Pyrethroid exposure and neurotoxicity: a mechanistic approach

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Pyrethroids are a class of synthetic insecticides that are used widely in and around households to control the pest. Concerns about exposure to this group of pesticides are now mainly related to their neurotoxicity and nigrostriatal dopaminergic neurodegeneration seen in Parkinson’s disease. The main neurotoxic mechanisms include oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The main neurodegeneration targets are ion channels. However, other receptors, enzymes, and several signalling pathways can also participate in disorders induced by pyrethroids. The aim of this review is to elucidate the main mechanisms involved in neurotoxicity caused by pyrethroids deltamethrin, permethrin, and cypermethrin. We also review common targets and pathways of Parkinson’s disease therapy, including Nrf2, Nurr1, and PPARγ, and how they are affected by exposure to pyrethroids. We conclude with possibilities to be addressed by future research of novel methods of protection against neurological disorders caused by pesticides that may also find their use in the management/treatment of Parkinson’s disease.

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  • 1. Parrón T Requena M Hernández AF Alarcón R. Association between environmental exposure to pesticides and neurodegenerative diseases. Toxicol Appl Pharmacol 2011;256:379–85. doi: 10.1016/j.taap.2011.05.006

  • 2. Dardiotis E Xiromerisiou G Hadjichristodoulou C Tsatsakis AM Wilks MF Hadjigeorgiou GM. The interplay between environmental and genetic factors in Parkinson’s disease susceptibility: the evidence for pesticides. Toxicology 2013;307:17–23. doi: 10.1016/j.tox.2012.12.016

  • 3. Sanchez-Santed F Colomina MT Hernández EH. Organophosphate pesticide exposure and neurodegeneration. Cortex 2016;74:417–26. doi: 10.1016/j.cortex.2015.10.003

  • 4. Mostafalou S Abdollahi M. Pesticides and human chronic diseases: evidences mechanisms and perspectives. Toxicol Appl Pharmacol 2013;268:157–77. doi: 10.1016/j.taap.2013.01.025

  • 5. Brown RC Lockwood AH Sonawane BR. Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 2005;113:1250–6. doi: 10.1289/ehp.7567

  • 6. Baltazar MT Dinis-Oliveira RJ de Lourdes Bastos M Tsatsakis AM Duarte JA Carvalho F. Pesticides exposure as etiological factors of Parkinson’s disease and other neurodegenerative diseases – a mechanistic approach. Toxicol Lett 2014;230:85–103. doi: 10.1016/j.toxlet.2014.01.039

  • 7. Johnson ME Bobrovskaya L. An update on the rotenone models of Parkinson’s disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. Neurotoxicology 2015;46:101–6. doi: 10.1016/j.neuro.2014.12.002

  • 8. Kumar A Leinisch F Kadiiska MB Corbett J Mason RP. Formation and implications of alpha-synuclein radical in Maneb- and paraquat-induced models of Parkinson’s disease. Mol Neurobiol 2016;53:2983–94. doi: 10.1007/s12035-015-9179-1

  • 9. Paul KC Sinsheimer JS Cockburn M Bronstein JM Bordelon Y Ritz B. Organophosphate pesticides and PON1 L55M in Parkinson’s disease progression. Environ Int 2017;107:75–81. doi: 10.1016/j.envint.2017.06.018

  • 10. Meissner WG Frasier M Gasser T Goetz CG Lozano A Piccini P Obeso JA Rascol O Schapira A Voon V Weiner DM Tison F Bezard E. Priorities in Parkinson’s disease research. Nature Rev Drug Discovery 2011;10:377–93. doi: 10.1038/nrd3430

  • 11. Recasens A Dehay B Bové J Carballo-Carbajal I Dovero S Pérez-Villalba A Fernagut PO Blesa J Parent A Perier C Fariñas I Obeso JA Bezard E Vila M. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014;75:351–62. doi: 10.1002/ana.24066

  • 12. Franco R Sánchez-Olea R Reyes-Reyes EM Panayiotidis MI. Environmental toxicity oxidative stress and apoptosis: menage a trois. Mutat Res 2009;674:3–22. doi: 10.1016/j.mrgentox.2008.11.012

  • 13. Furlong MA Barr DB Wolff MS Engel SM. Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning. Neurotoxicology 2017;62:231–8. doi: 10.1016/j.neuro.2017.08.005

  • 14. Costa LG. The neurotoxicity of organochlorine and pyrethroid pesticides. In: Handbook of clinical neurology. Vol. 131. Chapter 9. Amsterdam: Elsevier; 2015. p. 135–48. doi: 10.1016/B978-0-444-62627-1.00009-3

  • 15. Gasmi S Rouabhi R Kebieche M Boussekine S Salmi A Toualbia N Taib C Bouteraa Z Chenikher H Henine S Djabri B. Effects of Deltamethrin on striatum and hippocampus mitochondrial integrity and the protective role of Quercetin in rats. Environ Sci Pollut Res Int 2017;24:16440–57. doi: 10.1007/s11356-017-9218-8

