A State Of The Art Of Antioxidant Properties Of Curcuminoids in Neurodegenerative Diseases Part 1

Abstract: 

Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. 

Neurodegenerative diseases are a common type of elderly diseases, such as Alzheimer's disease, Alzheimer's disease, etc. As the aging of the population intensifies, the impact of these diseases on our lives and society is becoming more and more serious.

Neurodegenerative diseases are closely linked to memory. These diseases often cause organic brain changes,y affecting normal brain functions, including memory performance. Patients may feel forgotten or have amnesia in the early stages. Still, if they are constantly reminded and cared for, they may be able to maintain their ability to take care of themselves and maintain high social functions.

What should we do in the face of such a disease? First of all, we should take active preventive measures, such as exercising more, avoiding excessive fatigue, and adhering to a healthy diet. These measures can effectively slow down the development of the disease. At the same time, we also need to continue to learn and understand the knowledge of this disease and improve the medical skills and professionalism of elderly care service personnel to provide better services to patients.

In addition, we also need to start with appropriate exercise, social interaction, oxygen therapy, etc. to improve patients' quality of life and self-esteem and inspire their love and confidence in life. These positive factors can play a positive role in reducing patients' psychological pressure and anxiety, making them more optimistic about life.

In short, although neurodegenerative diseases can affect memory, we must face this situation proactively, take measures to slow down the progression of the disease, improve the quality of life, and take practical actions to bring warmth and help to patients and their families. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

Click Know Short-term Memory how to improve

Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). 

To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. 

In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potential in several neurodegenerative diseases. Curcuminoids are nutraceutical compounds, that have several therapeutic properties such as antioxidant, anti-inflammatory, and neuroprotective effects. 

In this context, this review aimed to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.

Keywords: neurodegenerative diseases; curcuminoids; anti-oxidant properties.

1. Introduction

Neurological diseases affect millions of people around the world [1]. The environmental alterations in the central nervous system (CNS) induce the activation of microglia and astrocytes, cells involved in maintaining homeostasis of the CNS. 

Following damage, these cells activate a response that induces the release of pro-inflammatory cytokines responsible for a local inflammatory reaction [2]. Furthermore, once active, microglia and astrocytes can produce reactive oxygen species (ROS). 

However, the brain, despite accounting for only 2% of total body weight, consumes about 20% of the body's oxygen (O2); thus, it is rich in the antioxidants involved in preventing the formation of ROS. Excessive ROS production, if not effectively counteracted by cellular constituents, causes pathological conditions such as neurodegenerative diseases [3–5]. 

This is particularly relevant in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Indeed neuroinflammation and oxidative stress are common features of neurodegenerative diseases [6,7]. 

Although therapies that delay or control symptoms are available for these disorders, there are currently no effective treatments available. Therefore, there is a growing interest in natural compounds that possess antioxidant and anti-inflammatory properties [8,9]. Curcuma is a spice extracted from the rhizomes of Curcuma Longa, belonging to the Zingiberaceae family, cultivated in India and Southeast Asia [10]. 

The main constituent of Curcuma is curcumin, a yellow pigment commonly used as a spice and food coloring. It is used as a natural medicine for the treatment of inflammatory diseases [11]. Indeed, curcumin is a nutriceutical compound that possesses numerous therapeutic properties against various diseases, including neurodegenerative diseases [12]. 

Among the several properties of curcuminoids [13–15], the anti-inflammatory [16,17] and antioxidant activities [18,19] are the most investigated due to their role in the pathogenesis of neurodegenerative diseases [20]. 

Indeed, curcuminoids play a key role in the inhibition of enzymes such as p38 Mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (c-JNK) and transcription factors (such as nuclear factor-κB, NF-κB) related to inflammatory processes. 

Also, they decrease the expression of several pro-inflammatory cytokines [21,22]. Moreover, many of curcumin's beneficial effects can be associated with its antioxidant properties [23]. 

Since oxidative stress, caused by excessive production of reactive oxygen species, lipid peroxidation, and oxidative damage to DNA and proteins, is responsible for many pathological complications such as neurodegenerative diseases, curcumin could play an important role in these conditions. Curcumin has been extensively investigated due to its beneficial properties against several neurological diseases such as PD [24], AD [25], and ALS [26]. 

The purpose of this review is to describe the antioxidant properties of curcuminoids associated with their efficacy in neurological disease. In the present review, preclinical and clinical evidence highlighting the curcuminoids' antioxidant effects in neurological disorders are summarized.

