Limits...
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

Chemical structure of (−)-Epigallocatechin-3-gallate. EGCG contains three heterocyclic rings, A, B, and C, and the free radical scavenging property of EGCG is attributed to the presence of trihydroxyl group on the B ring and the gallate moiety at the 3′  position in the C ring.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368517&req=5

fig3: Chemical structure of (−)-Epigallocatechin-3-gallate. EGCG contains three heterocyclic rings, A, B, and C, and the free radical scavenging property of EGCG is attributed to the presence of trihydroxyl group on the B ring and the gallate moiety at the 3′  position in the C ring.

Mentions: EGCG ([(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5-trihydroxybenzoate) (Figure 3) is the most common phenolic constituent of green tea with several pharmacological activities associated with different beneficial health effects. It was well documented a powerful free radical scavenging activity for this catechin which might be attributed to the presence of the trihydroxyl group on the B ring and the gallate moiety esterified at the 3′ position in the C ring [56]. Furthermore, it was demonstrated in a human model of BBB the pharmacokinetics of catechin and epicatechin that could cross the BBB in a time-dependent manner [57]. EGCG penetrates the BBB at a low rate and the bioavailability after oral administration was approximately 5% [58]. It should be noted that high doses of EGCG were associated to death in rat hippocampal neuron through the mitochondrial-dependent pathway [59] and also that at high concentrations it has a prooxidant/proapoptotic activity [60]. However, considering that Aβ can induce mitochondrial dysfunction, it was also demonstrated that EGCG treatment is able to restore mitochondrial respiratory rates, altered mitochondrial membrane potential, and ROS production or ATP levels [61]. An increasing number of publications reports the ability of EGCG to modulate multiple biological pathways. Indeed, it has been shown to regulate several biomedically important targets and to exert neuroprotection in many ways. In addition to the anti-inflammatory properties, EGCG exerts protection by regulating different survival genes and controlling numerous antioxidant protective enzymes [62]. Advanced glycation end-products are involved in the neuronal injury associated with several neurodegenerative disorders. EGCG increased SOD activity and protected against glycation end products-induced neurotoxicity by decreasing ROS and MDA [63]. Another demonstration that EGCG may have preventive and/or therapeutic potential in AD has been shown in BV2 microglia cell lines and in rat hippocampus where EGCG treatment increased cellular GSH pool through elevated mRNA expression of gamma-glutamylcysteine ligase (GCL) which provides neuroprotection from Aβ cytotoxicity [64]. On D-galactose-treated aged mice, EGCG treatment led to the increment of SOD and GSH-Px activities decreasing MDA contents in the hippocampus [65]. Moreover, it is interesting that the attenuation of monoamine oxidase (MAO) activity may provide protection against oxidative neurodegeneration. EGCG supplementation in adult rat brains was able to exert an inhibitory action on MAO-B preventing physiological peroxidation [66]. As mentioned above for the curcumin, EGCG acts as an antioxidant protecting rat hippocampal neurons against NO stress-induced neuronal damage by deoxidizing peroxynitrate/peroxynitrite produced after ischemia [67]. Recently, it was established the pivotal role of iron in neurodegeneration and recent studies