- Email: [email protected]
Same causes, same cures
BBRC Biochemical and Biophysical Research Communications 351 (2006) 578–581 www.elsevier.com/locate/ybbrc
Mini Review
Same causes, same cures Hong-Yu Zhang
*
Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center for Advanced Study, Shandong University of Technology, Zibo 255049, PR China Received 12 October 2006 Available online 26 October 2006
Abstract Thanks to the continuing bio-medicinal efforts, similar causes underlying the pathogenesis of Alzheimer’s disease (AD) and prion diseases (PDs) have been revealed, which include oxidative stress, excessive transition metal ions, and misfolded/aggregated proteins. Therefore, the therapeutic strategy for one disease may be effective for the other. More interestingly, accumulating evidence indicates that not just the strategies but also the prescriptions may be shared by AD and PD treatments. In this review, we first summarize the known dual fighters against AD and PDs (which include antioxidants, metal chelators, and protein aggregation inhibitors), and then indicate that some super-dual-fighters may hit multiple targets implicated in AD and PDs, whose structural features highlight the importance of aromatic moiety and phenolic groups. These findings not only provide important clues to accelerating the screening of anti-AD and antiPDs drugs but also help to understand the etiology of AD and PDs. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Prion diseases; Antioxidants; Metal chelators; Protein aggregation inhibitors
Alzheimer’s disease (AD) and prion diseases (PDs) are among the most serious threats to human health [1,2]. Although the underlying pathogenetic mechanisms are not very clear, the continuing bio-medicinal efforts in the past decade have revealed that similar pathogenic factors, such as reactive oxidative species (ROS), transition metal ions (e.g., copper ions), and misfolded, and aggregated proteins, are shared by these diseases [3–5]. As a result, the therapeutic strategy for one disease may be effective for the other [5]. More interestingly, not just the strategies but also the prescriptions may be shared by AD and PD treatments. These amazing dual fighters not only provide important clues to finding novel drugs to combat AD and PDs but also offer deeper insights into the etiology of both diseases. Hence, it is of interest and significance to portray the common combatants in the fight against AD and PDs.
*
Fax: +86 533 2780271. E-mail address: [email protected].
0006-291X/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2006.10.086
Portrait of dual fighters First, since ROS is involved in the pathogenesis of AD and PDs [4,5], antioxidants are expected to be of benefit for these diseases [6–9]. Although convincing clinical evidence is still lacking, some modest therapeutic effects on AD and PDs have been observed for antioxidant combinations [7–9]. It is interesting to note that mixed tocopherols (vitamins E) are the common components in antioxidant prescriptions for AD and PDs [6–9]. In addition, vitamin C, NADH, and coenzyme Q10 are also frequently employed in this strategy [6–9], suggesting that some basic antioxidants constitute the core of the antioxidant therapy. Second, the involvement of metal ions in AD and PDs has stimulated considerable interest to use metal chelators to combat both diseases. Some metal chelators indeed showed promising preventive effects [10–13]. For instance, desferrioxamine, clioquinol, and D-()-penicillamine are effective to prevent AD in vitro and/or in vivo [10–12] and D-()-penicillamine can delay the onset of PD in mice [13]. Hence, D-()-penicillamine is of dual interest in
H.-Y. Zhang / Biochemical and Biophysical Research Communications 351 (2006) 578–581
itors is becoming the core of anti-AD and anti-PDs strategies [16–18]. A large number of chemical and biological molecules have been revealed as efficient inhibitors of Ab peptide and prion protein (PrP) fibrillation, some of which share the same structures. These dual inhibitors belong to various chemical categories, such as azo dyes (e.g., Congo red) [16,19,20], acridines (e.g., quinacrine) [19,21–23], anthracyclines (e.g., 4 0 -iodo-4 0 -deoxydoxorubicin) [16,24,25], phthalocyanines (e.g., phthalocyanine tetrasulfonate) [23, 26,27], and phenolics (e.g., curcumin, ()-epicatechin-3gallate (ECG), ()-epigallocatechin-3-gallate (EGCG), and tannic acid) [17,19,22,23,28–31] (Fig. 1). The inhibitory activities of most inhibitors are rather strong (IC50< 1 lM).
