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Pioglitazone Attenuates Lipopolysaccharide-Induced Oxidative Stress, Dopaminergic Neuronal Loss and Neurobehavioral Impairment by Activating Nrf2/ARE/HO-1

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Abstract

The aim of the present study was to examine the neuroprotective potential of pioglitazone via activation of Nrf2/ARE-dependent HO-1 signaling pathway in chronic neuroinflammation and progressive neurodegeneration mouse model induced by lipopolysaccharide (LPS). After assessing spatial memory, anxiety and motor-coordination, TH+ neurons in substantia nigra (SN) were counted. The oxidative stress marker carbonyl protein levels and HO-1 enzyme activity were also evaluated. RT-qPCR was conducted to detect HO-1, Nrf2 and NF-κp65 mRNA expression levels and Nrf2 transcriptional activation of antioxidant response element (ARE) of HO-1 was investigated. Pioglitazone ameliorated LPS-induced dopaminergic neuronal loss, as well as mitigated neurobehavioral impairments. It enhanced Nrf2 mRNA expression, and augmented Nrf2/ARE-dependent HO-1 pathway activation by amplifying HO-1 mRNA expression. Moreover, it induced a significant decrease in NF-κB p65 mRNA expression, while reducing carbonyl protein levels and restoring the HO-1 enzyme activity. Interestingly, LPS induced Nrf2/antioxidant response element (ARE) of HO-1 activation, ultimately resulting in slight enhanced HO-1 mRNA expression. However, LPS elicited decrease in HO-1 enzyme activity. Zinc protoporphyrin-IX (ZnPPIX) administrated with pioglitazone abolished its effects in the LPS mouse model. The study results demonstrate that coordinated activation of Nrf2/ARE-dependent HO-1 pathway defense mechanism by the PPARγ agonist pioglitazone mediated its neuroprotective effects.

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References

  1. Niranjan R (2014) The Role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes. Mol Neurobiol 49:28–38. https://doi.org/10.1007/s12035-013-8483-x

    Article  CAS  PubMed  Google Scholar 

  2. Fan K, Wu X, Fan B et al (2012) Up-regulation of microglial cathepsin C expression and activity in lipopolysaccharide-induced neuroinflammation. J Neuroinflamm 9:96. https://doi.org/10.1186/1742-2094-9-96

    Article  CAS  Google Scholar 

  3. Fan K, Li D, Zhang Y et al (2015) The induction of neuronal death by up-regulated microglial cathepsin H in LPS-induced neuroinflammation. J Neuroinflamm 12:54. https://doi.org/10.1186/s12974-015-0268-x

    Article  CAS  Google Scholar 

  4. Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462. https://doi.org/10.1002/glia.20467

    Article  PubMed  PubMed Central  Google Scholar 

  5. Reinert KRS, Umphlet CD, Quattlebaum A, Boger HA (2014) Short-term effects of an endotoxin on substantia nigra dopamine neurons. Brain Res 1557:164–170. https://doi.org/10.1016/j.brainres.2014.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu SY, Wang TF, Yu L et al (2011) Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway. Brain Behav Immun 25:135–146. https://doi.org/10.1016/j.bbi.2010.09.006

    Article  CAS  PubMed  Google Scholar 

  7. Beier EE, Neal M, Alam G et al (2017) Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide. Neurobiol Dis 108:115–127. https://doi.org/10.1016/j.nbd.2017.08.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Prakash A, Kumar A, Ming LC et al (2015) Modulation of the nitrergic pathway via activation of PPAR-γ contributes to the neuroprotective effect of pioglitazone against streptozotocin-induced memory dysfunction. J Mol Neurosci 56:739–750. https://doi.org/10.1007/s12031-015-0508-7

    Article  CAS  PubMed  Google Scholar 

  9. Pilipović K, Župan Ž, Dolenec P et al (2015) A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats. Prog Neuropsychopharmacol Biol Psychiatry 59:8–20. https://doi.org/10.1016/j.pnpbp.2015.01.003

    Article  CAS  PubMed  Google Scholar 

  10. Fiander MDJ, Stifani N, Nichols M et al (2017) Kinematic gait parameters are highly sensitive measures of motor deficits and spinal cord injury in mice subjected to experimental autoimmune encephalomyelitis. Behav Brain Res 317:95–108. https://doi.org/10.1016/j.bbr.2016.09.034

