A State Of The Art Of Antioxidant Properties Of Curcuminoids in Neurodegenerative Diseases Part 3

In compliance with these results, Jaroonwitchawan et al. evaluated the ability of curcumin to reduce Aβ production and oxidative stress in SH-SY5Y cells exposed to paraquat. 

Curcumin is a natural compound thought to have a variety of benefits for brain and body health. And its relationship with memory has also attracted much attention.

Studies have found that curcumin can protect neurons from damage by reducing inflammation and oxidative stress. This compound stimulates the production of growth factors that promote neuron growth and connections, thereby improving memory. In addition, curcumin can also promote the metabolism of nerve cells, enhance the brain's energy metabolism and blood circulation, and improve memory and learning abilities.

Not only that but curcumin is also thought to be very beneficial in preventing the onset of Alzheimer's disease. Alzheimer's disease is a degenerative brain disease with complex causes that is often accompanied by a decline in memory and cognitive abilities. Curcumin may reduce the risk of Alzheimer's disease by inhibiting amyloid aggregation and reducing iron levels in the brain.

It is worth noting that curcumin does not immediately improve people's brain function. It requires long-term accumulation to achieve its best effect. Therefore, we should always insist on consuming curcumin-rich foods such as ginger, turmeric powder, etc. in moderation. At the same time, don't forget to maintain good living habits, such as eating properly, exercising moderately, maintaining good sleep, etc., to promote the positive effects of curcumin on our health.

To sum up, curcumin is closely related to memory. Moderate consumption of curcumin is beneficial for improving brain function and protecting health. It is of great significance for us to maintain a positive attitude toward life and improve our quality of life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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SH-SY5Y cells were treated with paraquat (0.5 mM) for 24 h, evaluating the effects on the expression of genes involved in AD progression. In detail, the paraquat treatment showed an increase in the mRNA transcription of APP and PSEN1 genes. Following 2 h of pre-treatment with curcumin (5 and 10 µM), it was observed a significant reduction of APP expression and APP proteins. 

Additionally, a significant reduction in the Bax/Bcl-2 ratio induced by curcumin would evidence the antiapoptotic effects of this compound. Furthermore, the pre-treatment with curcumin highlighted the antioxidant potential through an increase in SOD and GSH-Px levels. Noteworthy, curcumin enhanced autophagy activity by upregulating LC3I/II. 

As it is known that the impairment of the autophagic process could play a key role in the processing of APP, the improvement of this process could be a mechanism of action used by curcumin to protect against neurodegeneration [99]. 

Also, the neuroprotective effects of curcumin were evaluated by Shi et al. in a study conducted on mouse hippocampal HT-22 neuronal cells treated with acrolein to reproduce the AD model. 

The pre-treatment with curcumin (5 µg/mL) for 30 min showed an increase in cell viability and a decrease in the apoptotic process, reducing the neurotoxic effects of acrolein. Furthermore, pre-treatment with curcumin-induced an increase in SOD, and GSH levels and showed a reduction in MDA levels in acrolein-treated HT-22 cells. On the other hand, curcumin can counteract BDNF/TrkB signaling inhibition induced by acrolein toxicity. 

The results confirmed curcumin as a neuroprotective agent against AD. In particular, an increase in α-secretase (ADAM-10) was observed, which facilitates the breakdown of APP. 

Simultaneously, beta-amyloid converting enzyme 1 (BACE1) increased by acrolein exposure was restored [100]. Morales et al. carried out a study to evaluate the antioxidant properties of curcumin in N2a neuroblastoma cells after exposure to cytotoxic compounds. 

N2a cells were treated separately with ferric nitrilotriacetate and H2O2, and subsequently treated with curcumin (5–15 µM). Curcumin treatment showed an increase in cell viability, thus confirming the cytoprotective effect in neuronal cells. In addition, the researchers incubated human tau (htau40) in N2a cells to reproduce the AD model. 

N2a cells were incubated for 8 days with monomeric htau40 and heparin to form Tau aggregates. The experimental results were visualized using thioflavin-S fluorescence analysis, directly proportional to the aggregated Tau concentration. 

