The potential anti‐amyloidogenic candidate, SPA1413, for Alzheimer's disease

• Published in: British journal of pharmacology 2022-03, Vol.179 (5), p.1033-1048
• Main Authors: An, Seong Soo A., Shim, Kyu Hwan, Kang, Shinwoo, Kim, Young Kyo, Subedi, Lalita, Cho, Hyewon, Hong, Seong‐Min, Tan, Mario A., Jeon, Raok, Chang, Keun‐A, Kim, Sun Yeou
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloidogenesis; Animal models; Animals; Brain - metabolism; Cognitive ability; Cytotoxicity; Disease Models, Animal; drug discovery; Fibrillogenesis; Genistein; Inflammation; isoflavone; Isoflavones; Isoflavones - pharmacology; Mice; Mice, Transgenic; Microglia; Neurodegenerative diseases; neuroinflammation; Neurological diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oligomerization; Oral administration; Plaque, Amyloid; Senile plaques; Transgenic mice; β-Amyloid
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15691

Background and Purpose Recently, isoflavone derivatives have been shown to have neuroprotective effects against neurological disorders. For instance, genistein attenuated the neuroinflammation and amyloid‐β accumulation in Alzheimer's disease animal models, suggesting the potential for use to prevent and treat Alzheimer's disease. Experimental Approach Here, 50 compounds, including isoflavone derivatives, were constructed and screened for the inhibitory effects on amyloid‐β42 fibrilization and oligomerization using the high‐throughput screening formats of thioflavin T assay and multimer detection system, respectively. The potential neuroprotective effect of t3‐(4‐hydroxyphenyl)‐2H‐chromen‐7‐ol (SPA1413), also known as dehydroequol, idronoxil or phenoxodiol, was evaluated in cells and in 5xFAD (B6SJL) transgenic mouse, a model of Alzheimer's disease. Key Results SPA1413 had a potent inhibitory action on both amyloid‐β fibrilization and oligomerization. In the cellular assay, SPA1413 prevented amyloid‐β‐induced cytotoxicity and reduced neuroinflammation. Remarkably, the oral administration of SPA1413 ameliorated cognitive impairment, decreased amyloid‐β plaques and activated microglia in the brain of 5xFAD (B6SJL) transgenic mouse. Conclusion and Implications Our results strongly support the repurposing of SPA1413, which has already received fast‐track status from the US Food and Drug Administration (FDA) for cancer treatment, for the treatment of Alzheimer's disease due to its potent anti‐amyloidogenic and anti‐neuroinflammatory actions.