    Article  PubMed  Google Scholar 

  11. Barbiero JK, Santiago RM, Persike DS et al (2014) Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav Brain Res 274:390–399. https://doi.org/10.1016/j.bbr.2014.08.014

    Article  CAS  PubMed  Google Scholar 

  12. Kumar P, Kaundal RK, More S, Sharma SS (2009) Beneficial effects of pioglitazone on cognitive impairment in MPTP model of Parkinson’s disease. Behav Brain Res 197:398–403. https://doi.org/10.1016/j.bbr.2008.10.010

    Article  CAS  PubMed  Google Scholar 

  13. Swanson CR, Joers V, Bondarenko V et al (2011) The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. J Neuroinflamm 8:91. https://doi.org/10.1186/1742-2094-8-91

    Article  CAS  Google Scholar 

  14. Iranpour N, Zandifar A, Farokhnia M et al (2016) The effects of pioglitazone adjuvant therapy on negative symptoms of patients with chronic schizophrenia: a double-blind and placebo-controlled trial. Hum Psychopharmacol 31:103–112. https://doi.org/10.1002/hup.2517

    Article  CAS  PubMed  Google Scholar 

  15. Heneka MT, Fink A, Doblhammer G (2015) Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 78:284–294. https://doi.org/10.1002/ana.24439

    Article  CAS  PubMed  Google Scholar 

  16. Brakedal B, Flønes I, Reiter SF et al (2017) Glitazone use associated with reduced risk of Parkinson’s disease. Mov Disord 32:1594–1599. https://doi.org/10.1002/mds.27128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brauer R, Bhaskaran K, Chaturvedi N et al (2015) Glitazone treatment and incidence of Parkinson’s disease among people with diabetes: a retrospective cohort study. PLoS Med 12:e1001854. https://doi.org/10.1371/journal.pmed.1001854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cummings J, Morstorf T, Lee G (2016) Alzheimer’s drug-development pipeline: 2016. Alzheimer’s Dement 2:222–232. https://doi.org/10.1016/j.trci.2016.07.001

    Article  Google Scholar 

  19. NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators (2015) Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 14:795–803. https://doi.org/10.1016/S1474-4422(15)00144-1

    Article  CAS  Google Scholar 

  20. Chao X-J, Chen Z-W, Liu A-M et al (2014) Effect of tacrine-3-caffeic Acid, a novel multifunctional anti-Alzheimer’s dimer, against oxidative-stress-induced cell death in HT22 hippocampal neurons: involvement of Nrf2/HO-1 pathway. CNS Neurosci Ther 20:840–850. https://doi.org/10.1111/cns.12286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Piras S, Furfaro AL, Brondolo L et al (2017) Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells. Sci Rep 7:7568. https://doi.org/10.1038/s41598-017-08095-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ryter SW, Choi AMK (2002) Heme oxygenase-1: molecular mechanisms of gene expression in oxygen-related stress. Antioxid Redox Signal 4:625–632. https://doi.org/10.1089/15230860260220120

    Article  CAS  PubMed  Google Scholar 

  23. Hung S-Y, Liou H-C, Fu W-M (2010) The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology 58:321–329. https://doi.org/10.1016/j.neuropharm.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  24. Cho H-S, Kim S, Lee S-Y et al (2008) Protective effect of the green tea component, l-theanine on environmental toxins-induced neuronal cell death. NeuroToxicology 29:656–662. https://doi.org/10.1016/j.neuro.2008.03.004

    Article  CAS  PubMed  Google Scholar 

  25. Sheng X-J, Tu H-J, Chien W-L et al (2017) Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. PLoS ONE 12:e0183076. https://doi.org/10.1371/journal.pone.0183076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He Q, Song N, Jia F et al (2013) Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity. Int J Biochem Cell Biol 45:1019–1030. https://doi.org/10.1016/j.biocel.2013.02.012

    Article  CAS  PubMed  Google Scholar 

  27. Mateo I, Infante J, Sánchez-Juan P et al (2010) Serum heme oxygenase-1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease. Acta Neurol Scand 121:136–138. https://doi.org/10.1111/j.1600-0404.2009.01261.x