examined the effect of EGCG in the Fe2+ chelating process demonstrating neurorestorative activity and Fe2+-chelating properties [62]. Considering that the binding of EGCG to Fe2+ is essential for its antioxidant activity, among 12 phenolic compounds tested EGCG is the most potent inhibitor of the Fe2+-mediated DNA break [68]. A considerable number of evidence have elucidated the importance of several cell signaling pathways in the neuroprotective action of EGCG. Several studies indicate that EGCG affects mitogen-activated protein kinases (MAPK), NF-kβ and protein kinase C (PKC) pathways [69]. In support of these observations, EGCG has been shown to mediate the phosphorylation of PKC promoting the survival of human neuroblastoma SH-SY5Y cells from Aβ and 6-hydroxydopamine (6-OHDA)-induced neurotoxicity [70]. Other evidence on the pharmacological actions of EGCG and its potential therapeutic applications to various neurodegenerative diseases such as AD were provided by Kim et al. EGCG in human astrocytoma U373MG cells suppressed NF-kβ activation and phosphorylation of MAPK p38 and the c-Jun N-terminal kinase [71]. Additional investigations have indicated that EGCG prevented the expression of COX-2, iNOS, the release of NO, and proinflammatory cytokines from astrocytes and microglia by inhibiting MAPK signaling cascades [72]. Moreover, administration of EGCG prevented lipopolysaccharide-(LPS-) mediated apoptotic cell death through the reduction of the levels of Aβ and inhibited the elevation of the expression of iNOS and COX-2 [73]. Considerably, EGCG is able to modulate enzymes that are involved in amyloid precursor protein (APP) processing and reduces the formation of β-amyloid plaques in cell culture and in vivo [74]. Intraperitoneal administration of EGCG attenuated brain Aβ neuropathology and improved cognitive function in a transgenic AD mouse model [75]. In particular, EGCG inhibits the fibrillogenesis of Aβ through the binding to the natively unfolded polypeptides and preventing their conversion into toxic aggregates intermediates [76]. Considering the inhibitory function of EGCG on the Aβ generation, it was previously shown that catechins are able to inhibit formation, extension, and destabilization of β-amyloid fibrils [77] and EGCG mediates the block of β-secretase activity [78]. Additionally, Obregon and coworkers studied the involvement of three candidate α-secretase enzymes in EGCG-induced nonamyloidogenic APP metabolism. The results showed that a-disintegrin and metalloprotease-10 (ADAM-10) is necessary for EGCG-mediated α-secretase cleavage activity in APP processing; thus potential stimulators of ADAM-10 such as EGCG could prevent the amyloidosis associated to AD [79]. A further study revealed that through the inhibition of extracellular signal-regulated protein kinase (ERK) and NF-kβ pathways, the treatment with EGCG in mutant AD mice improved memory function enhancing the α-secretase function and reducing the activities of β-and γ-secretases with subsequently decrease in the levels of Aβ [80]. It has also been reported synergistic effects between EGCG and fish oil on the decrease in AD-like pathology in Tg2576 mice [81] and in a recent study Li et al. showed that the administration of this or similar compound may improve spatial memory preventing the decrease in the proteins involved in the synaptic function and structure [82]. EGCG has a wide array of biological effects and it is a promising compound which has been proven efficacious in AD animal models. Lastly, EGCG has an excellent tolerability and has resulted in ongoing Phase II/III clinical trials (NCT00951834).