combating AD and PDs. As transition metal ions can initiate oxidative injury, metal chelators are usually regarded as preventive antioxidants. However, during the pathogenic processes of AD, metals (e.g., iron) play additional roles, such as regulating amyloid precursor protein mRNA [14]. As a result, metal chelators can lower amyloid-b (Ab) peptide generation through reducing amyloid precursor protein [14,15]. It will be of interest to explore whether transition metals also play additional roles in PDs and whether metal chelators can exert multiple effects. Third, it is widely accepted that protein misfolding and aggregation is a key event in the pathogenesis of AD and PDs [1–5]. Therefore, screening protein-aggregation inhib-
NH 2
O
NH 2 N
N
N
579
OH
O OH
N OH
SO 3 -
OCH 3 O
SO 3 -
OH O
H 3C
Congo red
I OH H 3 CO
O
O
H 2N
4'-iodo-4'-deoxydoxorubicin -O S 3
OCH 3
C
SO 3N
H HO
OH NH
Curcumin
N N
N OH
N OH
HO
N
HN N
O
-O S 3
SO 3-
Phthalocyanine tetrasulfonate O
NH
OH
OH
OH
OCH 3
O
OH
OH
Cl
N
OH
HO
HO
HO OH
HO
OH
OH O
HO
Quinacrine
O
(-)-Epicatechin-3-gallate
O OH
O
OH
O
HO
O O
O
OH
OH
O
O
OH O
O
OH
OH
OH
O
O HO
HO
OH
O
O OH
O
OH
O
O
O OH
O OH
OH
HO
OH
O
O
O
HO O
OH
OH OH
(-)-Epigallocatechin-3-gallate
OH
OH OH
HO OH
(-)-Epicatechin
Tannic acid
Fig. 1. Dual inhibitors of Ab and PrP aggregation (in green) and single inhibitor of Ab aggregation (in orange). The inhibitory activities of most inhibitors are rather strong (IC50< 1 lM). It is interesting to note that all of the dual inhibitors hold conjugated structures, which strongly suggests that aromatic moiety is crucial for inhibiting amyloid fibril self-assembly of Ab and PrP.
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H.-Y. Zhang / Biochemical and Biophysical Research Communications 351 (2006) 578–581
The existence of numerous dual inhibitors implies that similar mechanisms are shared by Ab and PrP aggregation, despite their big differences in sequence, which is further supported by recent findings that not just PDs but also AD can be induced by exogenous amyloids [32]. Although the diverse structures of the dual fighters and the various evaluation methodologies prevent us from defining a common pharmacophore for Ab, PrP, and/or their polymers, the fact that all of the dual inhibitors hold conjugated structures strongly suggests that aromatic moiety is crucial for inhibiting amyloid fibril self-assembly, which is in support of the p-stacking hypothesis of amyloid formation [17,33]. However, it should be pointed out that the commonness in Ab and PrP aggregation does not mean that Ab amyloid blocker is necessarily effective to prevent PrP fibril formation. For instance, ()-epicatechin (EC) is efficient to inhibit Ab polymerization [17,34] but ineffective to block PrP aggregation [22]. Considering the fact that ECG and EGCG (which are dual inhibitors of Ab and PrP aggregation [17,22,23]) are larger than EC and PrP is also larger than Ab, it is reasonable to infer that the bigger body of PrP needs bigger intermediates to block its aggregation (as to EC, its poor conjugation is also a defect), which is partially supported by the finding that a side chain is essential to inhibit PrP fibril assembly by phenothiazines [21], but not required for blocking Ab aggregation [23]. Recently, it was revealed that PrP promotes Ab plaque formation [35] and the aggregation of PrP and Ab could be triggered by acetylcholinesterase (an intensively studied target in AD treatment) [36], which opened new doors to screening dual inhibitors of PrP and Ab aggregation. For instance, acetylcholinesterase inhibitors binding to the peripheral site of the enzyme, e.g., propidium iodide, may serve as dual blockers of PrP and Ab aggregation [36]. Multipotency of dual fighters Since multiple pathogenic factors are implicated in AD and PDs [1–5], the associated drug discovery paradigm is shifting from ‘‘one-drug, one-target’’ to ‘‘one-drug, multiple-targets’’ [37–39]. To fulfill the new strategy, one can resort to cocktails incorporating various