    Article  CAS  PubMed  Google Scholar 

  28. Lastres-Becker I, Ulusoy A, Innamorato NG et al (2012) α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Hum Mol Genet 21:3173–3192. https://doi.org/10.1093/hmg/dds143

    Article  CAS  PubMed  Google Scholar 

  29. Wang G, Liu L, Zhang Y et al (2014) Activation of PPARγ attenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGE levels. Eur J Pharmacol 726:27–32. https://doi.org/10.1016/j.ejphar.2014.01.030

    Article  CAS  PubMed  Google Scholar 

  30. Park SY, Bae JU, Hong KW, Kim CD (2011) HO-1 induced by cilostazol protects against TNF-α-associated cytotoxicity via a PPAR-γ-dependent pathway in human endothelial cells. Korean J Physiol Pharmacol 15:83. https://doi.org/10.4196/kjpp.2011.15.2.83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cho RL, Yang CC, Tseng HC et al (2018) Haem oxygenase-1 up-regulation by rosiglitazone via ROS-dependent Nrf2-antioxidant response elements axis or PPARγ attenuates LPS-mediated lung inflammation. Br J Pharmacol 175:3928–3946. https://doi.org/10.1111/bph.14465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Park EJ, Jang HJ, Tsoyi K et al (2013) The heme oxygenase-1 inducer THI-56 negatively regulates iNOS expression and HMGB1 release in LPS-activated RAW 264.7 cells and CLP-induced septic mice. PLoS ONE 8:e76293. https://doi.org/10.1371/journal.pone.0076293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jing X, Wei X, Ren M et al (2016) Neuroprotective effects of tanshinone I against 6-OHDA-induced oxidative stress in cellular and mouse model of Parkinson’s disease through upregulating Nrf2. Neurochem Res 41:779–786. https://doi.org/10.1007/s11064-015-1751-6

    Article  CAS  PubMed  Google Scholar 

  34. Lastres-Becker I, García-Yagüe AJ, Scannevin RH et al (2016) Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxid Redox Signal 25:61–77. https://doi.org/10.1089/ars.2015.6549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ramsey CP, Glass CA, Montgomery MB et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85. https://doi.org/10.1097/nen.0b013e31802d6da9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Polvani S, Tarocchi M, Galli A (2012) PPAR and oxidative stress: con() catenating NRF2 and FOXO. PPAR Res 2012:1–15. https://doi.org/10.1155/2012/641087

    Article  CAS  Google Scholar 

  37. Zhao XR, Gonzales N, Aronowski J (2015) Pleiotropic role of PPARγ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR and NF-κB. CNS Neurosci Ther 21:357–366. https://doi.org/10.1111/cns.12350

    Article  CAS  PubMed  Google Scholar 

  38. Corona JC, de Souza SC, Duchen MR (2014) PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1. Exp Neurol 253:16–27. https://doi.org/10.1016/j.expneurol.2013.12.012

    Article  CAS  PubMed  Google Scholar 

  39. Li Q, Tian Z, Wang M et al (2019) Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway. Int Immunopharmacol 66:309–316. https://doi.org/10.1016/J.INTIMP.2018.11.044

    Article  CAS  PubMed  Google Scholar 

  40. Armagan G, Sevgili E, Gürkan FT et al (2019) Regulation of the Nrf2 pathway by glycogen synthase kinase-3β in MPP+-induced cell damage. Molecules. https://doi.org/10.3390/molecules24071377

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ji M, Tang H, Luo D et al (2017) Environmental conditions differentially affect neurobehavioral outcomes in a mouse model of sepsis-associated encephalopathy. Oncotarget 8:82376–82389. https://doi.org/10.18632/oncotarget.19595

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kurauchi Y, Hisatsune A, Isohama Y et al (2012) Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic. Br J Pharmacol 166:1151–1168. https://doi.org/10.1111/j.1476-5381.2012.01833.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pan H, He M, Liu R et al (2014) Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway. PLoS ONE 9:e114186. https://doi.org/10.1371/journal.pone.0114186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Y, Li X, Zhang L et al (2015) Ginsenoside Rg1 suppressed inflammation and neuron apoptosis by activating PPARγ/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury. Int J Clin Exp Pathol 8:2484–2494

