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Pleiotropic protective effects of phytochemicals in Alzheimer's disease.

Davinelli S, Sapere N, Zella D, Bracale R, Intrieri M, Scapagnini G - Oxid Med Cell Longev (2012)

Bottom Line: Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD.Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms.We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

View Article: PubMed Central - PubMed

Affiliation: Clinical Biochemistry and Clinical Molecular Biology Laboratory, Department of Health Sciences, University of Molise, 86100 Campobasso, Italy.

ABSTRACT
Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

Show MeSH

Related in: MedlinePlus

Reaction mechanism of curcumin with free radicals. The reactions produce phenoxyl radicals and carbon-centered radical at the methylene CH2 group.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368517&req=5

fig2: Reaction mechanism of curcumin with free radicals. The reactions produce phenoxyl radicals and carbon-centered radical at the methylene CH2 group.

Mentions: Curcumin (1,7-bis [4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione) or diferuloylmethane is extracted from the rhizome of Curcuma longa [7]. The structure is often shown in the keto form, but recent NMR studies demonstrated that curcumin exists in solution as keto-enol tautomers [8] (Figure 1). Numerous pieces of evidence suggest that curcumin may be a promising therapy for AD because it has different neuroprotective activities, including antioxidant [9], anti-inflammatory [10] and antiamyloidogenic properties [11]. Curcumin has been demonstrated to have a strong antioxidant neuroprotective effects, scavenging ROS [12] and neutralizing nitric-oxide-(NO-) based free radicals [13]. However, one of the issues of curcumin as a therapeutic agent in the treatment of AD is its poor water solubility [14], which is one reason for its low bioavailability following oral administration or through parenteral route [15]. The poor bioavailability is one of the causes of its failure in randomized control trials for AD. The structural features of curcumin that can contribute to the antioxidant activity are the phenolic and the methoxy group on the phenyl ring and the 1,3-diketone system. Moreover, the antioxidant activity of curcumin increases when the phenolic group with a methoxy group is at the ortho position [16, 17]. The orthomethoxy group can form an intramolecular hydrogen bond with the phenolic hydrogen, making the H-atom abstraction from the orthomethoxyphenols surprisingly easy [18]. The H abstraction from these groups is responsible for the remarkable antioxidant activity of curcumin. Moreover, the reactions of curcumin with free radicals produce a phenoxyl radicals and a carbon-centered radical at the methylene CH2 group [19] (Figure 2). Additional experimental reports supporting the antioxidant property of curcumin were provided by Lim and coworkers using an AD transgenic mouse model which demonstrated that curcumin reduces brain levels of oxidized proteins containing carbonyl groups [20]. In vivo, the antioxidant activity of curcumin may be mediated through antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Curcumin has been shown to serve as a Michael acceptor, reacting with glutathione (GSH) and thioredoxin [21]. Depletion in cellular GSH levels is an important measure of oxidative stress, which is implicated in the pathogenesis of AD. A study on postmortem brain of AD patients has revealed decreased levels of GSH in some area of the brain [22]. Also, the GSH levels were low in the red blood cells of male AD subjects, confirming an association between GSH and AD [23]. Noteworthy, there are some studies