21 5 2009 5 PROGRESS IN CHEMISTRY Vol. 21 No. 5 May, 2009 3 3 3 ( 430079),,, ;,, : O614 ; R741 : A : 10052281X(2009) 0520903208 Metal2Based Therapeutic Strategies of Neurodegenerative Diseases Zhang Shibing Wang Ying Liu Changlin 3 3 ( Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal University,Wuhan 430079, China) Abstract The role of metal ions in both the pathology of neurodegenerative diseases and their treatments are summarized. The metal ion2mediated protein aggregation and oxidative stress in such as Alzheimer s and Parkinson s are discussed by integrating our preliminary data. The progress obtained to date shows that the metal chelation might be a preferred strategy in treatments of neurodegenerative diseases. Thus, a number of metal2chelating agents have been introduced into clinical trials. The alkylation of metal binding sites in the disease2linked proteins can significantly inhibit the formation of protein aggregates and reactive oxygen species, suggesting that this strategy may be a potential method to treat the diseases. Key words neurodegenerative diseases ; oxidative stress ; protein aggregation ; metal ions ; metal chelator Contents 1 Introduction 2 Brain metal ions and maintenance of their homeostasis 3 Metal ion2induced protein aggregation and oxidative stress 4 Protein aggregation and oxidative stress in Alzheimer s disease 5 Oxidative stress and 2synuclein aggregation in Parkinson s disease 6 Other neurodegenerative diseases 7 Therapeutic strategies 8 Conclusions 1 : 2008 12 ( ) 3 (No. 20571028) (No. 200601A04) 3 3 e2mail :liuchl @mail. ccnu. edu. cn
904 21 (, AD) (PD) (ALS), AD PD,65 10 %,85 50 %, AD, AD 500, 1Π4,, 21 [1 ],,, [2,3 ] AD (senile plaque), (A ),, Cu 2 + (0144mmol L - 1 ) Zn 2 + (1mmol L - 1 ) Fe 3 + (1mmol L - 1 ) [4,5 ], AD, A, [6 9 ] Zn 2 +, Zn 2 + [5 ], Cu 2 + A ( 1) Zn 2 + Znt3,, Zn 2 +, Zn 2 + 300 mol L - 1 Cu 2 +, 15 mol L - 1 A Zn 2 + Cu 2 +, 23 (MT3), A, AD MT3 [12 ] 2, Na + K + [5 ],Ca 2 +,, [10 ] Zn 2 + Cu 2 + Fe 3 +, Cu 2 +, Zn 2 +, Zn 2 +,,, ZnT Zip,, Zn 2 + 150 mol L - 1 [11 ], Cu 2 + [16 ] Cu 2 + 10 % 15 %,, Zn 2 +, Zn 2 +, 015 mol L - 1 [14 ],, Zn 2 + 300 mol L - 1 [12,14 ] 1 Zn 2 + Cu 2 + A [12 ] Fig. 1 Zn 2 + and Cu 2 + interaction with A in glutamatergic synapse [12 ], [5 ] Zn 2 +, ATP, ATP7a ATP7b, ATP7a,ATP7a ATP7b Menkes (Wilson ) [17 ],Cu 2 + mol