  • 16. Saoudi M Badraoui R Bouhajja H Ncir M Rahmouni F Grati M Jamoussi K Feki AE. Deltamethrin induced oxidative stress in kidney and brain of rats: Protective effect of Artemisia campestris essential oil. Biomed Pharmacother 2017;94:955–63. doi: 10.1016/j.biopha.2017.08.030

  • 17. Khan AM Raina R Dubey N Verma PK. Effect of deltamethrin and fluoride co-exposure on the brain antioxidant status and cholinesterase activity in Wistar rats. Drug Chem Toxicol 2018;41:123–7. doi: 10.1080/01480545.2017.1321009

  • 18. Hussien HM Abdou HM Yousef MI. Cypermethrin induced damage in genomic DNA and histopathological changes in brain and haematotoxicity in rats: the protective effect of sesame oil. Brain Res Bull 2013;92:76–83. doi: 10.1016/j.brainresbull.2011.10.020

  • 19. Singh A Tripathi P Prakash O Singh MP. Ibuprofen abates cypermethrin-induced expression of pro-inflammatory mediators and mitogen-activated protein kinases and averts the nigrostriatal dopaminergic neurodegeneration. Mol Neurobiol 2016;53:6849–58. doi: 10.1007/s12035-015-9577-4

  • 20. Agrawal S Singh A Tripathi P Mishra M Singh PK Singh MP. Cypermethrin-induced nigrostriatal dopaminergic neurodegeneration alters the mitochondrial function: a proteomics study. Mol Neurobiol 2015;51:448–65. doi: 10.1007/s12035-014-8696-7

  • 21. Agrawal S Dixit A Singh A Tripathi P Singh D Patel DK Singh MP. Cyclosporine A and MnTMPyP alleviate α-synuclein expression and aggregation in cypermethrin-induced Parkinsonism. Mol Neurobiol 2015;52:1619–28. doi: 10.1007/s12035-014-8954-8

  • 22. Nasuti C Brunori G Eusepi P Marinelli L Ciccocioppo R Gabbianelli R. Early life exposure to permethrin: a progressive animal model of Parkinson’s disease. J Pharmacol Toxicol Methods 2017;83:80–6. doi: 10.1016/j.vascn.2016.10.003

  • 23. Nasuti C Carloni M Fedeli D Gabbianelli R Di Stefano A Serafina CL Silva I Domingues V Ciccocioppo R. Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of presenescent rats. Toxicology 2013;303:162–8. doi: 10.1016/j.tox.2012.09.016

  • 24. Carloni M Nasuti C Fedeli D Montani M Amici A Vadhana MD Gabbianelli R. The impact of early life permethrin exposure on development of neurodegeneration in adulthood. Exp Gerontol 2012;47:60–6. doi: 10.1016/j.exger.2011.10.006

  • 25. Galal MK Khalaf AAA Ogaly HA Ibrahim MA. Vitamin E attenuates neurotoxicity induced by deltamethrin in rats. BMC Complementary Altern Med 2014;14:458. doi: 10.1186/1472-6882-14-458

  • 26. Tripathi P Singh A Agrawal S Prakash O Singh MP. Cypermethrin alters the status of oxidative stress in the peripheral blood: relevance to Parkinsonism. J Physiol Biochem 2014;70:915–24. doi: 10.1007/s13105-014-0359-7

  • 27. Al-Afifi SH Amani EY Abd Alaazem KM. Protective effect of garlic extract against deltamethrin induced oxidative stress in rats. Anim Health Res J 2017;5:67–80

  • 28. Carloni M Nasuti C Fedeli D Montani M Vadhana MD Amici A Gabbianelli R. Early life permethrin exposure induces long-term brain changes in Nurr1 NF-κB and Nrf-2. Brain Res 2013;1515:19–28. doi: 10.1016/j.brainres.2013.03.048

  • 29. Khalatbary AR Ghaffari E Mohammadnegad B. Protective role of oleuropein against acute deltamethrin-induced neurotoxicity in rat brain. Iran Biom J 2015;19:247. doi: 10.7508/ibj.2015.04.009

  • 30. Arslan H Özdemir S Altun S. Cypermethrin toxication leads to histopathological lesions and induces inflammation and apoptosis in common carp (Cyprinus carpio L.). Chemosphere 2017;180:491–9. doi: 10.1016/j.chemosphere.2017.04.057

  • 31. Abdelhafidh K Mhadhbi L Mezni A Badreddine S Beyrem H Mahmoudi E. Protective effect of Zizyphus lotus jujube fruits against cypermethrin-induced oxidative stress and neurotoxicity in mice. Biomarkers 2017;23:167–73. doi: 10.1080/1354750X.2017.1390609

  • 32. Mishra AK Mishra S Rajput C Ur Rasheed MS Patel DK Singh MP. Cypermethrin activates autophagosome formation albeit inhibits autophagy owing to poor lysosome quality: relevance to Parkinson’s disease. Neurotox Res 2018;33:377–87. doi: 10.1007/s12640-017-9800-3

