Mitochondrial Protection by the Mixed Muscarinic/O1 Ligand ANAVEX2-73
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Mitochondrial protection by the mixed muscarinic/o1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model Valentine Lahmy, Romain Long, Didier Morin, Vanessa Villard, Tangui Maurice To cite this version: Valentine Lahmy, Romain Long, Didier Morin, Vanessa Villard, Tangui Maurice. Mitochondrial pro- tection by the mixed muscarinic/o1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Frontiers in Cellular Neuroscience, Frontiers, 2015, 8, 10.3389/fncel.2014.00463. hal-01922607 HAL Id: hal-01922607 https://hal.archives-ouvertes.fr/hal-01922607 Submitted on 27 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ORIGINAL RESEARCH ARTICLE published: 20 January 2015 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2014.00463 Mitochondrial protection by the mixed muscarinic/s1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Ab25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model Valentine Lahmy 1,2, Romain Long 3,4, Didier Morin 3,4, Vanessa Villard 2 and Tangui Maurice 1,2* 1 Inserm U 710, University of Montpellier 2, Montpellier, France 2 Amylgen, Montferrier-sur-Lez, France 3 Inserm U 955, Team 03, Créteil, France 4 Faculty of Medicine, Université Paris-Est, Unité Mixte de Recherche S955, Université Paris-Est Créteil Val-de-Marne, Créteil, France Edited by: Alzheimer’s disease (AD), the most prevalent dementia in the elderly, is characterized Fabio Blandini, National Institute of by progressive synaptic and neuronal loss. Mitochondrial dysfunctions have been Neurology C. Mondino Foundation, Italy consistently reported as an early event in AD and appear before Ab deposition Reviewed by: and memory decline. In order to define a new neuroprotectant strategy in AD Rafael Linden, Federal University of targeting mitochondrial alterations, we develop tetrahydro-N,N-dimethyl-2,2-diphenyl-3- Rio de Janeiro, Brazil furanmethanamine (ANAVEX2-73, AE37), a mixed muscarinic receptor ligand and a Mohan Pabba, Center for Addiction sigma-1 receptor (s1R) agonist. We previously reported that ANAVEX2-73 shows anti- and Mental Health, Canada amnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) *Correspondence: Tangui Maurice, Inserm U 710, with oligomeric amyloid-b25–35 peptide (Ab25–35). The s1R is present at mitochondria- University of Montpellier, cc 105, associated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator place Eugène Bataillon, 34095 2 of ER stress responses and local Ca C exchanges with the mitochondria. We therefore Montpellier cedex 5, France evaluated the effect of ANAVEX2-73 and PRE-084, a reference s1R agonist, on e-mail: [email protected] preservation of mitochondrial integrity in Ab25–35-injected mice. In isolated mitochondria from hippocampus preparations of Ab25–35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Ab25–35 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 Ab25–35-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 s1R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD. Keywords: Alzheimer’s disease, mitochondrial damages, ANAVEX2-73, sigma-1 receptor, cytoprotection INTRODUCTION et al., 2005). Mitochondrial dysfunctions have been consistently Alzheimer’s disease (AD), the most common form of demen- reported as an early event in AD physiopathology and appear tia in the elderly is defined histologically by the presence of before Ab deposition and memory deficits in AD patients and the two hallmarks: extracellular senile plaques constituted with transgenic mice (Maurer et al., 2000; Caspersen et al., 2005; amyloid-b (Ab) proteins and intracellular inclusions of hyper- Mosconi et al., 2008). Indeed, during AD pathogenesis, Ab phosphorylated microtubule-associated Tau protein, refered as oligomers accumulate in mitochondria, resulting in disrupted neurofibrillary tangles (Selkoe, 2004). Clinically, the disease is energy metabolism, increased oxidative stress and apoptosis characterized by progressive cognitive decline associated with (Lustbader et al., 2004; Caspersen et al., 2005; Manczak et al., synaptic and neuronal loss in regions critical