5 905,, AD [4,5 ] [17 ], [18 ], AD PD (substantia nigra, SN) [12,13 ], PD SN [12,19 ], Cu 2 +, 2m Cu 2 + [24 ] 3 AD PD ALS,, AD A PD 2synuclein ALS (SOD1), NMR X, : (1), ; (2) ; (3) 5 13nm, ( ),, [20,21 ], ( ), [22,23 ],, 2 22 ( 2m) Cu 2 +, Cu 2 +, 2m ( ) ( 2a) ;Cu 2 + 2m (Cu ), ; Cu 2 +, 2m (Cu ), 1h, ( 2b c) 2m Cu 2 +, EDTA, 2 Cu 2 + 2m [24 ] Fig. 2 A model of Cu 2 + 2induced 2m amyloid aggregation [24 ],, Cu 2 + Zn 2 + A, A ; SOD1, Cu 2 + Zn 2 + ;Fe 3 + A [25 ] ; Ca 2 + A, 8 mol L - 1 Zn 2 + A ( 3), 3 (a) (b) 50 mol L - 1 8 mol L - 1 A Zn 2 + Zn 2 + Zn 2 +, Zn 2 + [26 ] Fe 3 + Cu 2 + Zn 2 +,,,,,,,DNA SOD1 ;, DNA EDTA,SOD1
906 21 3 A Zn 2 + [26 ] Fig. 3 Amorphous aggregates of A due to interaction with Zn 2 + [26 ] [27 ],, [28 ] 4 (AD) A Tau, A,Tau [5 ] A A 1 40 A 1 42, 413 415kD,A 1 42 A 1 40, A 1 42 A 1 40 ( EPR), A 1 40 Cu 2 +, ( 4a), Cu 2 + A 1 40, Cu 2 + ( 4b) [16 ], SOD1 A 1 40 Cu 2 + [29 ], EPR, Cu 2 + A 1 40, : Cu 2 + 70 mol L - 1, AD 390 mol L - 1 ; Zn 2 + 350 mol L - 1 1 055 mol L - 1 ; Fe 3 + 340 mol L - 1 940 mol L - 1 [30 ], A, A,,, A A, Fe 3 +, Cu 2 + Zn 2 + A,, Cu 2 + Zn 2 + A [8 ] AD [31 ], A, (ROS), A Cu 2 + Fe 3 + A ; Zn 2 +, [32,33 ],,Zn 2 + A [15 ] A Cu 2 + Fe 3 + [6 ] ROS, H 2 O 2, Fenton HO Fe 2+ + H 2 O 2 Fe 3+ + HO + OH - A Cu 2 + ROS ( 5), A Cu 2 + Cu +, A : Cu Cu + O 2 O 2 2 -, H 2 O 2,A Zn 2 + Cu 2 + H 2 O 2 [6 ] Cu 2 + A,NMR A 4 Cu 2 + A (a) (b) [16 ] Fig. 4 Proposed mononuclear (a) and dinuclear (b) structures of Cu 2 + bound to A peptides [16 ], Fe 3 + Zn 2 + Cu 2 + AD AD 5 A Cu 2 + H 2 O 2 [6 ] Fig. 5 A model for catalytic H 2 O 2 production by A interaction with Cu 2 + [6 ]
5 907 [34 ] 5 2synuclein, [5 ], [35 ], Fe 3 + ΠFe 2 + PD ( ), Fe 3 + [36 ],, [37 PD 40 ],, SOD1 Fe 3 +, ( ) [41 ],,, (Lewy body) PD, 2synuclein Fe 3 + 2synuclein 140, 14kD, 3 : (1) (1 60), 4 ( XKTKEGVXXXX),, ; (2) NAC (61 95),, ; (3) (96 140),,,, 2synuclein [42,43 ], 2synuclein,,,, 2synuclein [43 ], [44 ] 2Synuclein Zn 2 + Fe 3 + Cu 2 +, [45 ] 2synuclein A, [46,47 ], 2synuclein, 2 synuclein ROS [48 ] 6 ALS, PrP [49 ] ALS,, 100 SOD1 ALS [50 ], : SOD1? DNA RNA, SOD1,, [51 ] 7,,,,,,,,,,, [52 ] ;, [5,28 ], ( 6),,desferrioxamine,82, (clioquinol, CQ) 82 [52 ], Cu 2 + CQ A, CQ A (Cu 2 + Zn 2 + ), A [5,16 ] CQ A [5 ],CQ [52 ],,
908 21 6 Fig. 6 Potential metal chelators of the past and the future Desferrioxamine (DFO),,DFO,, [52 ], 82 ( bis282 hydroxyquinaldine), [53 ],82 A H 2 O 2, H 2 GL 1 ΠH 2 GL 2, [52 ] H 2 GL 1 ΠH 2 GL 2 Cu 2 + Zn 2 + Cu 2 + Zn 2 + A, [52 ] A (Cu 2 + Zn 2 + Fe 3 + ) Tyr210 His26 His213 His214 Met235, A 2 A 2, A [4,29 ], A,,, Barnham Pt2 ( 7a) A [54 ], DNA,, DNA,, A His Phe Tyr 2 Pt2His, Pt His Pt Met235 ( Phe Tyr), Pt His26 His213 His214, NMR (CD) His, Met235 Thioflavin T (ThT) Pt2 A ; Pt2 A :Cu H 2 O 2 7 (a) Pt2 ; (b) Pt2 A 1 42 [54 ] Fig. 7 The structures of cisplatin and L2PtCl 2 complexes (a) and inhibition of A 1 42 2induced neurotoxicity (b) [54 ]
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