reporting the restorative effect of curcumin on GSH depletion. For instance, it was demonstrated that curcumin is able to replenish the intracellular GSH pool by changing the nuclear content and/or activation of specific transcription factors such as 12-tetradecanoate 13-acetate (TPA-) responsive elements (TRE) and electrophilic response element (EpRE) [24]. Moreover, curcumin enhances the antioxidant enzyme activities of SOD and CAT in the striatum and mid-brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) injected mice [25]. Taking into account that in vivo evidence showed that peroxynitrite induces Alzheimer-like tau hyperphosphorylation, nitration, and accumulation [26], it was reported that curcumin mediates the direct detoxification of reactive nitrogen species such as peroxynitrite, thus exerting an antioxidant activity [27]. Furthermore, the pieces of evidence to support a role of oxidative stress in AD brain with elevated levels of lipid peroxidation increasing [28]. Oxidative damage of lipids generates toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) leading to cell death. Important cytopathologies in AD brain include a decreased activity of all electron transport chain complexes [29]. In particular, complex IV decreases in AD, which causes release of oxidants during mitochondrial electron transport [30]. It was reported that excessive Aβ binds to regulatory heme, triggering functional heme deficiency and causing the key cytopathologies of AD. Additionally, Aβ-heme complex is a peroxidase and curcumin significantly inhibits the peroxidase activity of Aβ-heme [31]. The Tg2576 mouse model of AD exhibits impaired mitochondria metabolic activity in the spinal cord and curcumin partially suppressed the mitochondrial impairment reversing motor function deficits [32]. Interestingly, curcumin treatment abrogates lipid peroxidation protecting mitochondria from oxidative damage and apoptosis in cortical neurons [33]. Moreover, curcumin has been also shown in PC12 cells to provide protection against the deleterious effects of 4-HNE on mitochondrial redox metabolism, cytochrome c release, and DNA fragmentation [34]. The increased level of oxidative stress in AD is reflected by the increased brain content of iron (Fe2+) and copper (Cu2+) both capable of stimulating free radical formation. In addition to its properties of quencher, curcumin showed to be able to bind Cu2+ and Fe2+ ions [35]. Since these redox-active metals ions can intensify Aβ aggregation, curcumin may prevent this aspect of AD pathogenesis. Other reports suggested that curcumin regulates Fe2+ metabolism by modulation of Fe2+ regulatory proteins; therefore it may act as an iron chelator [36]. Significantly, in vivo studies reported that another divalent metal cation such as zinc (Zn2+) is highly enriched in Aβ plaques [37, 38] but its role in the amyloid landscape is still poorly understood and under investigation. However, even though curcumin more readily binds to the redox-active metals such as Cu2+ and Fe2+, it was also reported relatively weak affinity for the redox-inactive metal Zn2+ which might exert a small protective effect against Aβ by inducing metal chelation [35]. Recently, a systematic review highlighted the importance of inflammatory processes in the pathogenesis of AD [39]. AD secretes increasing levels of multiple inflammatory mediators, and considering the anti-inflammatory characteristic of curcumin, it was reported that this polyphenol reduced the level of interleukin-1β (IL-1β), a proinflammatory cytokine that appears elevated in the brains of AD-like mice [20]. Findings on the anti-inflammatory effects of curcumin were also provided by Jin et al. demonstrating that this natural phenol