Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine

Autophagy

Volumn 10, Issue 12, 2014, Pages 2362-2378

  Vucicevic, Ljubica ^a   Misirkic Marjanovic, Maja ^a   Paunovic, Verica ^a   Kravic Stevovic, Tamara ^a   Martinovic, Tamara ^a   Ciric, Darko ^a   Maric, Nadja ^a   Petricevic, Sasa ^b   Harhaji Trajkovic, Ljubica ^a   Bumbasirevic, Vladimir ^a   Trajkovic, Vladimir ^a  

^a UNIVERSITY OF BELGRADE   (Serbia)

^b Institute of Biomedical Research   (Serbia)

Author keywords

Antipsychotic; Apoptosis; Autophagy; Mitophagy; Neurotoxicity; Olanzapine; Oxidative stress; SQSTM1

Indexed keywords

AUTOPHAGY PROTEIN 5; BECLIN 1; CHLOROQUINE; CYCLIN DEPENDENT KINASE INHIBITOR 1A; CYCLIN DEPENDENT KINASE INHIBITOR 1B; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MESSENGER RNA; OLANZAPINE; PROTEIN BAX; REACTIVE OXYGEN METABOLITE; BENZODIAZEPINE DERIVATIVE; NEUROLEPTIC AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; CELL DEATH; CELL MEMBRANE DEPOLARIZATION; CONTROLLED STUDY; DNA FRAGMENTATION; ELECTRON MICROSCOPY; FRONTAL CORTEX; GENE EXPRESSION; HUMAN; HUMAN CELL; LYSOSOME; MITOCHONDRION; MITOPHAGY; MOUSE; NERVE CELL; NEUROTOXICITY; NONHUMAN; OXIDATIVE STRESS; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; ANIMAL; APOPTOSIS; CELL LINE; CYTOLOGY; DRUG EFFECTS; METABOLISM;

ANIMALIA; MUS;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; ANTIPSYCHOTIC AGENTS; APOPTOSIS; AUTOPHAGY; BENZODIAZEPINES; CELL LINE; HUMANS; LYSOSOMES; MICE; MITOCHONDRIA; NEURONS; REACTIVE OXYGEN SPECIES;

EID: 84942077592     PISSN: 15548627     EISSN: 15548635     Source Type: Journal    
DOI: 10.4161/15548627.2014.984270     Document Type: Article

References (83)

