Paeonol Derivative, 6′-Methyl Paeonol, Attenuates Aβ-Induced Pathophysiology in Cortical Neurons and in an Alzheimer’s Disease Mice Model

Herbs themselves and various herbal medicines are great resources for discovering therapeutic drugs for various diseases, including Alzheimer’s disease (AD), one of the common neurodegenerative diseases. Utilizing mouse primary cortical neurons and DiBAC4(3), a voltage-sensitive indicator, we have set up a drug screening system and identified an herbal extraction compound, paeonol, obtained from Paeonia lactiflora; this compound is able to ameliorate the abnormal depolarization induced by Aβ42 oligomers. Our aim was to further find effective paeonol derivatives since paeonol has been previously studied. 6′-Methyl paeonol, one of the six paeonol derivatives surveyed, is able to inhibit the abnormal depolarization induced by Aβ oligomers. Furthermore, 6′-methyl paeonol is able to alleviate the NMDA- and AMPA-induced depolarization. When a molecular mechanism was investigated, 6′-methyl paeonol was found to reverse the Aβ-induced increase in ERK phosphorylation. At the animal level, mice injected with 6′-methyl paeonol showed little change in their basic physical parameters compared to the control mice. 6′-Methyl paeonol was able to ameliorate the impairment of memory and learning behavior in J20 mice, an AD mouse model, as measured by the Morris water maze. Thus, paeonol derivatives could provide a structural foundation for developing and designing an effective compound with promising clinical benefits.