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. 2024 Feb 22;29(5):957.
doi: 10.3390/molecules29050957.

Effect of Diacetylcurcumin Manganese Complex on Rotenone-Induced Oxidative Stress, Mitochondria Dysfunction, and Inflammation in the SH-SY5Y Parkinson's Disease Cell Model

Ekanong Pirunkaset  1 , Chantana Boonyarat  2 , Juthamart Maneenet  2   3 , Charinya Khamphukdee  4 , Supawadee Daodee  2 , Orawan Monthakantirat  2 , Suresh Awale  3 , Anake Kijjoa  5 , Yaowared Chulikhit  2
Affiliations

Effect of Diacetylcurcumin Manganese Complex on Rotenone-Induced Oxidative Stress, Mitochondria Dysfunction, and Inflammation in the SH-SY5Y Parkinson's Disease Cell Model

Ekanong Pirunkaset et al. Molecules. .

Abstract

Diacetylcurcumin manganese complex (DiAc-Cp-Mn) is a diacetylcurcumin (DiAc-Cp) derivative synthesized with Mn (II) to mimic superoxide dismutase (SOD). It exhibited superior reactive oxygen species (ROS) scavenging efficacy, particularly for the superoxide radical. The present study investigated the ROS scavenging activity, neuroprotective effects, and underlying mechanism of action of DiAc-Cp-Mn in a cellular model of Parkinson's disease. This study utilized rotenone-induced neurotoxicity in SH-SY5Y cells to assess the activities of DiAc-Cp-Mn by measuring cell viability, intracellular ROS, mitochondrial membrane potential (MMP), SOD, and catalase (CAT) activities. The mRNA expression of the nuclear factor erythroid 2 p45-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), inducible nitric oxide synthase (iNOS), and Interleukin 1β (IL-1β), which are oxidative and inflammatory genes, were also evaluated to clarify the molecular mechanism. The results of the in vitro assays showed that DiAc-Cp-Mn exhibited greater scavenging activity against superoxide radicals, hydrogen peroxide, and hydroxyl radicals compared to DiAc-Cp. In cell-based assays, DiAc-Cp-Mn demonstrated greater neuroprotective effects against rotenone-induced neurotoxicity when compared to its parent compound, DiAc-Cp. DiAc-Cp-Mn maintained MMP levels, reduced intracellular ROS levels, and increased the activities of SOD and CAT by activating the Nrf2-Keap1 signaling pathway. In addition, DiAc-Cp-Mn exerted its anti-inflammatory impact by down-regulating the mRNA expression of iNOS and IL-1β that provoked neuro-inflammation. The current study indicates that DiAc-Cp-Mn protects against rotenone-induced neuronal damage by reducing oxidative stress and inflammation.

Keywords: Nrf2 regulation; Parkinson’s disease; SOD mimics; diacetylcurcumin manganese complex; oxidative stress.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structure of (a) diacetylcurcumin (DiAc-Cp) and (b) diacetylcurcumin manganese complex (DiAc-Cp-Mn).
Figure 2
Figure 2
The cytotoxicity of DiAc-Cp and DiAc-Cp-Mn at 24 h in SH-SY5Y cells was determined by an MTT assay. Values are reported as the percentage of the untreated control and represent the mean ± SEM (n = 6).
Figure 3
Figure 3
(a) Rotenone-induced neurotoxicity for 24 h in SH-SY5Y cells showed a dose-dependent reduction in cell viability, determined by an MTT assay. (b) 20 µM rotenone-induced neurotoxicity in SH-SY5Y cells was determined by MTT assay. Values are reported as the percentage of the untreated control and represent the mean ± SEM (n = 6). Significance was calculated using ANOVA [* = p < 0.05, ** = p < 0.01, and *** = p < 0.001] compared to the control.
Figure 4
Figure 4
The neuroprotective effect of DiAc-Cp and DiAc-Cp-Mn against 20 μM rotenone-induced toxicity in SH-SY5Y cells for 24 h was determined by MTT assay. Values are reported as the percentage of the untreated control and represent the mean ± SEM (n = 6). Significance was calculated using a t-test [*** p < 0.001] compared to the control, an ANOVA [## = p < 0.01 and ### = p < 0.001] compared to the rotenone group, and an ANOVA [$ = p < 0.05, $$ = p < 0.01, and $$$ = p < 0.001] compared to the DiAc-Cp-Mn group.
Figure 5
Figure 5
Levels of intracellular ROS in rotenone-treated SH-SY5Y cells were determined by the DCFH-DA method. Cells were pretreated with DiAc-Cp and DiAc-Cp-Mn before rotenone exposure for 6 h. Values are reported as the mean ± SEM (n = 6). Significance was calculated using a t-test [*** = p < 0.01] compared to the control, an ANOVA [# = p < 0.05 and ### = p < 0.001] compared to the rotenone group, and an ANOVA [$ = p < 0.05] compared to the DiAc-Cp-Mn group.
Figure 6
Figure 6
MMP in rotenone-treated SH-SY5Y cells was determined by the Rh-123 method. Cells were pretreated with DiAc-Cp and DiAc-Cp-Mn before rotenone exposure for 6 h. Values are reported as the mean ± SEM (n = 6). Significance was calculated using a t-test [*** = p < 0.001] compared to the control, an ANOVA [# = p < 0.05 and ### = p < 0.001] compared to the rotenone group.
Figure 7
Figure 7
DiAc-Cp and DiAc-Cp-Mn mitigated rotenone-induced neurotoxicity on SH-SY5Y cells by improving (a) the SOD and (b) the CAT activities. Values are reported as the mean ± SEM (n = 6). Significance was calculated using a t-test [*** = p < 0.001] compared to control, an ANOVA [### = p < 0.001] compared to the rotenone group, and an ANOVA [$$ = p < 0.01 and $$$ = p < 0.001] compared to the DiAc-Cp-Mn group.
Figure 8
Figure 8
Effect of DiAc-Cp and DiAc-Cp-Mn on rotenone-induced expression of (a) NRF2, (b) KEAP1, (c) IL-1β, and (d) iNOS in SH-SY5Y cells. Values are reported as the percentage of the untreated control and represent the mean ± SEM (n = 6). Significance was calculated using a t-test [** = p < 0.01 and *** p < 0.001] compared to control, an ANOVA [## = p < 0.01 and ### = p < 0.001] compared to the rotenone group, and an ANOVA [$ = p < 0.05, $$ = p < 0.01, and $$$ = p < 0.001] compared to the DiAc-Cp-Mn group.
Figure 9
Figure 9
The neuroprotective effect of DiAc-Cp-Mn on rotenone-induced oxidative stress.
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