1. van Os J, Kapur S. Schizophrenia. Lancet 2009; 374: 635-45; PMID: 19700006; http://dx.doi.org/10.1016/S0140-6736(09)60995-8
2. Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry 2007; 164: 1890-9; ; http://dx.doi.org/10.1176/appi. ajp.2007.05111903
3. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128- 37; PMID: 21300943; http://dx.doi.org/10.1001/archgenpsychiatry.2010.199
4. Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: A comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005; 30: 1649-61; PMID: 15756305; http://dx.doi. org/10.1038/sj.npp.1300710
5. Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 2007; 32: 1216-23; PMID: 17063154; http://dx. doi.org/10.1038/sj.npp.1301233
6. Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008; 63: 759-65; PMID: 17945195; http://dx.doi. org/10.1016/j.biopsych.2007.08.018
7. Bonelli RM, Hofmann P, Aschoff A, Niederwieser G, Heuberger C, JirikowskiG, Kapfhammer HP. The influence of psychotropic drugs on cerebral cell death: Female neurovulnerability to antipsychotics. Int Clin Psychopharmacol 2005; 20: 145-9; PMID: 15812264; http://dx.doi.org/10.1097/00004850-200505000-00004
8. Ballard CG, Perry RH, McKeith IG, Perry EK. Neuroleptics are associated with more severe tangle pathology in dementia with Lewy bodies. Int J Geriatr Psychiatry 2005; 20: 872-5; PMID: 16116579; http://dx.doi.org/10.1002/gps.1378
9. Domino ME, Swartz MS. Who are the new users of antipsychotic medications? Psychiatr Serv 2008; 59: 507-14; PMID: 18451006; http://dx.doi.org/10.1176/appi.ps.59.5.507
10. Wang K, Klionsky DJ. Mitochondria removal by autophagy. Autophagy 2011; 7: 297-300; PMID: 21252623; http://dx.doi.org/10.4161/auto.7.3.14502
11. Yang Z, Klionsky DJ. Eaten alive: A history of macroautophagy. Nat Cell Biol 2010; 12: 814-22; PMID: 20811353; http://dx.doi.org/10.1038/ncb0910-814
12. White E. Autophagic cell death unraveled: Pharmacological inhibition of apoptosis and autophagy enables necrosis. Autophagy 2008; 4: 399-401; PMID: 18367872; http://dx.doi.org/10.4161/auto.5907
13. Jain MV, Paczulla AM, Klonisch T, Dimgba FN, Rao SB, Roberg K, Schweizer F, Lengerke C, Davoodpour P, Palicharla VR, et al. Interconnections between apoptotic, autophagic and necrotic pathways: Implications for cancer therapy development. J Cell Mol Med 2013; 17: 12-29; PMID: 23301705; http://dx.doi.org/10.1111/jcmm.12001
14. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene 2004; 23: 2891-906; PMID: 15077152; http://dx.doi.org/10.1038/sj.onc.1207521
15. Gozuacik D, Kimchi A. Autophagy and cell death. Curr Top Dev Biol 2007; 78: 217-45; PMID: 17338918; http://dx.doi.org/10.1016/S0070- 2153(06)78006-1
16. Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L, Tolkovsky A. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 2005; 1: 11-22; PMID: 16874045; http://dx.doi.org/10.4161/auto.1.1.1513
17. Xilouri M, Stefanis L. Autophagy in the central nervous system: Implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 2010; 9: 701-19; PMID: 20942791; http://dx.doi.org/10.2174/1871527 10793237421
18. Yang Z, Klionsky DJ. Mammalian autophagy: Core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22: 124-31; PMID: 20034776; http://dx.doi.org/10.1016/j.ceb.2009.11.014
19. Barnes MR, Huxley-Jones J, Maycox PR, Lennon M, Thornber A, Kelly F, Bates S, Taylor A, Reid J, Jones N, et al. Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia. J Neurosci Res 2011; 89: 1218-27; PMID: 21538462; http://dx.doi.org/10.1002/jnr.22647
20. Horesh Y, Katsel P, Haroutunian V, Domany E. Gene expression signature is shared by patients with Alzheimer's disease and schizophrenia at the superior temporal gyrus. Eur J Neurol 2011; 18: 410-24; PMID: 20695885; http://dx.doi.org/10.1111/j.1468- 1331.2010.03166.x
21. Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W, Zhu H, Yu AD, Xie X, Ma D, et al. Small molecule regulators of autophagy identified by an image-based highthroughput screen. Proc Natl Acad Sci USA 2007; 104: 19023-8; PMID: 18024584; http://dx.doi.org/10.1073/pnas.0709695104
