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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.

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Related in: MedlinePlus

Chemical structure of resveratrol. The 4′-OH in resveratrol provides its chemical and biological features.The transfer of protons or hydrogen atoms to reactive species appears to be crucial to its antioxidant mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig4: Chemical structure of resveratrol. The 4′-OH in resveratrol provides its chemical and biological features.The transfer of protons or hydrogen atoms to reactive species appears to be crucial to its antioxidant mechanism.

Mentions: Resveratrol (5-[(E)-2-(4-hydroxyphenyl) ethenyl] benzene-1,3-diol) is a phytoalexin polyphenolic compound (Figure 4) found in grapes and other plants. In recent years many studies have reported interesting insights about the antiaging effects of resveratrol in different organisms including nematodes, yeast, rat, and mice. Indeed, resveratrol modulates various systems that protect cells providing neuroprotective features both in vitro and in vivo in models of AD. Many studies reported that the central nervous system (CNS) is one of the resveratrol's targets. This compund is able to pass the BBB [83] but the bioavailability is low because it is quickly metabolized into glucuronide and sulfate conjugates. Several lines of evidence indicate a strong antioxidant functions together with other pharmacological activities, therapeutic and protective properties [84]. Regarding the radical-scavenging activity, structural studies and theoretical calculations demonstrate that in the antioxidant reaction of resveratrol the hydroxyl group at the 4′-position is much easier to subject to oxidation than other hydroxyl groups [85]. Intraperitoneally administration of resveratrol exerts neuroprotective properties up-regulating several endogenous antioxidant enzymes such as SOD and CAT [86]. Prolonged administration of resveratrol improves colchicine-induced cognitive impairment, reduces MDA and nitrite levels, and restores depleted GSH [87]. However, it is important to emphasize that resveratrol can exhibit prooxidant activities in the presence of transition metal ions such as Cu2+, leading to oxidative breakage of cellular DNA [88]. A substantial amount of research has attributed to this phytocompound the capacity to increase the activity of SIRT1 that are NAD+-dependent class III histone deacetylases [89]. Consequently, resveratrol appears to possess the ability to activate sirtuins and to mimic caloric restriction [84]. In a mouse model of AD, a calorie-restricted diet attenuates AD pathogenesis through an increase in SIRT1 activity [90]. Additionally, it was reported that caloric restriction reduces Aβ deposition and Aβ-associated neuropathology in different animal models [91, 92]. In a meaningful way Kim et al. showed in transgenic AD mouse model that resveratrol reduced neurodegeneration through a decrease in the acetylation of known SIRT1 substrates, for example, peroxisome-proliferator-activated receptor gamma coactivator alpha (PGC-1α) and p53 [93]. SIRT1 activated by resveratrol protects cells against Aβ-induced ROS production and reduces amyloid neuropathology in the brains of Tg2576 mice [94]. Taking into account that resveratrol can be considered a neuroprotective compound in the context of AD, it is possible to speculate that the ability to counteract Aβ toxicity can occur through its antioxidant properties but also through SIRT1 activation. Definitely, resveratrol is reported to possess antiamyloidogenic activity in several studies, for example, the treatment with this stilbenoid resulted in the inhibition of β-amyloid peptide polymerization even though the antiamyloidogenic mechanism is still unknown [95]. As illustrated by Marambaud and colleagues, resveratrol promotes clearance of intracellular Aβ by activating its proteasomal degradation [96]. Moreover, SIRT1 overexpression reduces Aβ pathology in APP-expressing neuronal cultures by delaying Aβ synthesis [96, 97]. A recent work offers interesting insights into the effects of resveratrol on the polymerization, cell toxicity, and destabilization of Aβ fibril suggesting that resveratrol disrupts Aβ hydrogen binds thus preventing fibril formation, destabilizing preformed fibril without affecting oligomerization [98]. Furthermore, in a different study it was noticed that the protective effects of resveratrol on β-amyloid protein-induced toxicity in rat hippocampal cells are related to activation of PKC [99]. It is noteworthy to mention that resveratrol might be involved in the attenuation of neuroinflammatory responses because it is able to reduce the concentration of 8-iso-prostaglandin F2α, an indicator of free radical generation [100]. It has also been shown that resveratrol inhibits COX-1 but in contrast it does not affect the expression of COX-2 [100]. Since NF-kβ signaling activation plays an important role in the neurodegeneration, another link between AD and neuroprotective activity of resveratrol is its ability to reduce the expression of genes modulated by NF-kβ, such as iNOS, prostaglandin E2 (PGE2), as well as cathepsin and NO [101]. One of the main findings reported by Lu et al. was that resveratrol attenuates LPS-stimulated NF-κB activation in murine primary microglia and astrocytes and suggests that the inflammatory responses induced by LPS could be limited by resveratrol, with different potencies [102]. Studies performed in ischemia-reperfusion models have demonstrated that resveratrol inhibits peroxisome proliferator-activated receptors alpha (PPARα) [103] and reduces NF-kβ p65 expression [104]. Moreover, resveratrol was found to activate AMPK and reduce cerebral Aβ levels and deposition in the mice cortex [105]. Using electron microscopy and biochemical methods, it was reported that resveratrol prevents the abnormal expression of peroxiredoxins but also mitochondrial structural abnormalities in a mouse model of primary AD and Aβ-incubated mouse neuroblastoma cells [106].