reduces the release of proinflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) [40]. Indeed, curcumin abolished the proliferative effects of IL-6 because it inhibits the phosphorylation of signal transducer and activator of transcription 3 (STAT3) [41]. In a similar manner, curcumin downregulates the transcription factor activator protein 1 (AP1) through direct interaction with its DNA binding motif [42] and inducing the inhibition of IL-1α and TNF-α [43]. Several experimental lines suggest that the anti-inflammatory capacity of curcumin is associated to the reduction of the activity of nuclear transcription factors NF-kβ signaling pathway [44]. NF-kβ enhances the transcription of proinflammatory genes, such as inducible nitric oxide synthase (iNOS). In inflammatory cells, iNOS catalyzes the synthesis of NO, which can react with superoxide to form peroxynitrite which damages proteins and DNA. Curcumin has been found to inhibit NF-kβ-dependent gene transcription and the induction of iNOS in animal studies and macrophages cell culture [45, 46]. Probably, the inhibition of AP1 and NF-kβ occurs through the chromatin remodelling activity of curcumin that is able to modulate some histone deacetylases (HDAC) activity [47]. Moreover, curcumin attenuates the inflammatory responses through the inhibition of lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, which are responsible of the synthesis of proinflammatory prostaglandins and leukotrienes [48]. Interestingly, the anti-inflammatory and neuroprotective effects of curcumin against dopamine induced neuronal death have also been demonstrated by Lee and coworkers which established that the inflammatory conditions induced by microglial activation are the main target for curcumin [49]. Noteworthy, curcumin exhibits protective effects on neuronal cells by inhibiting the aggregation of Aβ into oligomers and clearance effect on the exsting Aβ [50]. A very interesting in vivo approach with multiphoton microscopy showed the ability of curcumin to cross the blood-brain barrier (BBB) and disrupt amyloid plaques [51]. Additionally, in aged female rats with induced AD-like phenotype, curcumin prevented Aβ-induced spatial memory deficits in the Morris water maze assay, postsynaptic density loss, and reduced Aβ deposits [52]. As mentioned above, curcumin is able to clear amyloid plaques through several mechanisms and an additional activity that may be relevant is the induction of heat shock proteins (HSPs) molecular chaperones that are able to block protein aggregate formation [53]. However, even though several experimental research showed that curcumin exhibit high affinity binding to Aβ aggregates, one study reported the relationship between the tautomeric structures of curcumin, its derivatives, and their Aβ-binding activities. In particular, the results achieved by UV-visible spectroscopy revealed that the enolization is crucial for the binding and the enol forms of the curcumin derivatives are the predominant binding species for Aβ aggregates [54]. These important findings may represent a novel strategy for the design of therapeutic drugs or diagnostic tools in AD. Recently, Longvida, a curcumin formulation, has been evaluated in a Phase II Alzheimer's clinical trial (NCT01001637). Taking into account the low bioavailability of curcumin and its inability to reach required blood concentrations necessary to affect disease markers, Longvida is a solid lipid curcumin particle (SLCP) preparation and it was reported relatively higher bioavailability of SLCP compared to generic curcumin extract. Furthermore, this formulation is able to maintain plasma concentration of curcumin above the threshold required for the biological activity [55].


