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Journal of Psychopharmacology Journal of Psychopharmacology http://jop.sagepub.com/ Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative Vanessa Villard, Julie Espallergues, Emeline Keller, Alexandre Vamvakides and Tangui Maurice J Psychopharmacol published online 9 September 2010 DOI: 10.1177/0269881110379286 The online version of this article can be found at: http://jop.sagepub.com/content/early/2010/09/08/0269881110379286 Published by: http://www.sagepublications.com On behalf of: British Association for Psychopharmacology Additional services and information for Journal of Psychopharmacology can be found at: Email Alerts: http://jop.sagepub.com/cgi/alerts Subscriptions: http://jop.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Downloaded from jop.sagepub.com by guest on September 15, 2010 J Psychopharmacol OnlineFirst, published on September 9, 2010 as doi:10.1177/0269881110379286 Original Paper Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (p1) Journal of Psychopharmacology ligand ANAVEX2-73, a novel 0(0) 1–17 ! The Author(s) 2010 aminotetrahydrofuran derivative Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881110379286 jop.sagepub.com Vanessa Villard1,2,3, Julie Espallergues1,2,3, Emeline Keller1,2,3, Alexandre Vamvakides4 and Tangui Maurice1,2,3 Abstract Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) binds to muscarinic acetylcholine and sigma1 (s1) receptors with affinities in the low micromolar range. We characterized its anti-amnesic and neuroprotective potentials in pharmacological and pathological amnesia models. Spatial working memory was evaluated using spontaneous alternation in the Y-maze and non-spatial memory using passive avoidance procedures. ANAVEX2-73 (0.01–3.0 mg/kg i.p.) alleviated the scopolamine- and dizocilpine-induced learning impairments. ANAVEX2-73 (300 mg/kg) also reversed the learning deficits in mice injected with Ab25-35 peptide, a non-transgenic Alzheimer’s disease model. When the drug was injected simultaneously with Ab25-35, 7 days before the tests, it blocked the appearance of learning impairments. This protective activity was confirmed since ANAVEX2-73 blocked the Ab25-35-induced oxidative stress in the hippocampus. This effect was differentially sensitive to the muscarinic receptor antagonist scopolamine or the s1 protein antagonist BD1047, confirming the mixed muscarinic/s1 pharmacological action. Finally, its unique demethyl metabolite, ANAVEX19-144, was also effective and ANAVEX2-73 presented a longer duration of action, effective 12 h before Ab25-35, than its related compound ANAVEX1-41. The neuroprotective activity of ANAVEX2-73, its mixed cholinergic/s1 activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer’s disease. Keywords ANAVEX2-73, muscarinic receptors, sigma-1 protein, learning and memory, dizocilpine, scopolamine, amyloid Ab25-35 peptide Introduction proteins, in the brain of patients with Alzheimer’s disease The central cholinergic systems are involved in learning (AD). A well-characterized impairment of cholinergic neu- and memory processes. They represent valuable targets for rons within the septo-hippocampic pathway and nucleus drug therapy aiming at improving the cognitive deficits basalis magnocellularis is involved in the rapid loss of learn- associated with ageing or neurodegenerative diseases. ing and memory in patients with AD (Erme et al., 1992; Cholinergic blocking agents such as scopolamine provoke, Perry et al., 1978). In particular, formation of Ab peptides when injected systemically in rodents, impairments of learn- impairs the coupling of M1 receptors with G-proteins ing and memory, and pro-cholinergic drugs, especially cho- (Fisher, 2000; Fisher et al., 2003). Present strategies in AD linesterase inhibitors, can ameliorate them durably (Fibiger, aim at improving or at least maintaining central cholinergic 1991; Mohammed, 1993). Moreover, specific acetylcholine functions, particularly by treatments with cholinesterase receptor subtypes are differentially involved in the effects of inhibitors. This allows a symptomatic alleviation of the cog- acetylcholine on cognition. Blockade of the muscarinic M1 nitive deficits, but also putatively an effective neuroprotec- subtype of acetylcholine receptor is particularly associated tion. Several cholinesterase inhibitors, including tacrine, with memory impairments (Bymaster et al., 1993; Ohno et al., 1994). M2 receptor antagonists may be associated 1 with improvements in memory, including attenuation of the Inserm, U. 710, 34095 Montpellier, France. 2 effects due to M1 receptor blockade, by increasing acetylcho- University of Montpellier 2, 34095 Montpellier, France. 