmacology. 2009 May;34(6):1552-66
references: 19052542
references: Mol Neurobiol. 2012 Aug;46(1):186-93
references: 22833458
references: J Neurochem. 1990 Nov;55(5):1624-30
references: 2213015
references: J Psychopharmacol. 2011 Aug;25(8):1101-17
references: 20829307
references: Apoptosis. 2007 May;12(5):941-9
references: 17453161
references: Neurobiol Dis. 2013 Mar;51:3-12
references: 22266017
references: Neuropsychopharmacology. 2013 Aug;38(9):1706-23
references: 23493042
references: Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2577-88
references: 18296662
references: Cell Death Dis. 2013 May 23;4:e646
references: 23703391
references: Cell. 2010 Jul 23;142(2):270-83
references: 20655468
references: PLoS One. 2013;8(1):e53117
references: 23301030
references: Brain Res. 1996 Jan 15;706(2):181-93
references: 8822355
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22468-73
references: 20018732
references: FEBS Lett. 2003 Oct 9;553(1-2):157-62
references: 14550565
references: Free Radic Res. 2008 Jun;42(6):564-73
references: 18569014
references: Antioxid Redox Signal. 2007 Oct;9(10):1659-75
references: 17867931
references: Synapse. 2012 Jan;66(1):42-51
references: 21905129
references: J Pharmacol Exp Ther. 2010 Feb;332(2):388-97
references: 19855099
references: Neurobiol Dis. 2002 Aug;10(3):258-67
references: 12270688
references: Nat Cell Biol. 2004 Nov;6(11):1054-61
references: 15516999
references: Eur J Pharmacol. 2008 Jan 14;578(2-3):292-9
references: 17964567