Synthetic Cyclic C5-Curcuminoids Mitigate Oxidative, Apoptotic and Inflammatory Damage in a 6-OHDA-Induced Neuron–Microglia Co-Culture Model of Neuronal Damage

Pandur, Edina and Tóth, Zsombor Bence and Tyukodi, Levente and Gróf, Ilona and Veszelka, Szilvia and Deli, Mária A. and Rozmer, Zsuzsanna and Huber, Imre (2026) Synthetic Cyclic C5-Curcuminoids Mitigate Oxidative, Apoptotic and Inflammatory Damage in a 6-OHDA-Induced Neuron–Microglia Co-Culture Model of Neuronal Damage. ANTIOXIDANTS, 15 (9). No. 1085. ISSN 2076-3921

Preview

Text antioxidants-15-01085.pdf - Published Version Available under License Creative Commons Attribution. Download (8MB) | Preview

Abstract

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C5-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C5-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (Papp value 13.6 × 10−6 cm/s). Synthetic cyclic C5-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases.

Actions (login required)

View Item