  • 33. Sharma P Firdous S Singh R. Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats. Int J Nutr Pharmacol Neurol Dis 2014;4:104–11. doi: 10.4103/2231-0738.129598

  • 34. Kung TS Richardson JR Cooper KR White LA. Developmental deltamethrin exposure causes persistent changes in dopaminergic gene expression neurochemistry and locomotor activity in zebrafish. Toxicol Sci 2015;146:235–43. doi: 10.1093/toxsci/kfv087

  • 35. Guo J Xu J Zhang J An L. Alteration of mice cerebral cortex development after prenatal exposure to cypermethrin and deltamethrin. Toxicol Lett 2018;287:1–9. doi: 10.1016/j.toxlet.2018.01.019

  • 36. Nasuti C Falcioni ML Nwankwo IE Cantalamessa F Gabbianelli R. Effect of permethrin plus antioxidants on locomotor activity and striatum in adolescent rats. Toxicology 2008;251:45–50. doi: 10.1016/j.tox.2008.07.049

  • 37. Romero A Ramos E Castellano V Martínez MA Ares I Martínez M Martínez-Larrañaga MR Anadón A. Cytotoxicity induced by deltamethrin and its metabolites in SH-SY5Y cells can be differentially prevented by selected antioxidants. Toxicol in Vitro 2012;26:823–30. doi: 10.1016/j.tiv.2012.05.004

  • 38. Li H-Y Wu S-Y Shi N. Transcription factor Nrf2 activation by deltamethrin in PC12 cells: involvement of ROS. Toxicol Lett 2007;171:87–98. doi: 10.1016/j.toxlet.2007.04.007

  • 39. Ko J Park JH Park YS Koh HC. PPAR-γ activation attenuates deltamethrin-induced apoptosis by regulating cytosolic PINK1 and inhibiting mitochondrial dysfunction. Toxicol Lett 2016;260:8–17. doi: 10.1016/j.toxlet.2016.08.016

  • 40. Park YS Park JH Ko J Shin IC Koh HC. mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 cells. Environ Toxicol 2017;32:109–21. doi: 10.1002/tox.22216

  • 41. Bordoni L Fedeli D Nasuti C Capitani M Fiorini D Gabbianelli R. Permethrin pesticide induces NURR1 up-regulation in dopaminergic cell line: Is the pro-oxidant effect involved in toxicant-neuronal damage? Comp Biochem Physiol C 2017;201:51–7. doi: 10.1016/j.cbpc.2017.09.006

  • 42. Raszewski G Lemieszek MK Łukawski K. Cytotoxicity induced by cypermethrin in Human Neuroblastoma Cell Line SH-SY5Y. Ann Agric Environ Med 2016;23:106–10. doi: 10.5604/12321966.1196863

  • 43. Romero A Ramos E Ares I Castellano V Martínez M Martínez-Larrañaga M-R Anadón A Martínez MA. Oxidative stress and gene expression profiling of cell death pathways in alpha-cypermethrin-treated SH-SY5Y cells. Arch Toxicol 2017;91:2151–64. doi: 10.1007/s00204-016-1864-y

  • 44. Pandey A Jauhari A Singh T Singh P Singh N Srivastava AK Khan F Pant AB Parmar D Yadav S. Transactivation of P53 by cypermethrin induced miR-200 and apoptosis in neuronal cells. Toxicol Res 2015;4:1578–86. doi: 10.1039/C5TX00200A

  • 45. Raszewski G Lemieszek MK Łukawski K Juszczak M Rzeski W. Chlorpyrifos and cypermethrin induce apoptosis in human neuroblastoma cell line SH-SY5Y. Basic Clin Pharmacol Toxicol 2015;116:158–67. doi: 10.1111/bcpt.12285

  • 46. Liu G-P Shi N. The inhibitory effects of deltamethrin on dopamine biosynthesis in rat PC12 cells. Toxicol Lett 2006;161:195–9. doi: 10.1016/j.toxlet.2005.09.011

  • 47. Clark JM Symington SB. Advances in the mode of action of pyrethroids. Top Curr Chem 2012;314:49–72. doi: 10.1007/128_2011_268

  • 48. Breckenridge CB Holden L Sturgess N Weiner M Sheets L Sargent D Soderlund DM Choi JS Symington S Clark JM Burr S Ray D. Evidence for a separate mechanism of toxicity for the Type I and the Type II pyrethroid insecticides. Neurotoxicology 2009;30(Suppl 1):S17–31. doi: 10.1016/j.neuro.2009.09.002

  • 49. Taylor-Wells J Brooke BD Bermudez I Jones AK. The neonicotinoid imidacloprid and the pyrethroid deltamethrin are antagonists of the insect Rdl GABA receptor. J Neurochem 2015;135:705–13. doi: 10.1111/jnc.13290

  • 50. Kumar Singh A Nath Tiwari M Prakash O Pratap Singh M. A current review of cypermethrin-induced neurotoxicity and nigrostriatal dopaminergic neurodegeneration. Curr Neuropharmacol 2012;10:64–71. doi: 10.2174/157015912799362779