for memory pro- 2006). Studies in AD patients and transgenic mice have reported cess, e.g., hippocampus, entorhinal and frontal cortex (Crews consistent decreases in tricarboxylic acid cycle enzymes and and Masliah, 2010). Mitochondria, which are the main energy cytochrome c oxidase activities (Yates et al., 1990; Maurer et al., provider in the cell, are particularly enriched in synapses 2000; Caspersen et al., 2005; Leuner et al., 2007). Moreover, where energy is critical for synaptic transmission (Verstreken studies in isolated mitochondria from transgenic mice brains Frontiers in Cellular Neuroscience www.frontiersin.org January 2015 | Volume 8 | Article 463 | 1 Lahmy et al. Mitochondrial protection by ANAVEX2-73 in Alzheimer’s disease or in isolated mitochondria exposed to Ab oligomers showed in mice induced by the ICV injection of Ab25–35 peptide. In decreased respiration rates and ATP production and increased particular, ANAVEX2-73 attenuated cellular loss, Ab1–42 seeding, oxidative stress, suggesting Ab-related defects in mitochondrial Tau hyperphosphorylation and learning and memory deficits respiratory chain (Casley et al., 2002a; Aleardi et al., 2005; observed several days after Ab25–35 injection (Villard et al., Caspersen et al., 2005; Clementi et al., 2005; Leuner et al., 2009, 2011; Lahmy et al., 2013). The drug acts synergistically 2007). Disruption in mitochondrial respiratory chain results in on its two main targets, as an antagonist of M2 mAChR and increased production of oxidative stress by mitochondria, a key as an agonist of s1R. The s1R is an endoplasmic reticulum element in AD physiopathology (Smith et al., 1996; Leuner (ER)-resident molecular chaperone (Hayashi and Su, 2007), also et al., 2012). One other aspect of mitochondrial failure is the expressed at the mitochondrial membrane (Klouz et al., 2002), opening of mitochondrial permeability transition pore (mPTP) particularly at mitochondria-associated ER membranes (MAM). which can be triggered by different effectors, e.g., mitochon- Its activity regulates Ca2C exchange from ER to mitochondria drial Ca2C overload and oxidative stress (Kroemer and Reed, (Hayashi and Su, 2007), known to be critical for mitochondrial 2000). mPTP opening could also be triggered by the translo- bioenergetics (Cárdenas et al., 2010). Moreover, the s1R is cation to the mitochondrial outer membrane of the cytosolic involved in regulation of the mitochondrial membrane potential, proapototic members of the Bcl-2 family proteins. Among them reactive oxygen species (ROS) production and apoptosis (Tsai is the proapototic protein Bax which, in proapoptotic condi- et al., 2009; Meunier and Hayashi, 2010) and s1R agonists have tions, translocates to mitochondria, dimerizes and constitutes been shown to protect mitochondrial function in vivo against a pore in the mitochondrial membrane and/or contributes to ischemic damage (Klouz et al., 2008; Tagashira et al., 2013). the formation of mPTP (Jürgensmeier et al., 1998; Marzo et al., In this study, we analyzed whether the neuroprotective activ- 1998; Narita et al., 1998). Bax activity could be antagonized ity of ANAVEX2-73 involves mitochondrial protection. We ana- by heterodimerization with antiapoptotic Bcl-2 family proteins, lyzed the respiratory activity in mitochondria isolated from the including Bcl-2 itself (Hanada et al., 1995; Yin et al., 1995; Yang mouse hippocampus, five days after ICV injection of oligomer- et al., 1997). mPTP opening allows liberation of mitochondrial ized Ab25–35. We measured respiration rates of freshly extracted protein, such as cytochrome c, which promotes apoptosis, binding mitochondria and the activity of the respiratory chain complexes to the apoptosis protease activation factor (APAf-1) and forming I to IV. We then analyzed biochemical markers of mitochondrial a complex indicated as “apoptosome” (Liu et al., 1996; Yang et al., damage, including Bax, Bcl-2 protein expression and cytochrome 1997). c release from the mitochondria into the cytosol. PRE-084 was In the present study, we used the intracerebroventricular (ICV) used as a reference s1R agonist. injection of Ab25–35 fragment in oligomeric