Lecture 3 - Glutathione and Neurological Diseases PDF

Dr. med. Jan Lewerenz Klinik und Poliklinik für Neurologie !"#$%&#'()*&+(,,)%-$).#,(%,(,)/0)&1()2+%#- !"#$%&'"%&()*%&+,-&.)/)")-0 1)2"#3#45678)&9-5:)"65;35-57,3&1)2"#675)-7)&.)7;2")&?)"5)6&@?&ABAACAD !"#$%&'"$()#*'+$,-)./012&-)$-3$2"#$4*5&)...

Dr. med. Jan Lewerenz Klinik und Poliklinik für Neurologie !"#$%&#'()*&+(,,)%-$).#,(%,(,)/0)&1()2+%#- !"#$%&'"%&()*%&+,-&.)/)")-0 1)2"#3#45678)&9-5:)"65;35-57,3&1)2"#675)-7)&.)7;2")&?)"5)6&@?&ABAACAD !"#$%&'"$()#*'+$,-)./012&-)$-3$2"#$4*5&) !"#$%&' 67&852&9#$$:"-.1"-*+;52&-)'D'-$.:8$T5C>)8$Z5L)/*5[8,#$E5G/:6\Z5NQQ57L$5 might represent a useful biomarker @]XKJVE HXKP^B 8%:.7-$.)6 D)6$ of oxidative damage in AD4 Q%:8)6'5$85:/TE5U5V$"%'76)5IJJPE5N..5V$"%'/5IJJJ "5@A433BC('#)+-4D4-% :*-2#&)$,5*L-)+;52&-)$&.$U1*#'/;52#8$&)$AE$4*5&). E..................................1" E((3)**4# M:8$-.:5$85:/TE5U5V$"%'6>$D5IJJI 1#&')7"),6)&5-&K32;,;85#-)&5-&T308)5()"U6&'56),6) Glutathion und Alzheimer-Demenz Perry et al., Ann Neurol 1987 Glutathione Perry et al., Ann Neurol 1987 _ Adams et al., Mol Chem Neuropathol 1991 _/↑(Temporallappen) Makl et al., Neurochem Res 1995 _ Karelson et al., Neurochem Res 2001 _  R8)&!)-;#6)S8#6S8,;)&!,;8/,L&56&2S")423,;)*&5-&T' Glutathion und Alzheimer-Demenz G6PDH Martins et al, J Neurochem 1986 ` Palmer et al., J Neural Transm 1999 ` Russel et al., Arch Biochem Biophys 1999 ` Soucek et al., Neuron 2002 ` >$%!-#/24)'.1'?1@"+1%!7,7/).- 261?%#64%2.!12*2$424)'.12-2).641 '()*24)A!164%!661B Schubert, Ageing Res Review 2005 R"),;()-;V&W5;,(5-&X&56&Y-)$$)7;5:) Conversion from MCI to AD Petersen et al., NEJM 2005  EO5*,;5:)&?;")66&5-&!,"=5-6#-U6&'56),6) Lewy bodies containing α- synuclein Pathology starts in the brain stem and ascends to the cortex Movement disorder due to degeneration of the dopaminergic neurons in the substantia nigra G%::\5$85:/E5U5V$"%:/5=%:.7D5IJJa ?S#-;,-)#26&,-*&X-0L(,;57&')4",*,;5#-&#$&'#S,(5-)& !"#*27)6&NE? aE25S+QNZ5aE2&*)>,*%'(,#>$.,/:6$8:/*$>,*$E5!b5c57$D)d").'.$  Glutathion und neurologische K?I&5-&!,"=5-6#-U6&'56),6)&,-*&T;LS57,3&!,"=5-6#-&?L-*"#()6 Erkrankungen CD $5!V Markers of oxidative stress increased in post mortem SN in PD M8%/ Malondialdehyde (Dexter et al. J Neurochem 1989) QS 4-HNE (Yoritaka et al., PNAS 1996) Protein carbonylation (Floor et al., J Neurochem 1998) 8-Hydroxydeoxyguanosine (Alam et al., J Neurochem 1997) Markers of oxidative stress in the CSF of PD patients 3-fold higher CSF levels