  • 51. Ogaly HA Khalaf A Ibrahim MA Galal MK Abd-Elsalam RM. Influence of green tea extract on oxidative damage and apoptosis induced by deltamethrin in rat brain. Neurotoxicol Teratol 2015;50:23–31. doi: 10.1016/

  • 52. Nieradko-Iwanicka B Borzęcki A. Subacute poisoning of mice with deltamethrin produces memory impairment reduced locomotor activity liver damage and changes in blood morphology in the mechanism of oxidative stress. Pharmacol Rep 2015;67:535–41. doi: 10.1016/j.pharep.2014.12.012

  • 53. Mani VM Sadiq AMM. Naringin modulates the impairment of memory anxiety locomotor and emotionality behaviors in rats exposed to deltamethrin; a possible mechanism association with oxidative stress acetylcholinesterase and ATPase. Biomed Prev Nutr 2014;4:527–33. doi: 10.1016/j.bionut.2014.08.006

  • 54. Mani VM Asha S Sadiq AMM. Pyrethroid deltamethrin-induced developmental neurodegenerative cerebral injury and ameliorating effect of dietary glycoside naringin in male wistar rats. Biomed Aging Pathol 2014;4:1–8. doi: 10.1016/j.biomag.2013.11.001

  • 55. Khan AM Sultana M Raina R Dubey N Verma PK. Effect of sub-acute oral exposure of bifenthrin on biochemical parameters in crossbred goats. Proc Natl Acad Sci India Sec B Biol Sci 2013;83:323–8. doi: 10.1007/s40011-012-0150-x

  • 56. Starr JM Scollon EJ Hughes MF Ross DG Graham SE Crofton KM Wolansky MJ Devito MJ Tornero-Velez R. Environmentally relevant mixtures in cumulative assessments: an acute study of toxicokinetics and effects on motor activity in rats exposed to a mixture of pyrethroids. Toxicol Sci 2012;130:309–18. doi: 10.1093/toxsci/kfs245

  • 57. Ray DE Fry JR. A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacol Therap 2006;111:174–93. doi: 10.1016/j.pharmthera.2005.10.003

  • 58. Singh AK Tiwari MN Upadhyay G Patel DK Singh D Prakash O Singh MP. Long term exposure to cypermethrin induces nigrostriatal dopaminergic neurodegeneration in adult rats: postnatal exposure enhances the susceptibility during adulthood. Neurobiol Aging 2012;33:404–15. doi: 10.1016/j.neurobiolaging.2010.02.018

  • 59. Singh AK Tiwari MN Dixit A Upadhyay G Patel DK Singh D Prakash O Singh MP. Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: microglial activation-dependent and-independent regulations. Toxicol Sci 2011;122:526–38. doi: 10.1093/toxsci/kfr115

  • 60. Fedeli D Montani M Bordoni L Galeazzi R Nasuti C Correia-Sá L Domingues VF Jayant M Brahmachari V Massaccesi L Laudadio E Gabbianelli R. In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats. Neuroscience 2017;340:411–23. doi: 10.1016/j.neuroscience.2016.10.071

  • 61. Darney K Bodin L Bouchard M Côté J Volatier J-L Desvignes V. Aggregate exposure of the adult French population to pyrethroids. Toxicol Appl Pharmacol 2018;351:21–31. doi: 10.1016/j.taap.2018.05.007

  • 62. dos Santos Oliveira L da Silva LP da Silva AI Magalhães CP de Souza SL de Castro RM. Effects of early weaning on the circadian rhythm and behavioral satiety sequence in rats. Behav Processes 2011;86:119–24. doi: 10.1016/j.beproc.2010.10.001

  • 63. Vaiserman A. Early-life origin of adult disease: evidence from natural experiments. Exp Gerontol 2011;46:189–92. doi: 10.1016/j.exger.2010.08.031

  • 64. Nasuti C Gabbianelli R Falcioni ML Di Stefano A Sozio P Cantalamessa F. Dopaminergic system modulation behavioral changes and oxidative stress after neonatal administration of pyrethroids. Toxicology 2007;229:194–205. doi: 10.1016/j.tox.2006.10.015

  • 65. Falcioni M Nasuti C Bergamini C Fato R Lenaz G Gabbianelli R. The primary role of glutathione against nuclear DNA damage of striatum induced by permethrin in rats. Neuroscience 2010;168:2–10. doi: 10.1016/j.neuroscience.2010.03.053

  • 66. Nagatsu T Sawada M. Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects. J Neural Transm 2007(Suppl 72):113–20. doi: 10.1007/978-3-211-73574-9_14

  • 67. Fedeli D Montani M Nasuti C Gabbianelli R. Early life permethrin treatment induces in striatum of older rats changes in α-synuclein content. J Nutrigenet Nutrigenom 2014;7:75–93.