2. Curcumin

Curcuminoids are the active compounds found in turmeric and include curcumin (diferuloylmethane), demethoxycurcumin, and bisdemethoxycurcumin (Figure 1). Several in vitro and in vivo evidence describe the anti-inflammatory [27] and antioxidant properties [28] of curcuminoids. 

Among the curcuminoids, curcumin makes up about 90% of the curcuminoids present in turmeric. Curcumin is a polyphenol, with the molecular formula C21H20O6, characterized for the first time in 1910 [29].

Among them, curcumin is known to have neuroprotective effects, and its antioxidant and anti-inflammatory power is widely studied. The diketone group and two phenolic rings in its chemical structure act as electron traps, thus preventing the production of hydrogen peroxide (H2O2), hydroxyl radical (OH·), and superoxide anion (O2−·). 

Moreover, the b-diketone fraction and hydroxyl groups of curcumin are capable of complexing metals, such as copper (Cu2+) zinc (Zn2+), and and ferrous iron (Fe2+) [30]. Fe2+ is necessary for the Fenton reaction that generates OH· radicals; thus, curcumin by chelating the Fe2+ protects against metal-induced toxicity. 

Indeed, it is well known that curcumin contains antioxidant properties and it appears ten times more powerful than vitamin E as a free radical scavenger [31]. Due to the ability of curcumin to cross the blood-brain barrier [32], it also decreases the ROS level [33], protects the brain from lipid peroxidation, and reduces neuron death induced by oxidative insults [34]. 

Furthermore, curcumin, in addition to acting as direct scavenging of ROS, exerts its antioxidant properties by increasing glutathione (GSH) levels [35], improving the activity of glutathione peroxidase (GSHPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) [36]. Furthermore, curcumin reduces mitochondrial damage and apoptosis mediated by lipid peroxidation [37]. 

Curcumin can inhibit the activation of several transcription factors including NF-κB [38], activated protein-1 (AP-1) [39], Notch-1 [40], β -catenin [41], and peroxisome proliferator-activated receptor-gamma (PPAR-γ) [42], all involved in different biological processes, including inflammation. 

NF-κB is localized in the cytosol-after activation, it is translocated to the nucleus, where it promotes the expression of different genes involved in cell proliferation and inflammation [43]. The dysregulated activity of NF-κB underlies several inflammatory diseases, such as neurodegenerative diseases [44]. Curcumin inhibits NF-κB activation by suppressing the translocation of p65 and the inhibitor κB (IκB) into the nucleus [45]. 

In this way, it inhibits the activation of numerous genes involved in cell survival, including Bcl-2, Bcl-xL, cyclin D1, cyclooxygenase 2 (COX-2), and matrix metallopeptidase (MMP)-9, thus promoting the arrest cell cycle, inhibiting proliferation and inducing apoptosis [46]. 

Many of curcumin's effects are also mediated by its ability to inhibit several protein kinases (PKs) involved in various cellular processes, such as autophosphorylation activated(AK) protein kinase [47], Ca2+-dependent protein kinase (CDPK) [48], Janus kinase (JAK) [49], mitogen-activated protein kinase (MAPK) [50,51], the mammalian target of rapamycin (mTOR) [52,53], phosphorylase kinase (PhK) [47], cytosolic protein kinase (cPPK [47], PKA [47], PKB/Akt [54], PKC [47]. 

Furthermore, the inhibitory action on the MAPK pathway and the inhibition of the phosphorylation of the extracellular receptor kinase (ERK), c-JNKs, and p38 MAPKs are responsible for the powerful anti-inflammatory effects of curcumin [55]. 

Indeed, the inhibition of the NF-κB and MAPK pathways reduces the expression of numerous inflammatory interleukins (ILs) such as IL-1β, IL-6, Tumor necrosis factor-alpha (TNF-α) [56], IL-2 [57], IL-5 [58], IL-8 [59], IL-12 [60], IL-18 [61] and signal transducer and activator of transcription (STAT) proteins [49]. Therefore, curcumin by regulating transcription factors, such as NF-κB, inhibits the production of pro-inflammatory cytokines, thus exhibiting a powerful anti-inflammatory action [62]. 

These characteristic properties of curcumin make it a valid neuroprotective compound. Indeed, epidemiological studies show that in the Indian population, the consumption of turmeric is closely correlated with the low incidence of neurodegenerative diseases such as AD and PD, compared to the Caucasian population [63,64].