compounds, such as antioxidants, nonsteroidal antiinflammatory drugs, cholinergic drugs, metal chelators, and amyloid inhibitors [6]. Alternatively, one can expect that one compound is endowed with multiple pharmacological potentials [37–39]. For instance, antioxidants usually go beyond regulating ROS in vivo, because these molecules are possible to hit other targets than ROS that are also associated with AD and/or PDs [38–40]. A good example is that many efficient phenolic antioxidants, such as curcumin, ECG, and EGCG (Fig. 1), are powerful protein aggregation inhibitors [17,19,22,23,28–31]. Besides, these phenolics also can chelate transition metal ions, which have been implicated in their benefits to AD [15,41]. Hence, some anti-AD and anti-PDs dual fighters are super-warriors and phenolic com-
pounds are most likely to be the candidates. Considering the fact that some phenolics (including curcumin and EGCG) can penetrate blood–brain barriers [31,42] and phenolics’ beneficial effects on neurodegenerative diseases have been supported by epidemiological evidence [43–45], naturally occurring phenolic compounds deserve special attention in anti-AD and anti-PDs drug discovery. Conclusion Similar causes underlying the pathogenesis of AD and PDs implicate that similar cures may exist for both kinds of diseases, which is well-illuminated by the presented dual fighters. Moreover, some super-dual-fighters may hit multiple targets implicated in AD and PDs, whose structural features highlight the importance of aromatic moiety and phenolic groups. These findings not only provide important clues to accelerating the screening of anti-AD and anti-PDs drugs but also help to understand the etiology of AD and PDs. With the rapid growing of the union between biochemistry and chemical biology, it can be expected that the monster of amyloid diseases will be finally tamed by small-molecule weapons. Acknowledgments This study was supported by the National Basic Research Program of China (Grant 2003CB114400) and the National Natural Science Foundation of China (Grants 30100035 and 30570383). References [1] S.B. Prusiner, Prions, Proc. Natl. Acad. Sci. USA 95 (1998) 13363– 13383. [2] K. Blennow, M.J. de Leon, H. Zetterberg, Alzheimer’s disease, Lancet 368 (2006) 387–403. [3] A. Aguzzi, C. Haass, Games played by rogue proteins in prion disorders and Alzheimer’s disease, Science 302 (2003) 814–818. [4] D.R. Brown, H. Kozlowski, Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases, Dalton Trans. (2004) 1907–1917. [5] K.J. Barnham, R. Cappai, K. Beyreuther, C.L. Masters, A.F. Hill, Delineating common molecular mechanisms in Alzheimer’s and prion diseases, Trends Biochem. Sci. 31 (2006) 465–472. [6] K.N. Prasad, A.R. Hovland, W.C. Cole, K.C. Prasad, P. Nahreini, J. Edwards-Prasad, C.P. Andreatta, Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale, Clin. Neuropharmacol. 23 (2000) 2–13. [7] M. Grundman, P. Delaney, Antioxidant strategies for Alzheimer’s disease, Proc. Nutr. Soc. 61 (2002) 191–202. [8] C. Behl, B. Moosmann, Antioxidant neuroprotection in Alzheimer’s disease as preventive and therapeutic approach, Free Radic. Biol. Med. 33 (2002) 182–191. [9] J.A. Drisko, The use of antioxidants in transmissible spongiform encephalopathies: a case report, J. Am. Coll. Nutr. 21 (2002) 22–25. [10] R.A. Cherny, C.S. Atwood, M.E. Xilinas, D.N. Gray, W.D. Jones, C.A. McLean, K.J. Barnham, I. Volitakis, F.W. Fraser, Y.-S. Kim, X. Huang, L.E. Goldstein, R.D. Moir, J.T. Lim, K. Beyreuther, H. Zheng, R.E. Tanzi, C.L. Masters, A.I. Bush, Treatment with a copper–zinc chelator markedly and rapidly inhibits b-amyloid
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Mini Review
Same causes, same cures Hong-Yu Zhang
*
Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center for Advanced Study, Shandong University of Technology, Zibo 255049, PR China Received 12 October 2006 Available online 26 October 2006