Simultaneous treatment of curcumin and heparin after one day of incubation showed a reduction in fluorescence, thus a reduction in Tau aggregates. However, the administration of curcumin three days after heparin treatment alone showed a drastic reduction in fluorescence, demonstrating an incisive action against already-formed Tau aggregates [101]. 

In consideration of these findings, Buccarello et al. evaluated the antioxidant properties of curcumin in H2O2-treated SH-SY5Y cells. The cells were pre-treatment with curcumin (1, 2.5, 5, 10, and 15 µM) for 24, followed by treatment with 0.5 mM of H2O2 for 30 min. The LDH dosage and cell viability showed that curcumin protected cells against oxidative stress induced by H2O2. 

Pre-treatment with curcumin induced a decrease in caspase-3 level (at the high doses) and LC3B II/I ratio (at each dose tested). Conversely, cells treated with 10 µM of curcumin showed increased ubiquitin levels. Moreover, it was observed that curcumin caused a significant decrease in SUMO-1ylation and the phosphorylation of c-JNK and ERK. 

Additionally, among the doses of curcumin, only 5 µM induced a significant decrease in Tau phosphorylation compared to the control, demonstrating the role of curcumin in the prevention of Tau phosphorylation. 

Interestingly, immunofluorescence analysis showed that pre-treatment with curcumin (5 µM) reduced the co-localization of SUMO-1-p-JNK-Tau proteins in nuclear bodies induced by H2O2 treatment [102]. 

The efficacy of curcumin treatment against oxidative stress was evaluated in macrophages of patients with AD. Jairani et al. experimented with human monocytic THP-1 cells derived from acute monocytic leukemia, subsequently differentiated into macrophages. Macrophages were treated with H2O2 (500 µM) to reproduce the AD model. 

The findings showed less efficient phagocytosis in H2O2-treated macrophages. Subsequently, macrophages were incubated overnight with HiLyte Flour 488-labeled Aβ1–42 (1 µg/mL) to evaluate Aβ1–42 internalization. 

Additionally, the lysosomal marker was used to evaluate Aβ1–42 internalization into lysosomes. Therefore, the authors treated the macrophages with curcumin (10 µM). 

Curcumin improved Aβ1–42 internalization in macrophages and lysosomal localization. The investigation also evaluated the presence of Apolipoprotein E (APOE) polymorphisms in AD patients. APOEε3 patient macrophages treated with curcumin internalize more Aβ1–42 than APOEε4 patients. Therefore, curcumin ameliorated phagocytic activity in macrophages by preventing neurodegeneration [103]. 

A recent study illustrated the protective effect of curcumin in the SH-SY5Y cells transfected with the APPswe gene, a Swedish mutation, which causes an accumulation of Aβ peptides. 

The cells were treated with curcumin (0.625–5 µM) for 4 h and subsequently exposed to H2O2 (250 µM) for 24 h to induce oxidative stress. Curcumin treatment enhanced cell proliferation and reduced LDH release, showing that it decreased H2O2-induced cell damage. 

Curcumin reduces the structural changes of neuronal cells, causing less condensation of chromatin with a consequent reduction in the apoptotic process. To evaluate the damage induced by oxidative stress to mitochondrial function, it was observed that curcumin was able to decrease the damaging activity of the electron transport chain and reduce the H2O2–induced mitochondrial membrane depolarization. 

Oxidative stress has been shown to influence the expression of the APP and BACE1 genes which, conversely, was restored by curcumin. Moreover, curcumin prevented the APP βcleavage, and intracellular Aβ generation was stimulated from H2O2. 

Therefore, the antioxidant effects of curcumin, also able to reduce intracellular Aβ, strengthen the hypothesis that it can be used to treat AD [104]. In compliance with the previous study, Yan et al. also showed that curcumin (6.25–25 µM) reduced H2O2-induced oxidative stress in neuronal PC12 cells. However, curcumin, in addition to reducing ROS levels, is also capable of chelating several metal ions. 

Indeed, it has been shown that curcumin complexes with metallic ions work in a similar way to SOD. In this context, the authors investigated the protective effects of curcumin-Cu2+ or -Zn2+ complexes against injury in PC12 cells induced by H2O2. 

It was found that the curcumin-Cu2+ complex increased cell viability compared to the curcumin or curcuminZn2+ complex. Furthermore, the curcumin-Cu2+ complex showed a rapid increase in the levels of antioxidant enzymes such as SOD, CAT, and GSH-Px and it decreased the level of MDA, caspase-3, and caspase-9. 

On the other hand, curcumin and curcumin-Cu2+ or -Zn2+ complexes increased the Bcl-2/Bax ratio, and reduced the level of NF-κB p65, demonstrating that curcumin suppresses apoptosis. 

Therefore, these results highlight the potential therapeutic value of curcumin complexed with metal ions in AD [105]. However, curcumin is known to have low bioavailability, which makes it difficult to clearly understand its pharmacological effects. Djiokeng Paka et al., to increase the bioavailability of this compound, carried out an in vitro experiment through the encapsulation of curcumin inside poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) with a ratio of 50% lactic acid (LA) and 50% glycolic acid (GA) (NPs-Curcumin 50:50) or with a ratio of 65% LA and 35% GA (NPs-Curcumin 65:35). 

SKN-SH cells were treated with free curcumin (0.5 µM), NPs-Curcumin 50:50 and NPs-Curcumin 65:35 for 1 h. The findings showed good absorption of NPs-Curcumin 50:50 in neuronal cells. To evaluate the antioxidant effects of curcumin, the cells were exposed to H2O2. NPs-Curcumin 50:50 significantly reduced ROS levels. 

Therefore, the authors focused their attention on the Nrf2/Keap1 pathway showing that the treatment with free curcumin (0.5 µM) and NPs-Curcumin 50:50 in SK-N-SH H2O2-treated cells reduced the activation of Keap1 and consequently of Nrf2 activation.

Oxidative stress plays a key role also in Akt and Tau phosphorylation. In this case, NPsCurcumin 50:50 are effective in reducing their phosphorylation. 

It also evaluated the change expression of genes that play an important role in antioxidant and neuroprotective processes. In particular, NPs-Curcumin increased transcripts of glutaredoxine (GLRX), thioredoxine (TRX), and a decrease in apolipoprotein J (APOJ). Both NPs-Curcumin 50:50 and NPs-Curcumin 65:35 appear more effective than free curcumin in modulating these genes. 

In conclusion, the use of curcumin encapsulated in PLGA nanoparticles could be a valid therapeutic strategy to overcome the problems of the clinical application of curcumin related to its poor bioavailability [106]. 

The poor stability and low bioavailability of curcumin are due to a β-diketone moiety that induces rapid degradation. In this context, two mono-carbonyl analogs of curcumin, (1E, 4E)-1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (CB) and (1E, 4E)-1- (3,4-methoxyphenyl)-5-(4-hydroxy-3, 5-methoxyphenyl) Penta-1, 4-dien-3-one (FE) were synthesized. 

PC12 cells were treated with Aβ25–35 (10 µM) before, concurrently, or after treatment with curcumin, CB, and FE at different concentrations (0.1–20 µM).

Treatment with CB and FE showed improvements in cell viability and counteracted the increase in ROS following Aβ25–35 induced toxicity. 

Additionally, CB and FE are effective in restoring levels of antioxidant enzymes such as CAT and SOD. Significant reductions in MDA and LDH dosages were also found following treatment with curcumin and analogs. 

CB and FE also increased the Bcl2/BAX ratio and a reduction in cytochrome c release as a result of inhibition of apoptosis. However, proteins of the Keap1/Nrf2/HO-1 signaling pathway were evaluated in PC12 cells, a key pathway to protect the cells from oxidative stress and apoptosis. Curcumin, CB, and FE reduced Keap1 expression and simultaneously increased Nrf2 and HO-1 expression. 