22. Park J, Chung S, An H, Kim J, Seo J, Kim DH, Yoon SY. Haloperidol and clozapine block formation of autophagolysosomes in rat primary neurons. Neuroscience 2012; 209: 64-73; PMID: 22390943; http://dx.doi.org/10.1016/j.neuroscience.2012.02.035
23. Shin JH, Park SJ, Kim ES, Jo YK, Hong J, Cho DH. Sertindole, a potent antagonist at dopamine D(2) receptors, induces autophagy by increasing reactive oxygen species in SH-SY5Y neuroblastoma cells. Biol Pharm Bull 2012; 35: 1069-75; PMID: 22791154; http://dx.doi.org/10.1248/bpb.b12-00009
24. Shin SY, Lee KS, Choi YK, Lim HJ, Lee HG, Lim Y, Lee YH. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis 2013; 34: 2080-9; PMID: 23689352; http://dx.doi. org/10.1093/carcin/bgt169
25. Yan H, Li WL, Xu JJ, Zhu SQ, Long X, Che JP. D2 dopamine receptor antagonist raclopride induces noncanonical autophagy in cardiac myocytes. J Cell Biochem 2013; 114: 103-10; PMID: 22886761; http://dx. doi.org/10.1002/jcb.24306
26. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010; 17: CD006654; PMID: 20238348
27. Xie HR, Hu LS, Li GY. SH-SY5Y human neuroblastoma cell line: In vitro cell model of dopaminergic neurons in Parkinson's disease. Chin Med J (Engl) 2010; 123: 1086-92; PMID: 20497720
28. Lee JG, Cho HY, Park SW, Seo MK, Kim YH. Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1001-6; PMID: 20546816; http://dx.doi.org/10.1016/j.pnpbp.2010.05.013
29. Lu XH, Bradley RJ, Dwyer DS. Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. Brain Res 2004; 1011: 58-68; PMID: 15140644; http://dx.doi.org/10.1016/j. brainres. 2004.03.018
30. Klionsky DJ, Elazar Z, Seglen PO, Rubinsztein DC. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 2008; 4: 849-950; PMID: 18758232; http://dx.doi.org/10.4161/auto.6845
31. Niizuma K, Endo H, Chan PH. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 2009; 109 Suppl 1: 133-8; PMID: 19393019; http://dx.doi.org/10.1111/j.1471-4159.2009.05897.x
32. Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med 2007; 43: 4-15; PMID: 17561088; http://dx.doi.org/10.1016/j. freeradbiomed.2007.03.024
33. Cameron JM, Levandovskiy V, Mackay N, Ackerley C, Chitayat D, Raiman J, Halliday WH, Schulze A, Robinson BH. Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. Mitochondrion 2011; 11: 191-9; PMID: 20920610; http://dx. doi.org/10.1016/j.mito.2010.09.008
34. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007; 131: 1149-63; PMID: 18083104; http://dx.doi. org/10.1016/j.cell.2007.10.035
35. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjørkøy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007; 282: 24131-45; PMID: 17580304; http://dx.doi.org/10.1074/jbc. M702824200
36. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12: 119-31; PMID: 20098416; http://dx.doi.org/10.1038/ncb2012
37. Dodson M, Liang Q, Johnson MS, Redmann M, Fineberg N, Darley-Usmar VM, Zhang J. Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells. Autophagy 2013; 9: 1996-2008; PMID: 24145463; http://dx.doi.org/10.4161/auto.26094
38. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, Ong CN, Codogno P, Shen HM. Dual role of 3- methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010; 285: 10850-61; PMID: 20123989; http://dx.doi.org/10.1074/jbc.M109.080796
39. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010; 140: 313- 26; PMID: 20144757; http://dx.doi.org/10.1016/j. cell.2010.01.028
40. Janjetovic K, Misirkic M, Vucicevic L, Harhaji L, Trajkovic V. Synergistic antiglioma action of hyperthermia and nitric oxide. Eur J Pharmacol 2008; 583: 1-10; PMID: 18262519; http; http://dx.doi.org/10.1016/j. ejphar.2007.12.028
41. Sarkar S, Korolchuk VI, Renna M, Imarisio S, Fleming A, Williams A, Garcia-Arencibia M, Rose C, Luo S, Underwood BR, et al. Complex inhibitory effects of nitric oxide on autophagy. Mol Cell 2011; 43: 19-32; PMID: 21726807; http://dx.doi.org/10.1016/j. molcel.2011.04.029
42. Glaumann H, Ahlberg J. Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity-formation of crinosomes. Exp Mol Pathol 1987; 47: 346-62; PMID: 3678466; http://dx.doi.org/10.1016/0014- 4800(87)90018-9
43. Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: A double-edged sword of autophagy. Cancer Res 2013; 73: 3-7; PMID: 23288916; http://dx.doi.org/10.1158/0008- 5472.CAN-12-2464
44. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012; 8: 445-544; PMID: 22966490; http://dx.doi.org/10.4161/auto.19496
45. Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, Kimura M, Sato S, Hattori N, Komatsu M, et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 2010; 15: 887-900; PMID: 20604804
46. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 2010; 6: 1090-106; PMID: 20890124; http://dx.doi.org/10.4161/auto. 6.8.13426
47. Elmore SP, Qian T, Grissom SF, Lemasters JJ. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001; 15: 2286-7; PMID: 11511528
48. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010; 189: 211-21; PMID: 20404107; http://dx.doi.org/10.1083/jcb.200910140
49. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183: 795-803; PMID: 19029340; http://dx.doi.org/10.1083/jcb.200809125
50. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8: E1000298; PMID: 20126261; http://dx.doi.org/10.1371/journal. pbio.1000298
51. Hroudova J, Fisar Z. Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuro Endocrinol Lett 2010; 31: 336-42; PMID: 20588251
52. Streck EL, Rezin GT, Barbosa LM, Assis LC, Grandi E, Quevedo J. Effect of antipsychotics on succinate dehydrogenase and cytochrome oxidase activities in rat brain. Naunyn Schmiedebergs Arch Pharmacol 2007; 376: 127-33; PMID: 17673979; http://dx.doi.org/10.1007/s00210-007-0178-2
53. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: An update and review. Biochim Biophys Acta 2006; 1757: 509-17; PMID: 16829228; http://dx.doi.org/10.1016/j.bbabio. 2006.04.029
54. Tinari A, Garofalo T, Sorice M, Esposti MD, Malorni W. Mitoptosis: Different pathways for mitochondrial execution. Autophagy 2007; 3: 282-4; PMID: 17329965; http://dx.doi.org/10.4161/auto.3924
55. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67-93; PMID: 19653858; http://dx.doi.org/10.1146/annurev-genet-102808-114910
56. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40: 280-93; PMID: 20965422; http://dx.doi.org/10.1016/j. molcel.2010.09.023
57. Cai Z, Zhao B, Li K, Zhang L, Li C, Quazi SH, Tan Y. Mammalian target of rapamycin: A valid therapeutic target through the autophagy pathway for Alzheimer's disease? J Neurosci Res 2012; 90: 1105-18; PMID: 22344941; http://dx.doi.org/10.1002/jnr.23011
58. Schmidt RH, Jokinen JD, Massey VL, Falkner KC, Shi X, Yin X, Zhang X, Beier JI, Arteel GE. Olanzapine activates hepatic mammalian target of rapamycin: New mechanistic insight into metabolic dysregulation with atypical antipsychotic drugs. J Pharmacol Exp Ther 2013; 347: 126-35; PMID: 23926289; http://dx.doi. org/10.1124/jpet.113.207621
59. Aucello M, Dobrowolny G, Musaro A. Localized accumulation of oxidative stress causes muscle atrophy through activation of an autophagic pathway. Autophagy 2009; 5: 527-9; PMID: 19221466; http://dx.doi. org/10.4161/auto.5.4.7962
60. Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE. FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem 2011; 286: 7468-78; PMID: 21159781; http://dx.doi.org/10.1074/jbc.M110.179242
61. Zhao Y,Wang L, Yang J, Zhang P, Ma K, Zhou J, Liao W, Zhu WG. Anti-neoplastic activity of the cytosolic FoxO1 results from autophagic cell death. Autophagy 2010; 6: 988-90; PMID: 20798610; http://dx.doi.org/10.4161/auto.6.7.13289
62. Luo Y, Zou P, Zou J, Wang J, Zhou D, Liu L. Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKalpha dependent manner. Exp Gerontol 2011; 46: 860-7; PMID: 21816217; http://dx.doi. org/10.1016/j.exger.2011.07.005
63. Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum. J Biol Chem 2008; 283: 15370-80; PMID: 18356160; http://dx.doi.org/10.1074/jbc.M710209200
64. Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J, Ambrosio S. Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 2003; 73: 341-50; PMID: 12868068; http://dx.doi.org/10.1002/jnr.10663
