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Nutraceutical antioxidants as novel neuroprotective agents.

Kelsey NA, Wilkins HM, Linseman DA - Molecules (2010)

Bottom Line: These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic.All of these compounds are generally considered to be antioxidants.Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado 80208, USA. nkelsey@du.edu

ABSTRACT
A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic. All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.

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PKC is a key mediator of EGCG neuroprotection. The schematic shows the effects of PKC activation downstream of EGCG on the processing of APP being skewed towards the nonamyloidogenic product, sAPP, and the phosphorylation and targeting of pro-apoptotic Bad for degradation.
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Figure 7: PKC is a key mediator of EGCG neuroprotection. The schematic shows the effects of PKC activation downstream of EGCG on the processing of APP being skewed towards the nonamyloidogenic product, sAPP, and the phosphorylation and targeting of pro-apoptotic Bad for degradation.

Mentions: PKC is another protein involved in a myriad of signaling pathways including cell survival and programmed cell death [119]. In rat hippocampal neurons it was shown that resveratrol activates a PKC pathway which protects these neurons from Aβ toxicity [120]. EGCG is also known to activate a pro-survival PKC pathway. EGCG activation of PKC, via enhanced phosphorylation of this kinase, underlies its neuroprotective effects in SH-SY5Y and PC12 cells against Aβ toxicity [121]. The beta/gamma secretase-dependent processing of APP to the toxic Aβ peptide forms the basis of the pathophysiology underlying AD. There are however nontoxic processing pathways for APP, one of which is the alpha secretase-dependent production of nonamyloidogenic sAPPα. EGCG augments this nontoxic processing pathway through PKC activation [121]. PKC activation has also been implicated in EGCG neuroprotection from serum withdrawal in PC12 cells [122] and 6-OHDA toxicity in SH-SY5Y cells [35]. Finally, Kalfon et al. have connected EGCG to the PKC-mediated degradation of pro-apoptotic Bad in SH-SY5Y neuroblastoma cells [123]. Thus, the activation of PKC by EGCG may play as significant a role in its neuroprotective mechanism of action as its intrinsic antioxidant capacity (Figure 7). There are many isozymes of PKC that have been investigated individually for their neuroprotective effects. Specifically, PKCepsilon overexpression has been shown to reduce amyloid plaque burden and Aβ levels in human APP transgenic mice [124].


Nutraceutical antioxidants as novel neuroprotective agents.

Kelsey NA, Wilkins HM, Linseman DA - Molecules (2010)

PKC is a key mediator of EGCG neuroprotection. The schematic shows the effects of PKC activation downstream of EGCG on the processing of APP being skewed towards the nonamyloidogenic product, sAPP, and the phosphorylation and targeting of pro-apoptotic Bad for degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697862&req=5

Figure 7: PKC is a key mediator of EGCG neuroprotection. The schematic shows the effects of PKC activation downstream of EGCG on the processing of APP being skewed towards the nonamyloidogenic product, sAPP, and the phosphorylation and targeting of pro-apoptotic Bad for degradation.
Mentions: PKC is another protein involved in a myriad of signaling pathways including cell survival and programmed cell death [119]. In rat hippocampal neurons it was shown that resveratrol activates a PKC pathway which protects these neurons from Aβ toxicity [120]. EGCG is also known to activate a pro-survival PKC pathway. EGCG activation of PKC, via enhanced phosphorylation of this kinase, underlies its neuroprotective effects in SH-SY5Y and PC12 cells against Aβ toxicity [121]. The beta/gamma secretase-dependent processing of APP to the toxic Aβ peptide forms the basis of the pathophysiology underlying AD. There are however nontoxic processing pathways for APP, one of which is the alpha secretase-dependent production of nonamyloidogenic sAPPα. EGCG augments this nontoxic processing pathway through PKC activation [121]. PKC activation has also been implicated in EGCG neuroprotection from serum withdrawal in PC12 cells [122] and 6-OHDA toxicity in SH-SY5Y cells [35]. Finally, Kalfon et al. have connected EGCG to the PKC-mediated degradation of pro-apoptotic Bad in SH-SY5Y neuroblastoma cells [123]. Thus, the activation of PKC by EGCG may play as significant a role in its neuroprotective mechanism of action as its intrinsic antioxidant capacity (Figure 7). There are many isozymes of PKC that have been investigated individually for their neuroprotective effects. Specifically, PKCepsilon overexpression has been shown to reduce amyloid plaque burden and Aβ levels in human APP transgenic mice [124].

Bottom Line: These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic.All of these compounds are generally considered to be antioxidants.Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado 80208, USA. nkelsey@du.edu

ABSTRACT
A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic. All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.

Show MeSH
Related in: MedlinePlus