Abstract Thanks to the continuing bio-medicinal efforts, similar causes underlying the pathogenesis of Alzheimer’s disease (AD) and prion diseases (PDs) have been revealed, which include oxidative stress, excessive transition metal ions, and misfolded/aggregated proteins. Therefore, the therapeutic strategy for one disease may be effective for the other. More interestingly, accumulating evidence indicates that not just the strategies but also the prescriptions may be shared by AD and PD treatments. In this review, we first summarize the known dual fighters against AD and PDs (which include antioxidants, metal chelators, and protein aggregation inhibitors), and then indicate that some super-dual-fighters may hit multiple targets implicated in AD and PDs, whose structural features highlight the importance of aromatic moiety and phenolic groups. These findings not only provide important clues to accelerating the screening of anti-AD and antiPDs drugs but also help to understand the etiology of AD and PDs. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Prion diseases; Antioxidants; Metal chelators; Protein aggregation inhibitors
Alzheimer’s disease (AD) and prion diseases (PDs) are among the most serious threats to human health [1,2]. Although the underlying pathogenetic mechanisms are not very clear, the continuing bio-medicinal efforts in the past decade have revealed that similar pathogenic factors, such as reactive oxidative species (ROS), transition metal ions (e.g., copper ions), and misfolded, and aggregated proteins, are shared by these diseases [3–5]. As a result, the therapeutic strategy for one disease may be effective for the other [5]. More interestingly, not just the strategies but also the prescriptions may be shared by AD and PD treatments. These amazing dual fighters not only provide important clues to finding novel drugs to combat AD and PDs but also offer deeper insights into the etiology of both diseases. Hence, it is of interest and significance to portray the common combatants in the fight against AD and PDs.
*
Fax: +86 533 2780271. E-mail address: [email protected].
0006-291X/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2006.10.086
Portrait of dual fighters First, since ROS is involved in the pathogenesis of AD and PDs [4,5], antioxidants are expected to be of benefit for these diseases [6–9]. Although convincing clinical evidence is still lacking, some modest therapeutic effects on AD and PDs have been observed for antioxidant combinations [7–9]. It is interesting to note that mixed tocopherols (vitamins E) are the common components in antioxidant prescriptions for AD and PDs [6–9]. In addition, vitamin C, NADH, and coenzyme Q10 are also frequently employed in this strategy [6–9], suggesting that some basic antioxidants constitute the core of the antioxidant therapy. Second, the involvement of metal ions in AD and PDs has stimulated considerable interest to use metal chelators to combat both diseases. Some metal chelators indeed showed promising preventive effects [10–13]. For instance, desferrioxamine, clioquinol, and D-()-penicillamine are effective to prevent AD in vitro and/or in vivo [10–12] and D-()-penicillamine can delay the onset of PD in mice [13]. Hence, D-()-penicillamine is of dual interest in
H.-Y. Zhang / Biochemical and Biophysical Research Communications 351 (2006) 578–581
itors is becoming the core of anti-AD and anti-PDs strategies [16–18]. A large number of chemical and biological molecules have been revealed as efficient inhibitors of Ab peptide and prion protein (PrP) fibrillation, some of which share the same structures. These dual inhibitors belong to various chemical categories, such as azo dyes (e.g., Congo red) [16,19,20], acridines (e.g., quinacrine) [19,21–23], anthracyclines (e.g., 4 0 -iodo-4 0 -deoxydoxorubicin) [16,24,25], phthalocyanines (e.g., phthalocyanine tetrasulfonate) [23, 26,27], and phenolics (e.g., curcumin, ()-epicatechin-3gallate (ECG), ()-epigallocatechin-3-gallate (EGCG), and tannic acid) [17,19,22,23,28–31] (Fig. 1). The inhibitory activities of most inhibitors are rather strong (IC50< 1 lM).