  • 68. Vences-Mejía A Gómez-Garduño J Caballero-Ortega H Dorado-González V Nosti-Palacios R Labra-Ruíz N Espinosa-Aguirre JJ. Effect of mosquito mats (pyrethroid-based) vapor inhalation on rat brain cytochrome P450s. Toxicol Mech Methods 2012;22:41–6. doi: 10.3109/15376516.2011.591448

  • 69. García-Suástegui W Ramos-Chávez L Rubio-Osornio M Calvillo-Velasco M Atzin-Méndez J Guevara J Silva-Adaya D. The role of CYP2E1 in the drug metabolism or bioactivation in the brain. Oxid Med Cell Longev 2017;2017:4680732. doi: 10.1155/2017/4680732

  • 70. Singh A Mudawal A Maurya P Jain R Nair S Shukla RK Yadav S Singh D Khanna VK Chaturvedi RK Mudiam MKR Sethumadhavan R Siddiqi MI Parmar D. Prenatal exposure of cypermethrin induces similar alterations in xenobiotic-metabolizing cytochrome P450s and rate-limiting enzymes of neurotransmitter synthesis in brain regions of rat offsprings during postnatal development. Mol Neurobiol 2016;53:3670–89. doi: 10.1007/s12035-015-9307-y

  • 71. Singh A Mudawal A Shukla RK Yadav S Khanna VK Sethumadhavan R Parmar D. Effect of gestational exposure of cypermethrin on postnatal development of brain cytochrome P450 2D1 and 3A1 and neurotransmitter receptors. Mol Neurobiol 2015;52:741–56. doi: 10.1007/s12035-014-8903-6

  • 72. Rangel-Barajas C Coronel I Florán B. Dopamine receptors and neurodegeneration. Aging Dis 2015;6:349. doi: 10.14336/AD.2015.0330

  • 73. Shahabi HN Andersson D Nissbrandt H. Cytochrome P450 2E1 in the substantia nigra: relevance for dopaminergic neurotransmission and free radical production. Synapse 2008;62:379–88. doi: 10.1002/syn.20505

  • 74. Lukaszewicz-Hussain A. Role of oxidative stress in organophosphate insecticide toxicity – Short review. Pestic Biochem Physiol 2010;98:145–50. doi: 10.1016/j.pestbp.2010.07.006

  • 75. Li H Wu S Ma Q Shi N. The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain. Toxicol Ind Health 2011;27:579–90. doi: 10.1177/0748233710393400

  • 76. Amin KA Hashem KS. Deltamethrin-induced oxidative stress and biochemical changes in tissues and blood of catfish (Clarias gariepinus): antioxidant defense and role of alpha-tocopherol. BMC Vet Res 2012;8:45. doi: 10.1186/1746-6148-8-45

  • 77. Vakifahmetoglu-Norberg H Ouchida AT Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun 2017;482:426–31. doi: 10.1016/j.bbrc.2016.11.088

  • 78. Giray B Gürbay A Hincal F. Cypermethrin-induced oxidative stress in rat brain and liver is prevented by Vitamin E or allopurinol. Toxicol Lett 2001;118:139–46. doi: 10.1016/S0378-4274(00)00277-0

  • 79. Kanbur M Siliğ Y Eraslan G Karabacak M Sarıca ZS Şahin S. The toxic effect of cypermethrin amitraz and combinations of cypermethrin-amitraz in rats. Environ Sci Pollut Res Int 2016;23:5232–42. doi: 10.1007/s11356-015-5720-z

  • 80. Takahashi M Komada M Miyazawa K Goto S Ikeda Y. Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus. Toxicol Lett 2018;284:113–9. doi: 10.1016/j.toxlet.2017.12.010

  • 81. Long-Smith CM Sullivan AM Nolan YM. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol 2009;89:277–87. doi: 10.1016/j.pneurobio.2009.08.001

  • 82. Edison P Ahmed I Fan Z Hinz R Gelosa G Ray Chaudhuri K Walker Z Turkheimer FE Brooks DJ. Microglia amyloid and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology 2013;38:938-49. doi: 10.1038/npp.2012.255

  • 83. Purisai MG McCormack AL Cumine S Li J Isla MZ Di Monte DA. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 2007;25:392–400. doi: 10.1016/j.nbd.2006.10.008

  • 84. Prasad S Ravindran J Aggarwal BB. NF-κB and cancer: how intimate is this relationship. Mol Cell Biochem 2010;336:25–37. doi: 10.1007/s11010-009-0267-2

  • 85. Oeckinghaus A Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009;1:a000034. doi: 10.1101/cshperspect.a000034

  • 86. Shih R-H Wang C-Y Yang C-M. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 2015;8:77. doi: 10.3389/fnmol.2015.00077

  • 87. Tornatore L Thotakura AK Bennett J Moretti M Franzoso G. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol 2012;22:557–66. doi: 10.1016/j.tcb.2012.08.001

  • 88. Pacheco FJ Almaguel FG Evans W Rios-Colon L Filippov V Leoh LS Leoh LS Rook-Arena E Mediavilla-Varela M De Leon M Casiano CA. Docosahexanoic acid antagonizes TNF-α-induced necroptosis by attenuating oxidative stress ceramide production lysosomal dysfunction and autophagic features. Inflamm Res 2014;63:859–71. doi: 10.1007/s00011-014-0760-2