65. Gimenez-Xavier P, Francisco R, Santidrian AF, Gil J, Ambrosio S. Effects of dopamine on LC3-II activation as a marker of autophagy in a neuroblastoma cell model. Neurotoxicology 2009; 30: 658-65; PMID: 19410601; http://dx.doi.org/10.1016/j.neuro. 2009.04.007
66. Kim JS, He L, Lemasters JJ. Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 2003; 304: 463-70; PMID: 12729580; http://dx.doi.org/10.1016/S0006-291X(03)00618-1
67. Dwyer DS, Lu XH, Bradley RJ. Cytotoxicity of conventional and atypical antipsychotic drugs in relation to glucose metabolism. Brain Res 2003; 971: 31-9; PMID: 12691834; http://dx.doi.org/10.1016/S0006- 8993(03)02351-5
68. Heiser P, Enning F, Krieg JC, Vedder H. Effects of haloperidol, clozapine and olanzapine on the survival of human neuronal and immune cells in vitro. J Psychopharmacol 2007; 21: 851-6; PMID: 17881431; http://dx.doi.org/10.1177/0269881107077221
69. Wei Z, Bai O, Richardson JS, Mousseau DD, Li XM. Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide. J Neurosci Res 2003; 73: 364-8; PMID: 12868070; http://dx.doi.org/10.1002/jnr.10668
70. Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier- Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 2007; 129: 983-97; PMID: 17540177; http://dx.doi.org/10.1016/j. cell.2007.03.045
71. Tait SW, Parsons MJ, Llambi F, Bouchier-Hayes L, Connell S, Munoz-Pinedo C, Green DR. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev Cell 2010; 18: 802-13; PMID: 20493813; http://dx.doi.org/10.1016/j. devcel.2010.03.014
72. Batlevi Y, La Spada AR. Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiol Dis 2011; 43: 46-51; PMID: 20887789; http://dx.doi.org/10.1016/j. nbd.2010.09.009
73. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 2011; 333: 1109-12; PMID: 21868666; http://dx.doi.org/10.1126/science.1201940
74. Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SS, Strasser A, Cregan SP. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci 2007; 27: 12989-99; PMID: 18032672; http://dx.doi.org/10.1523/JNEUROSCI.3400-07.2007
75. Kim J,Wong PK. Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. Stem Cells 2009; 27: 1987-98; PMID: 19544430; http://dx.doi.org/10.1002/stem.125
76. Lu TH, Hsieh SY, Yen CC, Wu HC, Chen KL, Hung DZ, Chen CH, Wu CC, Su YC, Chen YW, et al. Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury. Toxicol Lett 2011; 204: 71-80; PMID: 21549813; http://dx.doi.org/10.1016/j. toxlet.2011.04.013
77. Blaise GA, Gauvin D, Gangal M, Authier S. Nitric oxide, cell signaling and cell death. Toxicology 2005; 208: 177-92; PMID: 15691583; http://dx.doi.org/10.1016/j.tox.2004.11.032
78. Bernstein HG, Keilhoff G, Steiner J, Dobrowolny H, Bogerts B. Nitric oxide and schizophrenia: Present knowledge and emerging concepts of therapy. CNS Neurol Disord Drug Targets 2011; 10: 792-807; PMID: 21999729; http://dx.doi.org/10.2174/187152711798072392
79. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez- Murillo R. Nitric oxide: Target for therapeutic strategies in Alzheimer's disease. Curr Pharm Des 2010; 16: 2837-50; PMID: 20698819; http://dx.doi.org/10.2174/138161210793176590
80. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013; 19: 983-97; PMID: 23921753; http://dx.doi.org/10.1038/nm.3232
81. Kaludjerovic GN, Miljkovic D, Momcilovic M, Djinovic VM, Mostarica Stojkovic M, Sabo TJ, Trajkovic V. Novel platinum(IV) complexes induce rapid tumor cell death in vitro. Int J Cancer 2005; 116: 479-86; PMID: 15818622; http://dx.doi.org/10.1002/ijc.21080
82. Vucicevic L, Misirkic M, Janjetovic K, Vilimanovich U, Sudar E, Isenovic E, Prica M, Harhaji-Trajkovic L, Kravic-Stevovic T, et al. Compound C induces protective autophagy in cancer cells through AMPK inhibition- independent blockade of Akt/mTOR pathway. Autophagy 2011; 7: 40-50; PMID: 20980833; http://dx.doi.org/10.4161/auto.7.1.13883
83. Lucocq JM, Hacker C. Cutting a fine figure: On the use of thin sections in electron microscopy to quantify autophagy. Autophagy 2013; 9: 1443-8; PMID: 23881027; http://dx.doi.org/10.4161/auto.25570