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)

Chemical structure of resveratrol. The 4′-OH in resveratrol provides its chemical and biological features.The transfer of protons or hydrogen atoms to reactive species appears to be crucial to its antioxidant mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Chemical structure of resveratrol. The 4′-OH in resveratrol provides its chemical and biological features.The transfer of protons or hydrogen atoms to reactive species appears to be crucial to its antioxidant mechanism.
Mentions: Resveratrol (5-[(E)-2-(4-hydroxyphenyl) ethenyl] benzene-1,3-diol) is a phytoalexin polyphenolic compound (Figure 4) found in grapes and other plants. In recent years many studies have reported interesting insights about the antiaging effects of resveratrol in different organisms including nematodes, yeast, rat, and mice. Indeed, resveratrol modulates various systems that protect cells providing neuroprotective features both in vitro and in vivo in models of AD. Many studies reported that the central nervous system (CNS) is one of the resveratrol's targets. This compund is able to pass the BBB [83] but the bioavailability is low because it is quickly metabolized into glucuronide and sulfate conjugates. Several lines of evidence indicate a strong antioxidant functions together with other pharmacological activities, therapeutic and protective properties [84]. Regarding the radical-scavenging activity, structural studies and theoretical calculations demonstrate that in the antioxidant reaction of resveratrol the hydroxyl group at the 4′-position is much easier to subject to oxidation than other hydroxyl groups [85]. Intraperitoneally administration of resveratrol exerts neuroprotective properties up-regulating several endogenous antioxidant enzymes such as SOD and CAT [86]. Prolonged administration of resveratrol improves colchicine-induced cognitive impairment, reduces MDA and nitrite levels, and restores depleted GSH [87]. However, it is important to emphasize that resveratrol can exhibit prooxidant activities in the presence of transition metal ions such as Cu2+, leading to oxidative breakage of cellular DNA [88]. A substantial amount of research has attributed to this phytocompound the capacity to increase the activity of SIRT1 that are NAD+-dependent class III histone deacetylases [89]. Consequently, resveratrol appears to possess the ability to activate sirtuins and to mimic caloric restriction [84]. In a mouse model of AD, a calorie-restricted diet attenuates AD pathogenesis through an increase in SIRT1 activity [90]. Additionally, it was reported that caloric restriction reduces Aβ deposition and Aβ-associated neuropathology in different animal models [91, 92]. In a meaningful way Kim et al. showed in transgenic AD mouse model that resveratrol reduced neurodegeneration through a decrease in the acetylation of known SIRT1 substrates, for example, peroxisome-proliferator-activated receptor gamma coactivator alpha (PGC-1α) and p53 [93]. SIRT1 activated by resveratrol protects cells against Aβ-induced ROS production and reduces amyloid neuropathology in the brains of Tg2576 mice [94]. Taking into account that resveratrol can be considered a neuroprotective compound in the context of AD, it is possible to speculate that the ability to counteract Aβ toxicity can occur through its antioxidant properties but also through SIRT1 activation. Definitely, resveratrol is reported to possess antiamyloidogenic activity in several studies, for example, the treatment with this stilbenoid resulted in the inhibition of β-amyloid peptide polymerization even though the antiamyloidogenic mechanism is still unknown [95]. As illustrated by Marambaud and colleagues, resveratrol promotes clearance of intracellular Aβ by activating its proteasomal degradation [96]. Moreover, SIRT1 overexpression reduces Aβ pathology in APP-expressing neuronal cultures by delaying Aβ synthesis [96, 97]. A recent work offers interesting insights into the effects of resveratrol on the polymerization, cell toxicity, and destabilization of Aβ fibril suggesting that resveratrol disrupts Aβ hydrogen binds thus preventing fibril formation, destabilizing preformed fibril without affecting oligomerization [98]. Furthermore, in a different study it was noticed that the protective effects of resveratrol on β-amyloid protein-induced toxicity in rat hippocampal cells are related to activation of PKC [99]. It is noteworthy to mention that resveratrol might be involved in the attenuation of neuroinflammatory responses because it is able to reduce the concentration of 8-iso-prostaglandin F2α, an indicator of free radical generation [100]. It has also been shown that resveratrol inhibits COX-1 but in contrast it does not affect the expression of COX-2 [100]. Since NF-kβ signaling activation plays an important role in the neurodegeneration, another link between AD and neuroprotective activity of resveratrol is its ability to reduce the expression of genes modulated by NF-kβ, such as iNOS, prostaglandin E2 (PGE2), as well as cathepsin and NO [101]. One of the main findings reported by Lu et al. was that resveratrol attenuates LPS-stimulated NF-κB activation in murine primary microglia and astrocytes and suggests that the inflammatory responses induced by LPS could be limited by resveratrol, with different potencies [102]. Studies performed in ischemia-reperfusion models have demonstrated that resveratrol inhibits peroxisome proliferator-activated receptors alpha (PPARα) [103] and reduces NF-kβ p65 expression [104]. Moreover, resveratrol was found to activate AMPK and reduce cerebral Aβ levels and deposition in the mice cortex [105]. Using electron microscopy and biochemical methods, it was reported that resveratrol prevents the abnormal expression of peroxiredoxins but also mitochondrial structural abnormalities in a mouse model of primary AD and Aβ-incubated mouse neuroblastoma cells [106].

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