combating AD and PDs. As transition metal ions can initiate oxidative injury, metal chelators are usually regarded as preventive antioxidants. However, during the pathogenic processes of AD, metals (e.g., iron) play additional roles, such as regulating amyloid precursor protein mRNA [14]. As a result, metal chelators can lower amyloid-b (Ab) peptide generation through reducing amyloid precursor protein [14,15]. It will be of interest to explore whether transition metals also play additional roles in PDs and whether metal chelators can exert multiple effects. Third, it is widely accepted that protein misfolding and aggregation is a key event in the pathogenesis of AD and PDs [1–5]. Therefore, screening protein-aggregation inhib-
NH 2
O
NH 2 N
N
N
579
OH
O OH
N OH
SO 3 -
OCH 3 O
SO 3 -
OH O
H 3C
Congo red
I OH H 3 CO
O
O
H 2N
4'-iodo-4'-deoxydoxorubicin -O S 3
OCH 3
C
SO 3N
H HO
OH NH
Curcumin
N N
N OH
N OH
HO
N
HN N
O
-O S 3
SO 3-
Phthalocyanine tetrasulfonate O
NH
OH
OH
OH
OCH 3
O
OH
OH
Cl
N
OH
HO
HO
HO OH
HO
OH
OH O
HO
Quinacrine
O
(-)-Epicatechin-3-gallate
O OH
O
OH
O
HO
O O
O
OH
OH
O
O
OH O
O
OH
OH
OH
O
O HO
HO
OH
O
O OH
O
OH
O
O
O OH
O OH
OH
HO
OH
O
O
O
HO O
OH
OH OH
(-)-Epigallocatechin-3-gallate
OH
OH OH
HO OH
(-)-Epicatechin
Tannic acid
Fig. 1. Dual inhibitors of Ab and PrP aggregation (in green) and single inhibitor of Ab aggregation (in orange). The inhibitory activities of most inhibitors are rather strong (IC50< 1 lM). It is interesting to note that all of the dual inhibitors hold conjugated structures, which strongly suggests that aromatic moiety is crucial for inhibiting amyloid fibril self-assembly of Ab and PrP.
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The existence of numerous dual inhibitors implies that similar mechanisms are shared by Ab and PrP aggregation, despite their big differences in sequence, which is further supported by recent findings that not just PDs but also AD can be induced by exogenous amyloids [32]. Although the diverse structures of the dual fighters and the various evaluation methodologies prevent us from defining a common pharmacophore for Ab, PrP, and/or their polymers, the fact that all of the dual inhibitors hold conjugated structures strongly suggests that aromatic moiety is crucial for inhibiting amyloid fibril self-assembly, which is in support of the p-stacking hypothesis of amyloid formation [17,33]. However, it should be pointed out that the commonness in Ab and PrP aggregation does not mean that Ab amyloid blocker is necessarily effective to prevent PrP fibril formation. For instance, ()-epicatechin (EC) is efficient to inhibit Ab polymerization [17,34] but ineffective to block PrP aggregation [22]. Considering the fact that ECG and EGCG (which are dual inhibitors of Ab and PrP aggregation [17,22,23]) are larger than EC and PrP is also larger than Ab, it is reasonable to infer that the bigger body of PrP needs bigger intermediates to block its aggregation (as to EC, its poor conjugation is also a defect), which is partially supported by the finding that a side chain is essential to inhibit PrP fibril assembly by phenothiazines [21], but not required for blocking Ab aggregation [23]. Recently, it was revealed that PrP promotes Ab plaque formation [35] and the aggregation of PrP and Ab could be triggered by acetylcholinesterase (an intensively studied target in AD treatment) [36], which opened new doors to screening dual inhibitors of PrP and Ab aggregation. For instance, acetylcholinesterase inhibitors binding to the peripheral site of the enzyme, e.g., propidium iodide, may serve as dual blockers of PrP and Ab aggregation [36]. Multipotency of dual fighters Since multiple pathogenic factors are implicated in AD and PDs [1–5], the associated drug discovery paradigm is shifting from ‘‘one-drug, one-target’’ to ‘‘one-drug, multiple-targets’’ [37–39]. To fulfill the new strategy, one can resort to cocktails incorporating various compounds, such as antioxidants, nonsteroidal antiinflammatory drugs, cholinergic drugs, metal chelators, and amyloid inhibitors [6]. Alternatively, one can expect that one compound is endowed with multiple pharmacological potentials [37–39]. For instance, antioxidants usually go beyond regulating ROS in vivo, because these molecules are possible to hit other targets than ROS that are also associated with AD and/or PDs [38–40]. A good example is that many efficient phenolic antioxidants, such as curcumin, ECG, and EGCG (Fig. 1), are powerful protein aggregation inhibitors [17,19,22,23,28–31]. Besides, these phenolics also can chelate transition metal ions, which have been implicated in their benefits to AD [15,41]. Hence, some anti-AD and anti-PDs dual fighters are super-warriors and phenolic com-
pounds are most likely to be the candidates. Considering the fact that some phenolics (including curcumin and EGCG) can penetrate blood–brain barriers [31,42] and phenolics’ beneficial effects on neurodegenerative diseases have been supported by epidemiological evidence [43–45], naturally occurring phenolic compounds deserve special attention in anti-AD and anti-PDs drug discovery. Conclusion Similar causes underlying the pathogenesis of AD and PDs implicate that similar cures may exist for both kinds of diseases, which is well-illuminated by the presented dual fighters. Moreover, some super-dual-fighters may hit multiple targets implicated in AD and PDs, whose structural features highlight the importance of aromatic moiety and phenolic groups. These findings not only provide important clues to accelerating the screening of anti-AD and anti-PDs drugs but also help to understand the etiology of AD and PDs. With the rapid growing of the union between biochemistry and chemical biology, it can be expected that the monster of amyloid diseases will be finally tamed by small-molecule weapons. Acknowledgments This study was supported by the National Basic Research Program of China (Grant 2003CB114400) and the National Natural Science Foundation of China (Grants 30100035 and 30570383). References [1] S.B. Prusiner, Prions, Proc. Natl. Acad. Sci. USA 95 (1998) 13363– 13383. [2] K. Blennow, M.J. de Leon, H. Zetterberg, Alzheimer’s disease, Lancet 368 (2006) 387–403. [3] A. Aguzzi, C. Haass, Games played by rogue proteins in prion disorders and Alzheimer’s disease, Science 302 (2003) 814–818. [4] D.R. Brown, H. Kozlowski, Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases, Dalton Trans. (2004) 1907–1917. [5] K.J. Barnham, R. Cappai, K. Beyreuther, C.L. Masters, A.F. Hill, Delineating common molecular mechanisms in Alzheimer’s and prion diseases, Trends Biochem. Sci. 31 (2006) 465–472. [6] K.N. Prasad, A.R. Hovland, W.C. Cole, K.C. Prasad, P. Nahreini, J. Edwards-Prasad, C.P. Andreatta, Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale, Clin. Neuropharmacol. 23 (2000) 2–13. [7] M. Grundman, P. Delaney, Antioxidant strategies for Alzheimer’s disease, Proc. Nutr. Soc. 61 (2002) 191–202. [8] C. Behl, B. Moosmann, Antioxidant neuroprotection in Alzheimer’s disease as preventive and therapeutic approach, Free Radic. Biol. Med. 33 (2002) 182–191. [9] J.A. Drisko, The use of antioxidants in transmissible spongiform encephalopathies: a case report, J. Am. Coll. Nutr. 21 (2002) 22–25. [10] R.A. Cherny, C.S. Atwood, M.E. Xilinas, D.N. Gray, W.D. Jones, C.A. McLean, K.J. Barnham, I. Volitakis, F.W. Fraser, Y.-S. Kim, X. Huang, L.E. Goldstein, R.D. Moir, J.T. Lim, K. Beyreuther, H. Zheng, R.E. Tanzi, C.L. Masters, A.I. Bush, Treatment with a copper–zinc chelator markedly and rapidly inhibits b-amyloid
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