The Synergistic Neuroprotective Effect of Honokiol and Magnolol Against Amyloid-β and MPP+-Induced Neurotoxicity in SH-SY5Y Cells: An Antioxidant, Molecular Orbital, and ADMET Study.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive-motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity in SH-SY5Y cells, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP+ (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP+-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol.