A State Of The Art Of Antioxidant Properties Of Curcuminoids in Neurodegenerative Diseases Part 2

To date, treatments for PD include drugs such as 1,3,4-dihydroxyphenylalanine (LDOPA) or anticholinergic, which help relieve symptoms but are not effective. In addition, many of these drugs have side effects that limit their use [72]. Therefore, effective and safe therapeutic interventions are necessary. 

Dihydroxyphenylalanine, also called DOPA, is a natural amino acid in the human body that can participate in neurotransmission as a neurotransmitter. As people pay more attention to health, people pay more attention to the role of dihydroxyphenylalanine in memory.

Studies have found that dihydroxyphenylalanine can strengthen the connections between neurons in the brain and promote the synthesis and release of neurotransmitters in the brain, thereby enhancing memory. In addition, dihydroxyphenylalanine can also increase the activity of tyrosine hydroxylase in the body, further promote the synthesis of neurotransmitters, and is more conducive to improving people's memory.

In addition to enhancing memory, dihydroxyphenylalanine has other health benefits. It can enhance the function of the immune system, resist the invasion of bacteria and diseases, and have a great protective effect on human health. At the same time, it also has the effect of regulating mood and suppressing mood swings, making people more peaceful and stable.

In summary, dihydroxyphenylalanine has many benefits for human health, including enhancing memory. If you want to improve your memory, you can increase your intake of foods containing dihydroxyphenylalanine, such as nuts, beans, meat, eggs, etc. At the same time, rationally arranging life and diet and increasing exercise will also help improve memory. Remember to eat a balanced diet and not overeat foods high in dihydroxyphenylalanine to allow your body to grow healthily and happily. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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In this context, interest is growing in the use of curcuminoids, which own antioxidant and anti-inflammatory properties, as alternative therapies.

4.1. Anti-Oxidant Effects of Curcuminoids In Vitro Models of PD

Several in vitro evidence has shown that curcumin has antiparkinsonian effects due to its antioxidant [73], anti-inflammatory [74], and anti-apoptotic properties [75], as well as its protective effects against mitochondrial damage [76]. 

Yu et al. evaluated the effects of curcumin through an in vitro experiment in primary mesencephalic astrocytes treated with 1-methyl-4-phenylpyridinium ion (MPP+ ) to induce a PD model. The cells were pre-treated with increasing curcumin concentrations (0–16 µM) for 48 h. 

Through the vitality assay, concentrations greater than 8 µM were found to induce a reduction in cell viability; therefore, 8 µM was chosen as the suitable concentration. Immunofluorescence analysis revealed that pre-treatment with curcumin did not cause significant morphological changes in the astrocytes but reduced their MPP+-induced activation. 

Furthermore, oxidative stress conditions were assessed through the measurement of ROS and GSH levels in astrocytes, which are determinants in Parkinsonian conditions. Curcumin substantially caused a reduction of ROS and an increase of GSH, compared to the primary astrocytes treated with MPP+. The anti-inflammatory property of curcumin was also evaluated in the present study, focusing in particular on Toll-like receptor 4 (TLR4), which appears to play a key role in PD neurophysiopathology. 

Pre-treatment with curcumin reduced the MPP+-induced toxicity by reducing the expression of MyD88 and TRIF, inhibiting the TLR4 pathway, a common MyD88-dependent signaling pathway. 

Curcumin significantly inhibited the NF-κB and IRF3 activation and reduced the TLR4 levels. In this way, the curcumin exerted its antiinflammatory effects through inhibition of TLR4 and its downstream signaling pathway. In conclusion, the findings of this experiment highlighted both the antioxidants and the anti-inflammatory properties exerted by curcumin, in MPP+-treated mesencephalic astrocytes [77]. 

U ˘guz A.C. et al. studied the molecular effects of curcumin on several intracellular signaling pathways in the cellular model of oxidative stress. Specifically, the researchers evaluated the effect of curcumin on Ca2+ signaling, measurement of ROS, mitochondrial depolarization levels, and caspase-3 and -9 activities in SH-SY5Y neuronal cells treated with H2O2. 

Curcumin protected the cells from H2O2-induced apoptosis. It reduced lipid peroxidation and intracellular Ca2+ concentrations compared to the H2O2-treated group of cells. Conversely, curcumin treatment increased GSH and GSH-Px levels. 

Furthermore, the increased H2O2-induced caspase-3 and caspase-9 expression were reduced by curcumin, thus protecting neuronal cells from oxidative damage [78]. Dehghani Z. et al. showed that curcumin (25 and 50 µM), in a dose-dependent manner, reduced the growth of α-syn fibrils in rat brain mitochondria. 

It has been observed that curcumin reduced the cytotoxicity of α-syn aggregates by reducing the release of mitochondrial Type 1 Hexokinase and ROS formation induced by α-syn fibrillation products [79]. Instead, Ramkumar et al. evaluated the demethoxycurcumin (DMC), a derivative of curcumin in an in vitro model of PD induced by rotenone (ROT), a phytoactive compound that causes toxicity in neuronal cells. 

Two hours before ROT (100 nM) treatment, SH-SY5Y neuroblastoma cells were pre-treated with DMC (5 nM, 10 nM, 20 nM, 50 nM, 100 nM, 200 nM, 500 nM, and 1 µM). The treatment showed that DMC doses higher than 50 nM were toxic to SH-SY5Y cells; thus, the dose of 50 nM of DMC was chosen for further investigation. 

The results showed that DMC increased cell viability and induced a decrease in both MMP and apoptotic processes. In this regard, immunoblotting analysis was performed to evaluate the expression of apoptotic proteins in the mitochondria and the cytosol, detecting that, DMC increased the Bcl-2, and Bcl-xL levels in the mitochondria. 

Moreover, the analysis found that pre-treatment with DMC restored the expression of increased proapoptotic proteins following exposure to ROT. DMC improved the ROT-induced oxidative stress through a significantly reduced ROS level in SH-SY5Y cells. 

In conclusion, these data highlighted that pre-treatment with DMC inhibited the apoptosis process reducing pro-apoptotic proteins, increasing anti-apoptotic proteins, and ameliorating oxidative stress [80]. The in vitro study conducted by Buratta et al. proves the therapeutic and antioxidant properties of curcumin. PC12 cells were treated simultaneously with ROT (0.1–1 µM) and curcumin (10 µM) for 24 h. 

PC12-treated curcumin increased cell viability and reduced oxidative stress induced by ROT treatment. Furthermore, the authors investigated the effect of curcumin on carbonylation and nitrosation of proteins and the activity of the proteasome. 

Immunoblot investigations showed that curcumin significantly reduced carbonylation and protein tyrosine nitration. PC12 treated with ROT reduced the activity of the proteasome, which is reflected in a concomitant increase in oxidized proteins. 

Conversely, treatment with curcumin in PC12 counteracted the inhibition of proteasomal activity ROT-induced, restoring the oxidized protein levels. The prevention of proteasome activity could be another beneficial effect used of curcumin for exerting its antioxidant properties [81].

4.2. Anti-Oxidant Effects of Curcuminoids in In Vivo Models of PD

In an in vivo study performed on adult male Sprague-Dawley rats injured unilaterally with 6-hydroxydopamine (6-OHDA) in the left striatum to induce the PD model, curcumin increased the levels of the dopamine transporter (DAT) and tyrosine hydroxylase (TH). 

Contrarily, it reduced the levels of the glial fibrillar acid protein (GFAP). In this way, curcumin could reduce the local tissue damage induced by 6-OHDA. Furthermore, curcumin-treated rats showed a significant increase in Wnt3a and β-catenin mRNA expression. Wnt/β-catenin signaling is involved in neuronal survival, differentiation, and axonal extension, promotes neurogenesis, synapse formation, and plasticity, and induces neuroprotection. Therefore, by activating the Wnt/β-catenin signaling pathway curcumin could improve the vitality and survival of neuronal cells. 

Furthermore, it was shown that activation of the Wnt/β-catenin pathway also increased the levels of endogenous antioxidant molecules such as GSH-Px, SOD, and reduced the concentration levels of malondialdehyde (MDA). 

Therefore, curcumin showed antioxidant effects against 6-OHDA injury in PD rats through activation of the Wnt/β-catenin signaling pathway [82]. Despite its beneficial effects, curcumin is a dietary polyphenol with poor bioavailability. 

In this regard, Hirata et al. evaluated the potential antioxidant effect of GIF-2165X-G1, a hybrid molecule containing an oxindole skeleton of GIF-0726-r and a polyphenol the skeleton of curcumin. The results of the in vitro study showed that GIF2165X-G1 (10 µM) increased cell viability, compared to alone oxindole derivative GIF-0726-r or curcumin. 

Conversely, GIF-2165X-G1 showed lower antioxidant effects compared to curcumin. However, GIF2165X-G1 has been seen to increase the transcriptional activity of ARE, consequently, the production of antioxidant enzymes such as heme oxygenase-1 (HO-1) is enhanced. 

To confirm the neuroprotective effects demonstrated in vitro study, further investigations were performed on rats injured unilaterally with 6-OHDA in the striatum. GIF-2165X-G1 (1.5 µg) was administered in PD mice. The results showed that these compounds, besides their antioxidant activity, increased TH and DAT levels. 

Therefore, compound GIF-2165XG1 shows promise in preserving the functionality of dopaminergic neurons and reducing ROS levels [83]. Instead, M. D. Pandareesh et al. evaluated the neuroprotective effects of curcumin mono glucoside (CMG), bioconjugated curcumin, against ROT-induced toxicity in N27 dopaminergic neuronal cells and Drosophila models. 

Pre-treatment of cells with CMG exerted antioxidant effects by increasing cell GSH levels and decreasing ROS. Furthermore, quantitative PCR analysis demonstrated that GMC reduces the upregulation of nitric oxide synthase 2 (NOS2) genes and induces upregulation of NAD(P)H: quinone oxidoreductase 1 (NQO1). 

Moreover, pretreatment with the synthetic conjugate of curcumin enhanced the activity of the mitochondrial complex I and IV inhibited by ROT. CMG also demonstrated anti-apoptotic effects mediated by a decrease in phosphorylation of JNK3 and c-jun, which induced a reduction of pro-caspase 3. 

Also in vivo, in the Drosophila ROT model, CMG enhanced intracellular antioxidant activity, decreased ROS levels, and prevented dopamine depletion [84]. In line with these results, the antioxidant effects of curcumin have also been demonstrated by Dharmendra K. Khatri et al. 

In this study, in mice treated with ROT after 21 days of treatment, curcumin reduced MDA and nitrite levels. All three doses of curcumin (50, 100, and 200 mg/kg) used also resulted in a significant reduction in acetylcholinesterase (AChE) activity compared with ROT-treated mice. 

Conversely, after 21 days, treatment with curcumin at all doses increased the activity of antioxidant enzymes such as SOD and GSH. Furthermore, it reduced oxidative stress also by restoring the activity of the mitochondrial enzyme complex compromised by the ROT. 

In this way, curcumin improved cognitive function, thus demonstrating its neuroprotective role against PD [85]. Cui Q. et al. demonstrated that pre-treatment with curcumin improved rotational behavior in ROT-treated rats. 

As shown by Western blot analysis, pretreatment with curcumin decreased ROT-induced loss of TH protein and reduced ROS and MDA production in the substantia nigra pars compact. 

Conversely, pre-treatment with curcumin-induced an increase in GSH levels reduced by ROT. Curcumin was shown to exert its antioxidant effects by activating the Akt/Nrf2 signaling pathway in dopaminergic neurons. Indeed, curcumin induced an increase in the expression of the HO-1 and NQO1 proteins and promoted Akt/Nrf2 phosphorylation. 

To confirm this result, rats were infused with a shNrf2 lentivirus or phosphoinositide 3-kinase inhibitor LY294002 before treatment with ROT or curcumin. Treatment with shNrf2 or LY294002 inhibited the effects of curcumin, demonstrating that the protective role of curcumin was associated with the Akt/Nrf2 signaling pathway [86]. 

Nguyen et al. conducted an in vivo experiment using Drosophila, which presents ubiquitin carboxyl-terminal hydrolase (dUCH), which is homologous to the human enzyme UCH-L1 and is useful for reproducing PD. 

Therefore, targeted studies were carried out on dUCH knockdown flies, in which the oxidative stress condition was highlighted. The authors evaluated the antioxidant properties of curcumin (1 mM). 

The study was performed both in the larval stage and adult stage; the flies revealed a decrease in ROS in the adult brain and also in the imaginal discs of the eyes. Of considerable interest is that the results found that curcumin improved the motor deficits caused by the knockdown of dUCH. 

Curcumin is relevant in preserving the structure and functionality of dopaminergic neurons by increasing dopamine levels. Notably, a 13% decrease in dopamine was found in curcumin-treated dUCH knockdown flies compared to the control. Instead, 52% of dopamine loss was found in untreated curcumin dUCH knockdown flies compared to the control. 

Therefore, curcumin confirms its beneficial effects on dopaminergic neurons [87]. The results of these in vivo and in vitro studies have demonstrated that curcuminoids can exert neuroprotective effects both in PD models induced by several environmental factors (such as 6-OHDA, MPTP, and ROT), and in PD models induced by genetic factors including α-syn and UCH-L1 (Table 1). 

Preclinical studies demonstrated that pre-treatment with curcuminoids attenuates the level of oxidative stress and mitochondrial dysfunction. Additionally, curcuminoids prevent α-syn aggregation and fibrillation, consequently, improving the impaired cognitive and motor function symptoms. 

To date, there are no available clinical studies that support the pre-clinical data. Therefore, clinical studies would be necessary to evaluate the efficacy of curcuminoids in patients with PD.

5. Alzheimer's Disease

AD is a neurodegenerative disease that occurs with aging and the cause can be determined by several concomitant risk factors [88]. Most AD cases occur sporadically. Alone in 10% of cases, AD is caused by genetic mutations in genes such as amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) [89]. 

AD is characterized by the deposition of extracellular deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) in brain tissue. Under physiological conditions, APP follows the non-amyloidogenic pathway and is cleaved by α- and γ-secretases [90]. 

Conversely, in pathological conditions, APP follows the amyloidogenic pathway, which involves the cleavage by two enzymes, β- and γ-secretase, involved in the formation of Aβ. Specifically, Aβ1–40 is the most abundant peptide in the brain. 

In patients with AD, Aβ1–42 represents the most abundant and most toxic form due to its predisposition to aggregate and form oligomers [91]. Instead, NFTs are composed of hyperphosphorylated Tau protein, which destabilizes the microtubules inducing tangles formation. The deposition of amyloid plaques and NFTs are the events responsible for the loss of neurons and synapses with consequent impairment of neurotransmission [92,93]. 

Several studies demonstrate the relationship between oxidative stress and AD development. Indeed, an oxidative imbalance, especially at the mitochondrial level, can cause an increase in ROS, which in turn implies neuronal damage [88,94]. 

Moreover, it was shown the activation of the N-methylD-aspartate receptor (NMDAR) is involved in oxidative stress, and in particular, in the development and progression of AD. NMDA activation induces an increase in intracellular Ca2+, which leads to mitochondrial dysfunctions with a consequent increase in oxidative stress [95]. 

For these reasons, antioxidant therapy in AD patients could be useful. In this context, several studies have been performed on natural compounds such as curcumin, whose antioxidant properties are widely known [96]. 

Curcumin appears able to inhibit Aβ formation, and attenuates the hyperphosphorylation of tau, thus reducing the progression of neuronal damage [97].

5.1. Antioxidant Effects of Curcumin in In Vitro AD Model

The efficacy of curcumin was evaluated by Qian et al., in an in vitro experiment on PC12 cells treated with Aβ25–35 to reproduce the AD model. The PC12 cells Aβ25–35 treated with different doses of curcumin (5, 10, 20, 30 µM/L) showed an increase in cell viability in a dose-dependent manner. 

Furthermore, the 24 h of pre-treatment with curcumin in a dose-dependent manner has allowed a considerable reduction of apoptosis, through a reduction of caspase 3 expression and an increase of Akt phosphorylation. 

To evaluate the antioxidant effects of curcumin, lactate dehydrogenase (LDH) and MDA levels were measured. The curcumin treatment, in a dose-dependent manner, has reduced LDH and MDA levels. 

Finally, the authors also evaluated that increasing doses of curcumin promoted the expression of NR2A, a subunit of NMDAR, which is important for the functionality of neuronal cells. The authors in this study highlighted the potential neuroprotective and antioxidant role of curcumin in AD [98].

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