  • 89. Fedeli D Montani M Carloni M Nasuti C Amici A Gabbianelli R. Leukocyte Nurr1 as peripheral biomarker of early-life environmental exposure to permethrin insecticide. Biomarkers 2012; 17 : 604–9. doi : 10.3109/1354750X.2012.706641

  • 90. Tiwari MN Singh AK Agrawal S Gupta SP Jyoti A Shanker R Prakash O Singh MP. Cypermethrin alters the expression profile of mRNAs in the adult rat striatum: a putative mechanism of postnatal pre-exposure followed by adulthood re-exposure-enhanced neurodegeneration. Neurotox Res 2012;22:321–34. doi: 10.1007/s12640-012-9317-8

  • 91. Wai T Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 2016;27:105–17. doi: 10.1016/j.tem.2015.12.001

  • 92. Guo C Sun L Chen X Zhang D. Oxidative stress mitochondrial damage and neurodegenerative diseases. Neural Regen Res 2013;8:2003–14. doi: 10.3969/j.issn.1673-5374.2013.21.009

  • 93. de Moura MB dos Santos LS Van Houten B. Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 2010;51:391–405. doi: 10.1002/em.20575

  • 94. Golpich M Amini E Mohamed Z Azman Ali R Mohamed Ibrahim N Ahmadiani A. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment. CNS Neurosci Therap 2017;23:5–22. doi: 10.1111/cns.12655

  • 95. Imaizumi Y Okada Y Akamatsu W Koike M Kuzumaki N Hayakawa H Nihira T Kobayashi T Ohyama M Sato S Takanashi M Funayama M Hirayama A Soga T Hishiki T Suematsu M Yagi T Ito D Kosakai A Hayashi K Shouji M Nakanishi A Suzuki N Mizuno Y Mizushima N Amagai M Uchiyama Y Mochizuki H Hattori N Okano H. Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol Brain 2012;5:35. doi: 10.1186/1756-6606-5-35

  • 96. Chen X Li J Hou J Xie Z Yang F. Mammalian mitochondrial proteomics: insights into mitochondrial functions and mitochondria-related diseases. Expert Rev Proteomics 2010;7:333–45. doi: 10.1586/epr.10.22

  • 97. Wang F Dai A-Y Tao K Xiao Q Huang Z-L Gao M Li H Wang X Cao WX Feng WL. Heat shock protein-70 neutralizes apoptosis inducing factor in Bcr/Abl expressing cells. Cell Signal 2015;27:1949–55. doi: 10.1016/j.cellsig.2015.06.006

  • 98. Fontanesi F Soto IC Horn D Barrientos A. Assembly of mitochondrial cytochrome c-oxidase a complicated and highly regulated cellular process. Am J Physiol Cell Physiol 2006;291:C1129–47. doi: 10.1152/ajpcell.00233.2006

  • 99. In S Hong C-W Choi B Jang B-G Kim M-J. Inhibition of mitochondrial clearance and Cu/Zn-SOD activity enhance 6-hydroxydopamine-induced neuronal apoptosis. Mol Neurobiol 2016;53:777–91. doi: 10.1007/s12035-014-9087-9

  • 100. Venkateshappa C Harish G Mythri RB Mahadevan A Bharath MS Shankar S. Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson’s disease. Neurochem Res 2012;37:358–69. doi: 10.1007/s11064-011-0619-7

  • 101. Lee W Choi K-S Riddell J Ip C Ghosh D Park J-H Park J-M. Human peroxiredoxin 1 and 2 are not duplicate proteins. The unique presence of Cys83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2. J Biol Chem 2007;282:22011–22. doi: 10.1074/jbc.M610330200

  • 102. Pennington K Peng J Hung C-C Banks RE Robinson PA. Differential effects of wild-type and A53T mutant isoform of alpha-synuclein on the mitochondrial proteome of differentiated SH-SY5Y cells. J Proteome Res 2010;9:2390–401. doi: 10.1021/pr901102d

  • 103. Dixit A Srivastava G Verma D Mishra M Singh PK Prakash O Singh MP. Minocycline levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson’s disease. Biochim Biophys Acta 2013;1832:1227–40. doi: 10.1016/j.bbadis.2013.03.019

  • 104. Redza-Dutordoir M Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016;1863:2977–92. doi: 10.1016/j.bbamcr.2016.09.012

  • 105. Hennequin C Azria D Riou O Castan F Coelho M Nguyen T Peignaux K Lemanski C Lagrange J-L Kirova Y Lartigau E Belkacemi Y Bourgier C Noel G Clippe S Mornex F Kramar A Pèlegrin A Ozsahin M. Abstract P3-12-18: Radiation-induced CD8 T-lymphocyte apoptosis as a predictor of late toxicity after radiotherapy: Results of the prospective multicenter French trial. Cancer Res 2016;76(4 Suppl):P3-12–18. doi: 10.1158/1538-7445.SABCS15-P3-12-18

  • 106. Olcina M Leszczynska K Senra J Isa N Harada H Hammond E. H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK. Oncogene 2016;35:793. doi: 10.1038/onc.2015.134

