Identification of naturally occurring spirostenols preventing β-amyloid-induced neurotoxicity

• Published in: Steroids 2004, Vol.69 (1), p.1-16
• Main Authors: Lecanu, Laurent, Yao, Wenguo, Teper, Gary L, Yao, Zhi-Xing, Greeson, Janet, Papadopoulos, Vassilios
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid-derived diffusible ligand (ADDL); Animals; Binding, Competitive - drug effects; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cholesterol; Computer Simulation; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Humans; Hydroxycholesterols - chemistry; Hydroxycholesterols - pharmacology; Medical sciences; Mice; Neurodegeneration; Neurology; Neurons - drug effects; Neurons - physiology; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - etiology; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Plant Structures - chemistry; Plants - chemistry; Rats; Spirostenol; Steroids; Tumor Cells, Cultured; Vertebrates: endocrinology
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2003.09.007

22 R-Hydroxycholesterol is an intermediate in the steroid biosynthesis pathway shown to exhibit a neuroprotective property against β-amyloid (1–42) (Aβ) toxicity in rat PCl2 and human NT2N neuronal cells by binding and inactivating Aβ. In search of potent 22 R-hydroxycholesterol derivatives, we assessed the ability of a series of naturally occurring entities containing the 22 R-hydroxycholesterol structure to protect PC12 cells against Aβ-induced neurotoxicity, determined by measuring changes in membrane potential, mitochondrial diaphorase activity, ATP levels and trypan blue uptake. 22 R-Hydroxycholesterol derivatives sharing a common spirost-5-en-3-ol or a furost-5-en-3-ol structure were tested. Although some of these compounds were neuroprotective against 0.1 μM Aβ, only three protected against the 1–10 μM Aβ-induced toxicity and, in contrast to 22 R-hydroxycholesterol, all were devoid of steroidogenic activity. These entities shared a common structural feature, a long chain ester in position 3 and common stereochemistry. The neuroprotective property of these compounds was coupled to their ability to displace radiolabeled 22R-hydroxycholesterol from Aβ, suggesting that the Aβ-22 R-hydroxycholesterol physicochemical interaction contributes to their beneficial effect. In addition, a 22 R-hydroxycholesterol derivative inhibited the formation of neurotoxic amyloid-derived diffusible ligands. Computational docking simulations of 22 R-hydroxycholesterol and its derivatives on Aβ identified two binding sites. Chemical entities, as 22 R-hydroxycholesterol, seem to bind preferentially only to one site. In contrast, the presence of the ester chain seems to confer the ability to bind to both sites on Aβ, leading to neuroprotection against high concentrations of Aβ. In conclusion, these results suggest that spirost-5-en-3-ol naturally occurring derivatives of 22 R-hydroxycholesterol might offer a new approach for Alzheimer’s disease therapy.