This study highlighted that the mono-carbonyl analogs of curcumin showed great efficacy at lower doses compared to curcumin. This demonstrated that the CB and FE used a similar mechanism of curcumin, and they showed major stability. 

Thus, the modification of mono-ketone moiety could improve the stability and bioavailability of curcumin. In conclusion, the results of this study demonstrated that mono-carbonyl analogs of curcumin might be implicated in the treatment of AD [107]. Instead, Pinkaew et al. evaluated the neuroprotective effects di-O-demethylcurcumin, a modified analog of curcumin. In this study, SK-N-SH cells were pre-treated with diO-demethylcurcumin (1–8 µM) for 2 h and then incubated with Aβ25–35 (10 µM) overnight. 

The di-O-demethylcurcumin pre-treatment showed a reduction in cell toxicity and in ROS and NO levels compared to the Aβ25–35 group. The pretreatment with di-odemethylcurcumin downregulated iNOS expression, thereby reducing NO production. Further, di-O-demethylcurcumin exposure increased Nrf2 protein expression in the nucleus with a consequent increase of pathway-related proteins such as HO-1, NQO1, and SOD. 

Additionally, di-O-demethylcurcumin showed anti-inflammatory properties avoiding the translocation of NF-kB p65 into the nucleus. Therefore, di-O-demethylcurcumin could be a valid candidate against Aβ25–35-induced neurotoxicity [108]. 

The curcumin derivatives behavior was also explored by Orteca et al. in hippocampal HT-22 mouse cells. To improve bioavailability and curcumin stability, the researchers modified the molecule of curcumin through the removal of the keto-enol fraction, the addition of a pyrazole ring, or the insertion of the phthalimide-functionalized chain. 

To induce neurotoxicity, HT-22 cells were treated with glutamate (2 µM) and subsequently were co-treated with curcumin and curcumin derivatives (1 µM) for 24 h. The curcumin derivatives compared to curcumin showed a greater reduction in the cytotoxic effects and the apoptotic process induced by the treatment with glutamate. 

Additionally, curcumin derivatives downregulated iNOS and decreased the ratio of Bax/Bcl2 transcripts, thus confirming their cytoprotective and antiapoptotic actions against oxidative stress. 

Further, fluorescence analysis was done to study the interaction between curcumin derivatives and amyloid fibrils. In this regard, HT-22 cells were treated with Aβ1–40 (10 µM) to induce the AD model. The treatment with curcumin derivative (10 µM) for 24 h, displayed that these compounds own higher binding affinity and depolymerization of fibrillar aggregates compared to curcumin. 

Therefore the curcumin-derived compounds exhibited a high bioavailability compared to curcumin, and they reveal satisfactory ability to counteract oxidative stress and depolymerize fibrillar aggregates [109].

5.2. Antioxidant Effects in In Vivo AD Model

The effects of curcumin on behaviors and biochemical markers related to AD-like symptoms were investigated in vivo experimental model AD. 

The AD model was induced by bilateral hippocampal injection of streptozotocin (3.0 mg/kg), associated with subcutaneous administration of D-galactose (125 mg/kg) for 7 weeks, which served to promote neurodegeneration and increase oxidative stress. 

Rats were treated with curcumin (10 mg/kg) via intraperitoneal injection for 7 weeks. After treatment, an increase in GSHPx enzymatic activity was observed in the blood samples of the curcumin-treatment group compared to the AD groups. 

Curcumin reduced oxidative stress damage induced by the combination of streptozotocin and D-galactose. The histochemical investigations allowed it to visualize the effects of curcumin-mediated treatment in the cortex and hippocampus regions CA1 and CA3. 

The curcumin-mediated treatment avoided a substantial loss of neurons in the hippocampal tissue. Moreover, curcumin reduced the APP β-cleavage and formation of amyloid-like and reduced the Aβ1–42 in the hippocampal compared to the AD group. Also, in the curcumin group, it was observed the reduction of PSEN1 and BACE1 expression. 

Therefore, curcumin prevented neurodegeneration and preserved the integrity of hippocampal tissue [110].

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