  • 107. Liu Y Zeng X Hui Y Zhu C Wu J Taylor DH Ji J Fan W Huang Z Hu J. Activation of α7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson’s disease. Neuropharmacology 2015;91:87–96. doi: 10.1016/j.neuropharm.2014.11.028

  • 108. Wang Y Zhen Y Wu X Jiang Q Li X Chen Z Zhang G Dong L. Vitexin protects brain against ischemia/reperfusion injury via modulating mitogen-activated protein kinase and apoptosis signaling in mice. Phytomedicine 2015;22:379–84. doi: 10.1016/j.phymed.2015.01.009

  • 109. Cottini F Hideshima T Xu C Sattler M Dori M Agnelli L ten Hacken E Bertilaccio MT Antonini E Neri A Ponzoni M Marcatti M Richardson PG Carrasco R Kimmelman AC Wong KK Caligaris-Cappio F Blandino G Kuehl WM Anderson KC Tonon G. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nature Med 2014;20:599–606. doi: 10.1038/nm.3562

  • 110. Eum K-H Lee M. Crosstalk between autophagy and apoptosis in the regulation of paclitaxel-induced cell death in v-Ha-ras-transformed fibroblasts. Mol Cell Biochem 2011;348:61–8. doi: 10.1007/s11010-010-0638-8

  • 111. Fei Q McCormack AL Di Monte DA Ethell DW. Paraquat neurotoxicity is mediated by a Bak-dependent mechanism. J Biol Chem 2008;283:3357–64. doi: 10.1074/jbc.M708451200

  • 112. Hsu S-S Jan C-R Liang W-Z. The investigation of the pyrethroid insecticide lambda-cyhalothrin (LCT)-affected Ca2+ homeostasis and-activated Ca2+-associated mitochondrial apoptotic pathway in normal human astrocytes: The evaluation of protective effects of BAPTA-AM (a selective Ca2+ chelator). Neurotoxicology 2018;69:97–107. doi: 10.1016/j.neuro.2018.09.009

  • 113. Park JH Ko J Hwang J Koh HC. Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells. Neurotoxicology 2015;51:145–57. doi: 10.1016/j.neuro.2015.10.008

  • 114. El-Demerdash FM. Lipid peroxidation oxidative stress and acetylcholinesterase in rat brain exposed to organophosphate and pyrethroid insecticides. Food Chem Toxicol 2011;49:1346–52. doi: 10.1016/j.fct.2011.03.018

  • 115. Thornton C Hagberg H. Role of mitochondria in apoptotic and necroptotic cell death in the developing brain. Clin Chim Acta 2015;451:35–8. doi: 10.1016/j.cca.2015.01.026

  • 116. Martinez MM Reif RD Pappas D. Detection of apoptosis: A review of conventional and novel techniques. Anal Methods 2010;2:996–1004. doi: 10.1039/C0AY00247J

  • 117. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 2011;30:87. doi: 10.1186/1756-9966-30-87

  • 118. Li GY Xie P Li HY Hao L Xiong Q Qiu T. Involment of p53 Bax and Bcl-2 pathway in microcystins-induced apoptosis in rat testis. Environ Toxicol 2011;26:111–7. doi:

  • 119. Tung WH Lee IT Hsieh HL Yang CM. EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-κB in rat brain astrocytes. J Cell Physiol 2010;224:376–86. doi: 10.1002/jcp.22133

  • 120. Kumagai T Usami H Matsukawa N Nakashima F Chikazawa M Shibata T Noguchi N Uchida K. Functional interaction between cyclooxygenase-2 and p53 in response to an endogenous electrophile. Redox Biol 2015;4:74–86. doi: 10.1016/j.redox.2014.11.011

  • 121. Kim EK Choi E-J. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010;1802:396–405. doi: 10.1016/j.bbadis.2009.12.009

  • 122. Ray A Sehgal N Karunakaran S Rangarajan G Ravindranath V. MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model. Free Rad Biol Med 2015;87:312–25. doi: 10.1016/j.freeradbiomed.2015.06.041

  • 123. Ki Y-W Park JH Lee JE Shin IC Koh HC. JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis. Toxicol Lett 2013;218:235–45. doi: 10.1016/j.toxlet.2013.02.003

  • 124. Salminen A Kaarniranta K. Genetics vs. entropy: longevity factors suppress the NF-κB-driven entropic aging process. Ageing Res Rev 2010;9:298–314. doi: 1016/j.arr.2009.11.001

  • 125. Hybertson BM Gao B Bose SK McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Aspects Med 2011;32:234–46. doi: 10.1016/j.mam.2011.10.006

  • 126. Zhao X Wang R Xiong J Yan D Li A Wang S Xu J Zhou J. JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2. Toxicol Lett 2017;277:32–40. doi: 10.1016/j.toxlet.2017.04.011

  • 127. Deshmukh P Unni S Krishnappa G Padmanabhan B. The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev 2017;9:41–56. doi: 10.1007/s12551-016-0244-4

  • 128. Taguchi K Motohashi H Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011;16:123–40. doi: 10.1111/j.1365-2443.2010.01473.x

  • 129. Ai B Liu Y Shi N. The effects of deltamethrin on HO activity and HO-1 protein expression in rat brain. Acta Universitatis Medicinae Tongji 2000;29:236–8.