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 (−)-Epigallocatechin-3-gallate. EGCG contains three heterocyclic rings, A, B, and C, and the free radical scavenging property of EGCG is attributed to the presence of trihydroxyl group on the B ring and the gallate moiety at the 3′  position in the C ring.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Chemical structure of (−)-Epigallocatechin-3-gallate. EGCG contains three heterocyclic rings, A, B, and C, and the free radical scavenging property of EGCG is attributed to the presence of trihydroxyl group on the B ring and the gallate moiety at the 3′  position in the C ring.
Mentions: EGCG ([(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5-trihydroxybenzoate) (Figure 3) is the most common phenolic constituent of green tea with several pharmacological activities associated with different beneficial health effects. It was well documented a powerful free radical scavenging activity for this catechin which might be attributed to the presence of the trihydroxyl group on the B ring and the gallate moiety esterified at the 3′ position in the C ring [56]. Furthermore, it was demonstrated in a human model of BBB the pharmacokinetics of catechin and epicatechin that could cross the BBB in a time-dependent manner [57]. EGCG penetrates the BBB at a low rate and the bioavailability after oral administration was approximately 5% [58]. It should be noted that high doses of EGCG were associated to death in rat hippocampal neuron through the mitochondrial-dependent pathway [59] and also that at high concentrations it has a prooxidant/proapoptotic activity [60]. However, considering that Aβ can induce mitochondrial dysfunction, it was also demonstrated that EGCG treatment is able to restore mitochondrial respiratory rates, altered mitochondrial membrane potential, and ROS production or ATP levels [61]. An increasing number of publications reports the ability of EGCG to modulate multiple biological pathways. Indeed, it has been shown to regulate several biomedically important targets and to exert neuroprotection in many ways. In addition to the anti-inflammatory properties, EGCG exerts protection by regulating different survival genes and controlling numerous antioxidant protective enzymes [62]. Advanced glycation end-products are involved in the neuronal injury associated with several neurodegenerative disorders. EGCG increased SOD activity and protected against glycation end products-induced neurotoxicity by decreasing ROS and MDA [63]. Another demonstration that EGCG may have preventive and/or therapeutic potential in AD has been shown in BV2 microglia cell lines and in rat hippocampus where EGCG treatment increased cellular GSH pool through elevated mRNA expression of gamma-glutamylcysteine ligase (GCL) which provides neuroprotection from Aβ cytotoxicity [64]. On D-galactose-treated aged mice, EGCG treatment led to the increment of SOD and GSH-Px activities decreasing MDA contents in the hippocampus [65]. Moreover, it is interesting that the attenuation of monoamine oxidase (MAO) activity may provide protection against oxidative neurodegeneration. EGCG supplementation in adult rat brains was able to exert an inhibitory action on MAO-B preventing physiological peroxidation [66]. As mentioned above for the curcumin, EGCG acts as an antioxidant protecting rat hippocampal neurons against NO stress-induced neuronal damage by deoxidizing peroxynitrate/peroxynitrite produced after ischemia [67]. Recently, it was established the pivotal role of iron in neurodegeneration and recent studies examined the effect of EGCG in the Fe2+ chelating process demonstrating neurorestorative activity and Fe2+-chelating properties [62]. Considering that the binding of EGCG to Fe2+ is essential for its antioxidant activity, among 12 phenolic compounds tested EGCG is the most potent inhibitor of the Fe2+-mediated DNA break [68]. A considerable number of evidence have elucidated the importance of several cell signaling pathways in the neuroprotective action of EGCG. Several studies indicate that EGCG affects mitogen-activated protein kinases (MAPK), NF-kβ and protein kinase C (PKC) pathways [69]. In support of these observations, EGCG has been shown to mediate the phosphorylation of PKC promoting the survival of human neuroblastoma SH-SY5Y cells from Aβ and 6-hydroxydopamine (6-OHDA)-induced neurotoxicity [70]. Other evidence on the pharmacological actions of EGCG and its potential therapeutic applications to various neurodegenerative diseases such as AD were provided by Kim et al. EGCG in human astrocytoma U373MG cells suppressed NF-kβ activation and phosphorylation of MAPK p38 and the c-Jun N-terminal kinase [71]. Additional investigations have indicated that EGCG prevented the expression of COX-2, iNOS, the release of NO, and proinflammatory cytokines from astrocytes and microglia by inhibiting MAPK signaling cascades [72]. Moreover, administration of EGCG prevented lipopolysaccharide-(LPS-) mediated apoptotic cell death through the reduction of the levels of Aβ and inhibited the elevation of the expression of iNOS and COX-2 [73]. Considerably, EGCG is able to modulate enzymes that are involved in amyloid precursor protein (APP) processing and reduces the formation of β-amyloid plaques in cell culture and in vivo [74]. Intraperitoneal administration of EGCG attenuated brain Aβ neuropathology and improved cognitive function in a transgenic AD mouse model [75]. In particular, EGCG inhibits the fibrillogenesis of Aβ through the binding to the natively unfolded polypeptides and preventing their conversion into toxic aggregates intermediates [76]. Considering the inhibitory function of EGCG on the Aβ generation, it was previously shown that catechins are able to inhibit formation, extension, and destabilization of β-amyloid fibrils [77] and EGCG mediates the block of β-secretase activity [78]. Additionally, Obregon and coworkers studied the involvement of three candidate α-secretase enzymes in EGCG-induced nonamyloidogenic APP metabolism. The results showed that a-disintegrin and metalloprotease-10 (ADAM-10) is necessary for EGCG-mediated α-secretase cleavage activity in APP processing; thus potential stimulators of ADAM-10 such as EGCG could prevent the amyloidosis associated to AD [79]. A further study revealed that through the inhibition of extracellular signal-regulated protein kinase (ERK) and NF-kβ pathways, the treatment with EGCG in mutant AD mice improved memory function enhancing the α-secretase function and reducing the activities of β-and γ-secretases with subsequently decrease in the levels of Aβ [80]. It has also been reported synergistic effects between EGCG and fish oil on the decrease in AD-like pathology in Tg2576 mice [81] and in a recent study Li et al. showed that the administration of this or similar compound may improve spatial memory preventing the decrease in the proteins involved in the synaptic function and structure [82]. EGCG has a wide array of biological effects and it is a promising compound which has been proven efficacious in AD animal models. Lastly, EGCG has an excellent tolerability and has resulted in ongoing Phase II/III clinical trials (NCT00951834).

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