3. Methodology

This manuscript aims to provide an overview of experimental and clinical studies that report the antioxidant effects of curcuminoids in neurodegenerative diseases, such as PD, AD, and ALS. 

To write this review, a search was carried out in PubMed using the following keywords: "Curcuminoids", "antioxidant effects", "Parkinson's Disease", "Alzheimer's Disease", "and Amyotrophic Lateral Sclerosis". 

We considered articles published between 2015 and 2021 demonstrating the neuroprotective role of curcuminoids. In this search, 65 articles were found, as shown in the Prisma flow diagram (Figure 2). In the "Records screened" section, 20 articles were excluded; among them, 12 were not considered because they were different from the focus of our review. 

Two other articles were excluded because they focused on the antioxidant role of other compounds. Moreover, since we focused on curcuminoids, we also excluded six articles that evaluated the effects of curcumin combined with other compounds. 

As this review is intended to provide an overview of experimental studies, in the "Full-text articles assessed for eligibility" section, 13 articles were excluded because they are reviews. 

Finally, this manuscript considered 27 studies that evaluate the biochemical and molecular mechanisms underlying the antioxidant effects of curcuminoids and their therapeutic application in neurological diseases.

In support of the findings of pre-clinical studies, we also provide a summary of current clinical trials recorded on ClinicalTrial.gov (https://clinicaltrials.gov/ accessed on 12 February 2021), using the following keywords: "Curcumin", "Parkinson's Disease" or "Alzheimer's In Disease" In or In "Amyotrophic Lateral Sclerosis".

4. Parkinson's Disease

y role in contributing to or exacerbating nigrostriatal degeneration [68]. The distinctive clinical features of PD are tremors, bradykinesia, rigidity, and balance disturbances. Additionally, in patients with PD also occurs non-motor deficits such as anxiety, dementia, depression, sleep disturbances, and psychosis that negatively condition the quality of life [69]. 

Moreover, the hallmark of PD is the formation of Lewy bodies, which are cytoplasmic inclusions of alpha-synuclein (α-syn) [70]. However, oxidative stress and inflammation play a key role in PD. In 90% of cases, PD occurs in a sporadic form; only 10% of cases present as a familial form. 

Familial forms of PD involve α-synuclein gene mutations (SNCA), ubiquitin C-terminal hydrolase L1 (UCHL-1), phosphatase and tensin homolog induced putative kinase 1 (PINK1), Parkin (PRKN), protein delicate (DJ-1), and leucine-rich repeat kinase 2 (LRRK2) [71]. Figure 2. 

Prisma flow diagram illustrating the selection methodology of the preclinical studies used for the writing of the review. Duplicate articles were excluded from the total of the studies recorded. 

Instead, they were considered articles that evaluate the antioxidant effects of curcuminoid in neurological disease. The PRISMA Statement was published in [65]. To support the findings of pre-clinical studies, we also provide a summary of current clinical trials recorded on ClinicalTrial.gov (https://clinicaltrials.gov/ accessed on 12 February 2021), using the following keywords: "Curcumin", "Parkinson's Disease" or "Alzheimer's Disease" or "Amyotrophic Lateral Sclerosis". 4. 

Parkinson's Disease PD is a progressive and neurodegenerative disease induced by the progressive loss of neurons in the substantia nigra, followed by a decrease in dopamine levels in the striatum [66]. 

These events lead to a dysfunction of the nigrostriatal pathway which consequent movement disorders [67]. The oxidative stress and inflammation response play a key role in contributing to or exacerbating nigrostriatal degeneration [68]. The distinctive clinical features of PD are tremors, bradykinesia, rigidity, and balance disturbances. 

Additionally, in patients with PD also occurs non-motor deficits such as anxiety, dementia, depression, sleep disturbances, and psychosis that negatively condition the quality of life [69]. Moreover, the hallmark of PD is the formation of Lewy bodies, which are cytoplasmic inclusions of alpha-synuclein (α-syn) [70]. However, oxidative stress and inflammation play a key role in PD. 

In 90% of cases, PD occurs in a sporadic form; only 10% of cases present as a familial form. Familial forms of PD involve α-synuclein gene mutations (SNCA), ubiquitin C-terminal hydrolase L1 (UCHL-1), phosphatase and tensin homolog-induced putative kinase 1 (PINK1), Parkin (PRKN), protein delicate (DJ-1), and leucine-rich repeat kinase 2 (LRRK2) [71].

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