Synthetic Mono-Carbonyl Curcumin Analogues Attenuate Oxidative Stress in Mouse Models

Abstract

Alzheimer’s disease is the commonest form of dementia associated with short-term memory loss and impaired cognition and, worldwide, it is a growing health issue. A number of therapeutic strategies have been studied to design and develop an effective anti-Alzheimer drug. Curcumin has a wide spectrum of biological properties. In this regard, the antioxidant potentials of mono-carbonyl curcumin analogues (h1−h5) were investigated using in vitro antioxidant assays and hippocampal-based in vivo mouse models such as light−dark box, hole board, and Y-maze tests. In the in vitro assay, mono-carbonyl curcumin analogues h2 and h3 with methoxy and chloro-substituents, respectively, showed promising 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2′-azinobis-3-ethylbenzothiazo-line-6-sulfonate (ABTS) free radical scavenging activities. In the in vivo studies, scopolamine administration significantly (p < 0.001) induced oxidative stress and memory impairment in mice, in comparison to the normal control group. The pretreatment with mono-carbonyl curcumin analogues, specifically h2 and h3, significantly decreased (123.71 ± 15.23 s (p < 0.001), n = 8; 156.53 ± 14.13 s (p < 0.001), n = 8) the duration of time spent in the light chamber and significantly enhanced (253.95 ± 19.05 s (p < 0.001), n = 8, and 239.57 ± 9.98 s (p < 0.001), n = 8) the time spent in the dark compartment in the light−dark box arena. The numbers of hole pokings were significantly (p < 0.001, n = 8) enhanced in the hole board test and substantially increased the percent spontaneous alternation performance (SAP %) in the Y-maze mouse models in comparison to the stress control group. In the biomarker analysis, the significant reduction in the lipid peroxidation (MDA) level and enhanced catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) activities in the brain hippocampus reveal their antioxidant and memory enhancing potentials. However, further research is needed to find out the appropriate mechanism of reducing oxidative stress in pathological models.

Keywords: Alzheimer’s disease; Y-maze; antioxidants; biomarkers; hippocampus; hole board; in vivo study; light–dark box; mono-carbonyl curcumin analogues; oxidative stress.

Figure 1

Chemical structures of mono-carbonyl curcumin analogues (h1–h5).

Figure 2

Effect of mono-carbonyl curcumin analogues (h1–h5) in the light–dark test on (A) time spent (s) on day 1 in light compartment, (B) time spent (s) on day 1 in dark compartment, (C) day 2, time spent (s) in light compartment, and (D) day 2, time spent (s) in dark compartment. Results are shown as mean ± SD, n = 8. Kolmogorov–Smirnov test was applied for normality distribution and each data set was found to have a normal distribution. One-way ANOVA, followed by Bonferroni’s multiple comparison tests (post hoc), was applied and expressed as ^### p < 0.001 vs. normal control group, and *** p < 0.001, ** p < 0.01, * p < 0.05, “ns” p ˃ 0.05 vs. stress control group.

Figure 2

Effect of mono-carbonyl curcumin analogues (h1–h5) in the light–dark test on (A) time spent (s) on day 1 in light compartment, (B) time spent (s) on day 1 in dark compartment, (C) day 2, time spent (s) in light compartment, and (D) day 2, time spent (s) in dark compartment. Results are shown as mean ± SD, n = 8. Kolmogorov–Smirnov test was applied for normality distribution and each data set was found to have a normal distribution. One-way ANOVA, followed by Bonferroni’s multiple comparison tests (post hoc), was applied and expressed as ^### p < 0.001 vs. normal control group, and *** p < 0.001, ** p < 0.01, * p < 0.05, “ns” p ˃ 0.05 vs. stress control group.

Figure 3

Effect of mono-carbonyl curcumin analogues (h1–h5) on (A) no. of hole pokings on day 1 and (B) no. of hole pokings on day 2. Results are shown as mean ± SD, n = 8. Kolmogorov–Smirnov test was applied for normality distribution and each data set was found to have a normal distribution. One-way ANOVA, followed by Bonferroni’s multiple comparison tests (post hoc), was applied on each data set and expressed as ^### p < 0.001 vs. normal control group, and *** p < 0.001, ** p < 0.01, * p < 0.05, “ns” p ˃ 0.05 vs. stress control group.

Figure 4

Effects of mono-carbonyl curcumin analogues (h1–h5) on percent spontaneous alternation performance in Y-maze behavioral mouse model. Results are shown as mean ± SD, n = 8. Kolmogorov–Smirnov test was applied for normality distribution and each data set was found to have a normal distribution. One-way ANOVA, followed by Bonferroni’s multiple comparison tests (post hoc), was applied on each data set and expressed as ^### p < 0.001 vs. normal control group, and *** p < 0.001, “ns” p ˃ 0.05 vs. stress control group.

Figure 5

Effect of mono-carbonyl curcumin analogues (h1–h5) on the (A) malondialdehyde (MDA) level, (B) catalase (CAT) activity, (C) superoxide dismutase (SOD) activity, (D) glutathione (GSH) activity in the hippocampus while donepezil served as standard control. Results are shown as mean ± SD, n = 8. Kolmogorov–Smirnov test was applied for normality distribution and each data set was found to have a normal distribution. One-way ANOVA, followed by Bonferroni’s multiple comparison tests (post hoc), was applied on each data set and expressed as ^### p < 0.001 vs. normal control group, and *** p < 0.001, ** p < 0.01, * p < 0.05, “ns” p ˃ 0.05 vs. stress control group.