  • 130. Corona JC de Souza SC Duchen MR. PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1. Exp Neurol 2014;253:16–27. doi: 10.1016/j.expneurol.2013.12.012

  • 131. Schintu N Frau L Ibba M Caboni P Garau A Carboni E Carta AR. PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 2009;29:954–63. doi: 10.1111/j.1460-9568.2009.06657.x

  • 132. Lee EY Lee JE Park JH Shin IC Koh HC. Rosiglitazone a PPAR-γ agonist protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. Toxicol Lett 2012;213:332–44. doi: 10.1016/j.toxlet.2012.07.016

  • 133. Martin HL Mounsey RB Mustafa S Sathe K Teismann P. Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson’s disease. Exp Neurol 2012;235:528–38. doi: 10.1016/j.expneurol.2012.02.017

  • 134. Yang J Wu L-J Tashino S-I Onodera S Ikejima T. Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells. Free Radic Res 2008;42:492–504. doi: 10.1080/10715760802112791

  • 135. Srivastava A Kumar V Pandey A Jahan S Kumar D Rajpurohit C Singh S Khanna VK Pant AB. Adoptive autophagy activation: a much-needed remedy against chemical induced neurotoxicity/developmental neurotoxicity. Mol Neurobiol 2017;54:1797–807. doi: 10.1007/s12035-016-9778-5

  • 136. Wu Y Li X Zhu JX Xie W Le W Fan Z Jankovic J Pan T. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neurosignals 2011;19:163–74. doi: 10.1159/000328516

  • 137. Pan T Kondo S Le W Jankovic J. The role of autophagylysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 2008;131:1969–78. doi: 10.1093/brain/awm318

  • 138. Giordano S Darley-Usmar V Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol 2014;2:82–90. doi: 10.1016/j.redox.2013.12.013

  • 139. Hou Y-S Guan J-J Xu H-D Wu F Sheng R Qin Z-H. Sestrin2 protects dopaminergic cells against rotenone toxicity through AMPK-dependent autophagy activation. Mol Cell Biol 2015;35:2740–51. doi: 10.1128/MCB.00285-15

  • 140. Ghavami S Shojaei S Yeganeh B Ande SR Jangamreddy JR Mehrpour M Christoffersson J Chaabane W Moghadam AR Kashani HH Hashemi M Owji AA Łos MJ. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014;112:24–49. doi: 10.1016/j.pneurobio.2013.10.004

  • 141. Wu F Xu HD Guan JJ Hou YS Gu JH Zhen XC Qin Z. Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease. Neuroscience. 2015;284:900-11. doi: 10.1016/j.neuroscience.2014.11.004

  • 142. Wills J Credle J Oaks AW Duka V Lee J-H Jones J et al. Paraquat but not maneb induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PloS One 2012;7(1):e30745. doi: 10.1371/journal.pone.0030745

  • 143. Bordoni L Nasuti C Mirto M Caradonna F Gabbianelli R. Intergenerational effect of early life exposure to permethrin: Changes in global DNA methylation and in Nurr1 gene expression. Toxics 2015;3:451–61. doi: 10.3390/toxics3040451

  • 144. Decressac M Volakakis N Björklund A Perlmann T. NURR1 in Parkinson disease-from pathogenesis to therapeutic potential. Nat Rev Neurol 2013;9:629. doi: 10.1038/nrneurol.2013.209

  • 145. Le W Pan T Huang M Xu P Xie W Zhu W Zhang X Deng H Jankovic J. Decreased NURR1 gene expression in patients with Parkinson’s disease. J Neurol Sci 2008;273:29–33. doi: 10.1016/j.jns.2008.06.007

  • 146. Saijo K Winner B Carson CT Collier JG Boyer L Rosenfeld MG Gage FH Glass CK. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009;137:47–59. doi: 10.1016/j.cell.2009.01.038

  • 147. Devine MJ. Proteasomal inhibition as a treatment strategy for Parkinson’s disease: the impact of α-synuclein on Nurr1. J Neurosci 2012;32:16071–3. doi: 10.1523/JNEUROSCI.4224-12.2012

  • 148. Decressac M Kadkhodaei B Mattsson B Laguna A Perlmann T Björklund A. α-synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci Translat Med 2012;4(163):163ra56– ra56. doi: 10.1126/scitranslmed.3004676

  • 149. Dong J Li S Mo JL Cai HB Le WD. Nurr1-based therapies for Parkinson’s disease. CNS Neurosci Therap 2016;22:351–9. doi: 10.1111/cns.12536

  • 150. Bordoni L Nasuti C Mirto M Caradonna F Gabbianelli R. Intergenerational effect of early life exposure to permethrin: changes in global DNA methylation and in Nurr1 gene expression. Toxic 2015;3:451–61. doi: 10.3390/toxics3040451

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