Mitochondrial protection by the mixed muscarinic/sigma(1) ligand ANAVEX2-73, a tetrahydrofuran derivative, in A beta(25-35) peptide-injected mice, a nontransgenic Alzheimer's disease model

作者：Lahmy Valentine; Long Romain; Morin Dider; Villard Vanessa; Maurice Tangui^*

来源：Frontiers in Cellular Neuroscience, 2015, 8: 463.

DOI：10.3389/fncel.2014.00463

• Alzheimer's disease
• mitochondrial damages
• ANAVEX2-73
• sigma-1 receptor
• cytoprotection

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 A beta 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 (sigma R-1) agonist. We previously reported that ANAVEX2-73 shows antiamnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-beta(25-35) peptide (A beta(25-35)). The sigma 1R is present at mitochondria-associated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator of ER stress responses and local Ca2+ exchanges with the mitochondria. We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference sigma R-1 agonist, on preservation of mitochondrial integrity in A beta(25-35)-injected mice. In isolated mitochondria from hippocampus preparations of A beta(25-35) injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after A beta(25-35) 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 A beta(25-35)-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 sigma R-1, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.

• 出版日期2015-1-20