of 8- hydroxyguanosine (Abe et al., Neurosci Lett 2003) Increased markers of lipid peroxidaton (Buhmann et al., Neurobiol Dis 2003) g'%)8:\:5$85:/TE5QVN!5PWWX EO5*,;5:)&6;")66&5-&!,"=5-6#-U6&'56),6) H:%8).5h5=$)7D:..E53N!eG5U5IJJW R"),;()-;V&'#)6&[TE&\&Y-85]5;5#-&[#*5$5)6& !,"=5-6#-U6&'56),6) NSN;i05=%):/E50/:.'L5$85:/TE5VeUH5IJJW EO5*,;5:)&6;")66&5-&Y678)(57&?;"#=) Energy failure due to lack of oxygen Depolarization Massive release glutamate Massive influx of calcium Cell death  ?#2"7)6&#$&EO5*,;5:)&?;")66&5-&Y678)(57&?;"#=) Activation of Ca++-dependent enzymes, 6,6/''(,-$.:7$5:.*5 Neutrophil invasion #>'7#>'/)#:7$5N! Microglia activation Mitochondrial damage ROS ROS Dirnagl et al. TINS 1999  EO5*,;5:)&?;")66&5-&>)")]",3&Y678)(5,HN)S)"$265#-&Y-^2"L Glutathion und zerebrale Ischämie Increased lipid peroxidation (MDA) and cysteine oxidation And decreased reduced GSH upon 1 h of reperfusion F(G1"4%!66 0!*G1@"+ @/#4245G1C%'4G C%'4!).&"+ 30 min forbrain ischemia in the rat due to bilateral carotide artery occlusion Shivakumar et al., J Pharmacol Exp Ther 1995  R8)&!,;8#S8L65#3#457,3&N)3):,-7)&#$&EO5*,;5:)&?;")66 Zerebrale Ischämie und Glutathion Y-&Y678)(57&?;"#=) H.?2%7416)I!1)61).7%!26!* ).1J'1;)7!1?'% GPx1 ko mice, MCAO K L#M.&"FD /F(C&(.#-.)GH.>IL H.?2%7416)I!1)61*!7%!26!* ).14%2.6-!.)71;)7!1 'A!%!($%!66).- KN(4%27!//#/2%1"FD1/2$#CM.#-.)GH7.5#B'(*+4#C+#.IJJJL K@C(9/P#4*,'(-AN#QO(R4-S.#-.)GH7.:')4C.T#*.9(G.:')4C.T#*.IJJUL M%:6\5$85:/TE5U5V$"%'6>$D5IJJP R8)&?TY1R&R"5,3V&R8)&_"))HN,*57,3&?7,:)-4)"&1`aHBbc Zerebrale Ischämie und Glutathion 56&Y-)$$)7;5:)&5-&?;"#=)&5-&I2(,-6& H'*)A)$*5F:.\).- !>":)Y5$85:/TE5VeUH5IJJK Efficacy of NXY-059 in animal models: NXY-059 improved infarct volume by 43.3% (95% CI, 34.7 to 52.8). Only 2 of 9 publications reported randomization, concealment of treatment allocation, and blinded outcome assessment !! NXY-059 might have been the wrong choice (McLeod et al., Stroke 2009)  ()**+,- Reactive oxygen species: the hydroxyl and superoxide radical, hydrogen peroxide generated in the mitochondria and by diverse enzyme induce lipid, protein and DNA/RNA oxidation subsequent cellular damage Oxidative stress: dysbalance of ROS production and the antioxidant defence the brain is vulnerable (high oxygen consumption, unsaturated FAs, metals) present in important diseases of the brain includung AD, PD and stroke antioxidant treatment strategies have failed so far Dr. med. Jan Lewerenz Klinik und Poliklinik für Neurologie !"#$%&