Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Abstract

The antiamnesic and neuroprotective activities of the new aminotetrahydrofuran derivative tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41), a nonselective muscarinic receptor ligand and s 1 protein activator, were examined in mice injected intracerebroventricularly with amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) peptide (9 nmol). Ab 25-35 impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1-1000 mg/kg i.p.) was administered 7 days after Ab 25-35 , ie, 20 min before the behavioral tests, it significantly reversed the Ab 25-35 -induced deficits, the most active doses being in the 3-100 mg/kg range. When the compound was preadministered 20 min before Ab 25-35 , ie, 7 days before the tests, it prevented the learning impairments at 30-100 mg/kg. Morphological analysis of corticolimbic structures showed that Ab 25-35 induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 mg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Ab 25-35 -induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Ab 25-35 -induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Ab 25-35 -induced caspase-9 expression. The compound also blocked the Ab 25-35 -induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the s 1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 mg/kg) against Ab 25-35 -induced learning impairments, suggesting that muscarinic and s 1 targets are involved in the drug effect. A synergic effect could indeed account for the very low active doses measured in vivo. These data outline the therapeutic potential of ANAVEX1-41 as a neuroprotective agent in Alzheimer's disease.

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…At 1 week after injection, A␤ [25][26][27][28][29][30][31][32][33][34][35] induced significant oxidative stress in the hippocampus, as reflected by measured increases in lipid peroxidation, protein nitration, and superoxide generation. [11][12][13]40 In the present study, the early increases in lipid peroxidation levels observed after peptide injection were gradually reduced, particularly in the rat frontal cortex and amygdala, suggesting that oxidative stress could be alleviated by endogenous protective systems (putatively neurotrophins, such as BDNF).…”

“…9 and 10) and after 1 week in mouse. 11 The extent of cell loss was limited to a 30% to 40% decrease in the number of viable cells in the most vulnerable areas, whereas a significantly greater loss was noted in all pyramidal cell layers. The neurodegenerative process thus appeared to be generalized, contrary to what is usually observed in excitotoxic or chemical neurotoxicity models.…”

“…They demonstrated that A␤ and A␤ [25][26][27][28][29][30][31][32][33][34][35] induce apoptosis through caspase-dependent pathways. [41][42][43][44][45][46][47] In vivo, 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] , an increase in caspase-3 activity in the hippocampus of rats 9 and increases in levels of pro-caspases 9, 12, and 3 in the hippocampus of mice 11 were observed. In the present study, we observed increases in pro-and cleaved forms for caspase-9 (mitochondrial stress marker) and caspase-12 (endoplasmic reticulum stress marker) in all structures except the hypothalamus.…”

“…In particular, at 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] injection, reactive gliosis was observed in the rat hippocampus, 9 caspase-3 activity was induced in the hippocampus and cortex, 9 a reduction in the number of neurons was measured in the CA1 or CA3 hippocampal area, 9 -11 and significant oxidative stress was observed. [11][12][13] Nonetheless, this amyloid toxicity model remains controversial with respect to AD. The grounds for objection center on three points.…”

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

“…Modifying s 1 protein activation using effective agonists therefore mediates a unique pharmacological action on Ca 2 þ homeostasis and signal transduction pathways, with major impacts on cellular response and plasticity. The idea of developing mixed s 1 /muscarinic ligands was therefore based on the capability to simultaneously activate a neuroprotective pathway, eg, the M1/PLC/PKC pathway, and amplify it, through a concomitant activation of the s 1 protein (Vamvakides, 2002a, b;Espallergues et al, 2007;Villard et al, 2009Villard et al, , 2011. Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) presents such a mixed s 1 /muscarinic receptor profile, with a moderate affinity range.…”