Mitochondrial protection by the mixed muscarinic/σ(1) ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ(25–35) peptide-injected mice, a nontransgenic Alzheimer’s disease model

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 (σ(1)R) agonist. We previously reported that ANAVEX2-73 shows anti-amnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-β(25–35) peptide (Aβ(25–35)). 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 σ(1)R agonist, on preservation of mitochondrial integrity in Aβ(25–35)-injected mice. In isolated mitochondria from hippocampus preparations of Aβ(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 Aβ(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 Aβ(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 σ(1)R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.