Pleiotropic protective effects of phytochemicals in Alzheimer's disease.

Davinelli S, Sapere N, Zella D, Bracale R, Intrieri M, Scapagnini G - Oxid Med Cell Longev (2012)

Reaction mechanism of curcumin with free radicals. The reactions produce phenoxyl radicals and carbon-centered radical at the methylene CH2 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368517&req=5

fig2: Reaction mechanism of curcumin with free radicals. The reactions produce phenoxyl radicals and carbon-centered radical at the methylene CH2 group.
Mentions: Curcumin (1,7-bis [4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione) or diferuloylmethane is extracted from the rhizome of Curcuma longa [7]. The structure is often shown in the keto form, but recent NMR studies demonstrated that curcumin exists in solution as keto-enol tautomers [8] (Figure 1). Numerous pieces of evidence suggest that curcumin may be a promising therapy for AD because it has different neuroprotective activities, including antioxidant [9], anti-inflammatory [10] and antiamyloidogenic properties [11]. Curcumin has been demonstrated to have a strong antioxidant neuroprotective effects, scavenging ROS [12] and neutralizing nitric-oxide-(NO-) based free radicals [13]. However, one of the issues of curcumin as a therapeutic agent in the treatment of AD is its poor water solubility [14], which is one reason for its low bioavailability following oral administration or through parenteral route [15]. The poor bioavailability is one of the causes of its failure in randomized control trials for AD. The structural features of curcumin that can contribute to the antioxidant activity are the phenolic and the methoxy group on the phenyl ring and the 1,3-diketone system. Moreover, the antioxidant activity of curcumin increases when the phenolic group with a methoxy group is at the ortho position [16, 17]. The orthomethoxy group can form an intramolecular hydrogen bond with the phenolic hydrogen, making the H-atom abstraction from the orthomethoxyphenols surprisingly easy [18]. The H abstraction from these groups is responsible for the remarkable antioxidant activity of curcumin. Moreover, the reactions of curcumin with free radicals produce a phenoxyl radicals and a carbon-centered radical at the methylene CH2 group [19] (Figure 2). Additional experimental reports supporting the antioxidant property of curcumin were provided by Lim and coworkers using an AD transgenic mouse model which demonstrated that curcumin reduces brain levels of oxidized proteins containing carbonyl groups [20]. In vivo, the antioxidant activity of curcumin may be mediated through antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Curcumin has been shown to serve as a Michael acceptor, reacting with glutathione (GSH) and thioredoxin [21]. Depletion in cellular GSH levels is an important measure of oxidative stress, which is implicated in the pathogenesis of AD. A study on postmortem brain of AD patients has revealed decreased levels of GSH in some area of the brain [22]. Also, the GSH levels were low in the red blood cells of male AD subjects, confirming an association between GSH and AD [23]. Noteworthy, there are some studies reporting the restorative effect of curcumin on GSH depletion. For instance, it was demonstrated that curcumin is able to replenish the intracellular GSH pool by changing the nuclear content and/or activation of specific transcription factors such as 12-tetradecanoate 13-acetate (TPA-) responsive elements (TRE) and electrophilic response element (EpRE) [24]. Moreover, curcumin enhances the antioxidant enzyme activities of SOD and CAT in the striatum and mid-brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) injected mice [25]. Taking into account that in vivo evidence showed that peroxynitrite induces Alzheimer-like tau hyperphosphorylation, nitration, and accumulation [26], it was reported that curcumin mediates the direct detoxification of reactive nitrogen species such as peroxynitrite, thus exerting an antioxidant activity [27]. Furthermore, the pieces of evidence to support a role of oxidative stress in AD brain with elevated levels of lipid peroxidation increasing [28]. Oxidative damage of lipids generates toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) leading to cell death. Important cytopathologies in AD brain include a decreased activity of all electron transport chain complexes [29]. In particular, complex IV decreases in AD, which causes release of oxidants during mitochondrial electron transport [30]. It was reported that excessive Aβ binds to regulatory heme, triggering functional heme deficiency and causing the key cytopathologies of AD. Additionally, Aβ-heme complex is a peroxidase and curcumin significantly inhibits the peroxidase activity of Aβ-heme [31]. The Tg2576 mouse model of AD exhibits impaired mitochondria metabolic activity in the spinal cord and curcumin partially suppressed the mitochondrial impairment reversing motor function deficits [32]. Interestingly, curcumin treatment abrogates lipid peroxidation protecting mitochondria from oxidative damage and apoptosis in cortical neurons [33]. Moreover, curcumin has been also shown in PC12 cells to provide protection against the deleterious effects of 4-HNE on mitochondrial redox metabolism, cytochrome c release, and DNA fragmentation [34]. The increased level of oxidative stress in AD is reflected by the increased brain content of iron (Fe2+) and copper (Cu2+) both capable of stimulating free radical formation. In addition to its properties of