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A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases

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A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases International Journal of Molecular Sciences Review A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases Serena Silvestro † , Cinzia Sindona †, Placido Bramanti and Emanuela Mazzon * IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; [email protected] (S.S.); [email protected] (C.S.); [email protected] (P.B.) * Correspondence: [email protected]; Tel.: +39-090-60128172 † These authors contributed equally as first author. 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. 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 potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical Citation: Silvestro, S.; Sindona, C.; evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Bramanti, P.; Mazzon, E. A State of Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration the Art of Antioxidant Properties of prevention and treatment. Curcuminoids in Neurodegenerative Diseases. Int. J. Mol. Sci. 2021, 22, Keywords: neurodegenerative diseases; curcuminoids; anti-oxidant properties 3168. https://doi.org/10.3390/ ijms22063168 Academic Editors: Cecilia Prata, 1. Introduction Tullia Maraldi and Cristina Angeloni Neurological diseases affect millions of people around the world [1]. The environmen- tal alterations in the central nervous system (CNS) induce the activation of microglia and Received: 12 February 2021 astrocytes, cells involved in maintaining homeostasis of the CNS. Following damage, these Accepted: 18 March 2021 Published: 20 March 2021 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 Publisher’s Note: MDPI stays neutral can produce reactive oxygen species (ROS). However, the brain, despite accounting for with regard to jurisdictional claims in only 2% of total body weight, consumes about 20% of the body’s oxygen (O2); thus, it published maps and institutional affil- is rich in the antioxidants involved in preventing the formation of ROS. Excessive ROS iations. production, if not effectively counteracted by cellular constituents, causes pathological conditions such as neurodegenerative diseases [3–5]. This is particularly relevant in neu- rodegenerative 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 Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. control symptoms are available for these disorders, there are currently no effective treat- This article is an open access article ments available. Therefore, there is a growing interest in natural compounds that possess distributed under the terms and antioxidant and anti-inflammatory properties [8,9]. conditions of the Creative Commons Curcuma is a spice extracted from the rhizomes of Curcuma Longa, belonging to the Attribution (CC BY) license (https:// Zingiberaceae family, cultivated in India and in southeast Asia [10]. The main constituent creativecommons.org/licenses/by/ of Curcuma is curcumin, a yellow pigment commonly used as a spice and food coloring. 4.0/). It is used as a natural medicine for the treatment of inflammatory diseases [11]. Indeed, Int. J. Mol. Sci. 2021, 22, 3168. https://doi.org/10.3390/ijms22063168 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3168 2 of 27 curcumin is a nutriceutical compound that possesses numerous therapeutic properties against various diseases, including neurodegenerative diseases [12]. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEWAmong the several properties of curcuminoids [13–15], the anti-inflammatory [163 ,of17 26] and antioxidant activities [18,19] are the most investigated due to their role in the patho- genesis of neurodegenerative diseases [20]. Indeed, curcuminoids play a key role in the inhibitionsurvival, including of enzymes Bcl-2, such Bcl-xL, as p38 cyclin Mitogen-activated D1, cyclooxygenase protein 2 kinase (COX-2) (MAPK) and matrix and c-Jun metal- N- terminallopeptidase kinase (MMP)-9, (c-JNK) thus and promoting transcription the factors arrest (suchcell cycle, as nuclear inhibiting factor- proliferationκB, NF-κB) relatedand in- toducing inflammatory apoptosis processes. [46]. Also, they decrease the expression of several pro-inflammatory cytokinesMany [ 21of, 22curcumin’s]. Moreover, effects many are of also curcumin’s mediated beneficial by its ability effects to caninhibit be associated several protein with itskinases antioxidant (PKs) involved properties in [23various]. Since cellular oxidative processes, stress, causedsuch as by autophosphorylation-acti- excessive production of reactivevated (AK) oxygen protein species, kinase lipid [47], peroxidation Ca2+-dependent and protein oxidative kinase damage (CDPK) to DNA [48], and Janus proteins, kinase is(JAK) responsible [49], mitogen-activated for many pathological protein complicationskinase (MAPK) such [50,51], as neurodegenerative the mammalian target diseases, of ra- curcumin could play an important role in these conditions. pamycin (mTOR) [52,53], phosphorylase kinase (PhK) [47], cytosolic protein kinase (cPK) Curcumin has been extensively investigated due to its beneficial properties against [47], PKA [47], PKB/Akt [54], PKC [47]. Furthermore, the inhibitory action on the MAPK several neurological diseases such as PD [24], AD [25] and ALS [26]. pathway and the inhibition of the phosphorylation of the extracellular receptor kinase The purpose of this review is to describe the antioxidant properties of curcuminoids (ERK), c-JNKs and p38 MAPKs are responsible for the powerful anti-inflammatory effects associated with the efficacy in neurological disease. In the present review, preclinical of curcumin [55]. Indeed, the inhibition of the NF-κB and MAPK pathways reduce the and clinical evidence highlighting the curcuminoids’ antioxidants effects in neurological expression of numerous inflammatory interleukins (ILs) such as IL-1β, IL-6, Tumor necro- disorders are summarized. sis factor-alpha (TNF-α) [56], IL-2 [57], IL-5 [58], IL-8 [59], IL-12 [60], IL-18 [61] and signal 2.transducer Curcumin and activator of transcription (STAT) proteins [49]. Therefore, curcumin by regulating transcription factors, such as NF-κB, inhibits the production of pro-inflamma- Curcuminoids are the active compounds found in turmeric and include curcumin tory cytokines, thus exhibiting a powerful anti-inflammatory action [62]. (diferuloyl methane), demethoxycurcumin and bisdemethoxycurcumin (Figure1). Sev- eral inThese vitro characteristicand in vivo evidence properties describes of curcumin the anti-inflammatory make it a valid neuroprotective [27] and antioxidant com- propertiespound. Indeed, [28] of epidemiological curcuminoids. Amongstudies show the curcuminoids, that in the Indian curcumin population, makes upthe aboutconsump- 90% oftion the ofcurcuminoids turmeric is closely present correlated in turmeric. with the Curcumin low incidence is a polyphenol, of neurodegenerative with the molecular diseases such as AD and PD, compared to the Caucasian population [63,64]. formula C21H20O6, characterized for the first time in 1910 [29]. FigureFigure 1.1. ChemicalChemical structurestructure of of curcumin curcumin and and other other curcuminoids curcuminoids such such as as Demethoxycurcumin Demethoxycurcumin and and Bisdemethoxycurcumin, Bisdemethoxycurcu- obtainedmin, obtained from thefrom rhizomes the rhizomes of Curcuma of Curcuma Longa .Longa. Among them, curcumin is known to have neuroprotective effects and its antioxidant 3. Methodology and anti-inflammatory power is widely studied. The diketone group and two phenolic rings in itsThe chemical aim of structure this manuscript act as electron was to traps, provide thus an preventing overview of the experimental production of and hydrogen clinical studies that report the antioxidant effects of curcuminoids in neurodegenerative2− diseases, peroxide (H2O2), hydroxyl radical (OH·) and superoxide anion (O ·). Moreover, the b-diketonesuch as PD, fractionAD and andALS. hydroxyl In order to groups write ofthis curcumin review, a are search capable was ofcarried complexing out in PubMed metals, suchusing asthe copper following (Cu 2+keywords:) and zinc “Curcuminoids”
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