3EPHE, 75017 Paris, France. line release in forebrain structures (Baratti et al., 1993; 4Anavex life Sciences, Pallini, Greece. Bymaster et al., 1993; Vamvakides, 2002b). Cholinergic systems are very sensitive to the neurodegen- Corresponding author: erative toxicity associated with the presence of deposits of Dr Tangui Maurice, INSERM U 710, EPHE, University of Montpellier 2, c.c. aggregated amyloid-b (Ab) proteins and neurofibrillary tan- 105, place Euge`ne Bataillon, 34095 Montpellier cedex 5, France gles, composed of abnormal and hyper-phosphorylated Tau Email: [email protected] Downloaded from jop.sagepub.com by guest on September 15, 2010 2 Journal of Psychopharmacology 0(0) donepezil and galantamine attenuated Ab1-40-orAb25–35- Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine induced toxicity in rodent models (Arias et al., 2004; hydrochloride (ANAVEX2-73) is a related aminotetrahydro- Kihara et al., 2004; Meunier et al., 2006; Svensson and furan derivative also presenting a mixed muscarinic/s1 Nordberg, 1998). The therapeutic potential of M1 receptor protein profile, but with a better selectivity for the s1 subtype selective agonists, directly activating post-synaptic M1 mus- as compared with s2 sites (Vamvakides, 2002a). Indeed, bind- carinic receptors in persistent cholinergic neurons, has also ing analyses of the compound performed by CEREP (Paris, been reported (Fisher, 2000). France), showed an IC50 ¼ 860 nM for s1 and no affinity for New ways for enhancing brain cholinergic functions s2 receptors. Moreover, the screening profile performed by are also in development. Among them, ligands activating the MDS PharmaServices (King of Prussia, PA, USA) showed sigma-1 (s1) protein have been reported to act as anti-amnesic micromolar affinities for muscarinic M1–M4 receptors and neuroprotective agents (Maurice and Su, 2009; Maurice (3.3–5.2 mL), sodium channel site 2 (5.1 mM), and NMDA et al., 1994, 1997, 1999; Monnet and Maurice, 2006). The s1 receptors (8.0 mL). Negligible interaction with 60 other protein is an intracellular neuromodulatory protein recently receptor and enzyme assays was found (data not shown). identified as a ligand-operated molecular chaperone, present In the present study, we first examined the anti-amnesic prop- at mitochondrion-associated endoplasmic reticulum (ER) erties of ANAVEX2-73 in mice in which learning abilities membranes (Hayashi and Su, 2007). Anti-amnesic s1 protein have been impede using a systemic treatment with the mus- activators show potent anti-amnesic properties partly by facil- carinic non-selective antagonist scopolamine, the NMDA itating acetylcholine release in the forebrain cortex (Matsuno receptor antagonist dizocilpine, or in mice that received a et al., 1992, 1993). Activation of s1 protein also modulates central administration of Ab25–35 peptide. Short-term spatial intracellular calcium mobilization (Hayashi et al., 2000), ion memory was evaluated using the spontaneous alternation channel activation (Aydar et al., 2002; Martina et al., 2007) performance in the Y-maze and long-term non-spatial and membrane recomposition, particularly within lipid rafts memory using the step-through type passive avoidance pro- microdomains (Hayashi and Su, 2001). In turn, s1 protein cedure. Second, we examine the neuroprotective activity of agonists, including (þ)-SKF-10047, (þ)-pentazocine, PRE- ANAVEX2-73 by injecting the drug intraperitoneally (i.p.) 084 or SA4503, have been shown to attenuate the learning at the same time as the intracerebroventricularly (i.c.v.) injec- impairments induced by scopolamine, by the N-methyl- tion of Ab25-35 peptide, 7 days before the behavioural or bio- D-aspartic acid (NMDA) receptor non-competitive antagonist chemical analyses. We analysed the learning deficits and dizocilpine (Maurice et al., 1994; Matsuno et al., 1997; Senda oxidative stress induction in the hippocampus. We used sco- et al., 1996, 1997), or in mice treated with the Ab25–35 peptide, a polamine and BD1047 as muscarinic and s1 receptor antag- non-transgenic model of AD (Maurice et al., 1998; Meunier onists, respectively, to analyse the involvement of these et al., 2006). The particular localization of s1 protein at the targets in the drug effect. Third, we analysed the activity of ER and function as sensor/regulator of Ca2þ homeostasis by the main metabolite of ANAVEX2-73 and ANAVEX1-41 regulating activity of inositol-1,2,4 trisphophate receptors and their putative involvement in the pharmacological (Hayashi and Su, 2001; Hayashi et al., 2000) may partly action of the parent
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