quencher, curcumin showed to be able to bind Cu2+ and Fe2+ ions [35]. Since these redox-active metals ions can intensify Aβ aggregation, curcumin may prevent this aspect of AD pathogenesis. Other reports suggested that curcumin regulates Fe2+ metabolism by modulation of Fe2+ regulatory proteins; therefore it may act as an iron chelator [36]. Significantly, in vivo studies reported that another divalent metal cation such as zinc (Zn2+) is highly enriched in Aβ plaques [37, 38] but its role in the amyloid landscape is still poorly understood and under investigation. However, even though curcumin more readily binds to the redox-active metals such as Cu2+ and Fe2+, it was also reported relatively weak affinity for the redox-inactive metal Zn2+ which might exert a small protective effect against Aβ by inducing metal chelation [35]. Recently, a systematic review highlighted the importance of inflammatory processes in the pathogenesis of AD [39]. AD secretes increasing levels of multiple inflammatory mediators, and considering the anti-inflammatory characteristic of curcumin, it was reported that this polyphenol reduced the level of interleukin-1β (IL-1β), a proinflammatory cytokine that appears elevated in the brains of AD-like mice [20]. Findings on the anti-inflammatory effects of curcumin were also provided by Jin et al. demonstrating that this natural phenol reduces the release of proinflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) [40]. Indeed, curcumin abolished the proliferative effects of IL-6 because it inhibits the phosphorylation of signal transducer and activator of transcription 3 (STAT3) [41]. In a similar manner, curcumin downregulates the transcription factor activator protein 1 (AP1) through direct interaction with its DNA binding motif [42] and inducing the inhibition of IL-1α and TNF-α [43]. Several experimental lines suggest that the anti-inflammatory capacity of curcumin is associated to the reduction of the activity of nuclear transcription factors NF-kβ signaling pathway [44]. NF-kβ enhances the transcription of proinflammatory genes, such as inducible nitric oxide synthase (iNOS). In inflammatory cells, iNOS catalyzes the synthesis of NO, which can react with superoxide to form peroxynitrite which damages proteins and DNA. Curcumin has been found to inhibit NF-kβ-dependent gene transcription and the induction of iNOS in animal studies and macrophages cell culture [45, 46]. Probably, the inhibition of AP1 and NF-kβ occurs through the chromatin remodelling activity of curcumin that is able to modulate some histone deacetylases (HDAC) activity [47]. Moreover, curcumin attenuates the inflammatory responses through the inhibition of lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, which are responsible of the synthesis of proinflammatory prostaglandins and leukotrienes [48]. Interestingly, the anti-inflammatory and neuroprotective effects of curcumin against dopamine induced neuronal death have also been demonstrated by Lee and coworkers which established that the inflammatory conditions induced by microglial activation are the main target for curcumin [49]. Noteworthy, curcumin exhibits protective effects on neuronal cells by inhibiting the aggregation of Aβ into oligomers and clearance effect on the exsting Aβ [50]. A very interesting in vivo approach with multiphoton microscopy showed the ability of curcumin to cross the blood-brain barrier (BBB) and disrupt amyloid plaques [51]. Additionally, in aged female rats with induced AD-like phenotype, curcumin prevented Aβ-induced spatial memory deficits in the Morris water maze assay, postsynaptic density loss, and reduced Aβ deposits [52]. As mentioned above, curcumin is able to clear amyloid plaques through several mechanisms and an additional activity that may be relevant is the induction of heat shock proteins (HSPs) molecular chaperones that are able to block protein aggregate formation [53]. However, even though several experimental research showed that curcumin exhibit high affinity binding to Aβ aggregates, one study reported the relationship between the tautomeric structures of curcumin, its derivatives, and their Aβ-binding activities. In particular, the results achieved by UV-visible spectroscopy revealed that the enolization is crucial for the binding and the enol forms of the curcumin derivatives are the predominant binding species for Aβ aggregates [54]. These important findings may represent a novel strategy for the design of therapeutic drugs or diagnostic tools in AD. Recently, Longvida, a curcumin formulation, has been evaluated in a Phase II Alzheimer's clinical trial (NCT01001637). Taking into account the low bioavailability of curcumin and its inability to reach required blood concentrations necessary to affect disease markers, Longvida is a solid lipid curcumin particle (SLCP) preparation and it was reported relatively higher bioavailability of SLCP compared to generic curcumin extract. Furthermore, this formulation is able to maintain plasma concentration of curcumin above the threshold required for the biological activity [55].

Bottom Line: Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD.Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms.We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

View Article: PubMed Central - PubMed

Affiliation: Clinical Biochemistry and Clinical Molecular Biology Laboratory, Department of Health Sciences, University of Molise, 86100 Campobasso, Italy.

ABSTRACT
Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

Show MeSH
Related in: MedlinePlus