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pérez-de-Puig I, Martín A, Gorina R et al (2013) Induction of hemeoxygenase-1 expression after inhibition of hemeoxygenase activity promotes inflammation and worsens ischemic brain damage in mice. Neuroscience 243:22–32. https://doi.org/10.1016/j.neuroscience.2013.03.046

    Article  CAS  PubMed  Google Scholar 

  46. Ouyang Y, Li D, Wang H et al (2019) MiR-21-5p/dual-specificity phosphatase 8 signalling mediates the anti-inflammatory effect of haem oxygenase-1 in aged intracerebral haemorrhage rats. Aging Cell. https://doi.org/10.1111/acel.13022

    Article  PubMed  Google Scholar 

  47. Tronel C, Rochefort GY, Arlicot N et al (2013) Oxidative stress is related to the deleterious effects of heme oxygenase-1 in an in vivo neuroinflammatory rat model. Oxid Med Cell Longev. https://doi.org/10.1155/2013/264935

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wan J, Gong X, Jiang R et al (2013) Antipyretic and anti-inflammatory effects of asiaticoside in lipopolysaccharide-treated rat through up-regulation of heme oxygenase-1. Phytother Res 27:1136–1142. https://doi.org/10.1002/ptr.4838

    Article  CAS  PubMed  Google Scholar 

  49. Ghosh A, Birngruber T, Sattler W et al (2014) Assessment of blood–brain barrier function and the neuroinflammatory response in the rat brain by using cerebral open flow microperfusion (cOFM). PLoS ONE 9:e98143. https://doi.org/10.1371/journal.pone.0098143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang C-Y, Wang Z-Y, Xie J-W et al (2016) Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer’s disease mouse model. Neurobiol Aging 38:32–46. https://doi.org/10.1016/j.neurobiolaging.2015.10.024

    Article  CAS  PubMed  Google Scholar 

  51. André C, Dinel AL, Ferreira G et al (2014) Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2014.03.012

    Article  PubMed  Google Scholar 

  52. Metz GA, Whishaw IQ (2009) The ladder rung walking task: a scoring system and its practical application. J Vis Exp. https://doi.org/10.3791/1204

    Article  PubMed  PubMed Central  Google Scholar 

  53. Nie S, Xu Y, Chen G et al (2015) Small molecule TrkB agonist deoxygedunin protects nigrostriatal dopaminergic neurons from 6-OHDA and MPTP induced neurotoxicity in rodents. Neuropharmacology 99:448–458. https://doi.org/10.1016/J.NEUROPHARM.2015.08.016

    Article  CAS  PubMed  Google Scholar 

  54. Shih R-H, Cheng S-E, Tung W-H, Yang C-M (2010) Up-regulation of heme oxygenase-1 protects against cold injury-induced brain damage: a laboratory-based study. J Neurotrauma 27:1477–1487. https://doi.org/10.1089/neu.2009.1201

    Article  PubMed  Google Scholar 

  55. Schmittgen TD, Jiang J, Liu Q, Yang L (2004) A high-throughput method to monitor the expression of microRNA precursors. Nucleic Acids Res 32:43e–43. https://doi.org/10.1093/nar/gnh040

    Article  CAS  Google Scholar 

  56. Dalle-Donne I, Aldini G, Carini M et al (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406. https://doi.org/10.1111/j.1582-4934.2006.tb00407.x

    Article  CAS  PubMed  Google Scholar 

  57. Müllebner A, Moldzio R, Redl H et al (2015) Heme degradation by heme oxygenase protects mitochondria but induces ER stress via formed bilirubin. Biomolecules 5:679–701. https://doi.org/10.3390/biom5020679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cho H-S, Shin M-S, Song W et al (2013) Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinson’s rats. J Exerc Rehabil 9:354–361. https://doi.org/10.12965/jer.130048

    Article  PubMed  PubMed Central  Google Scholar 

  59. Anderson ST, Commins S, Moynagh PN, Coogan AN (2015) Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse. Brain Behav Immun 43:98–109. https://doi.org/10.1016/j.bbi.2014.07.007

    Article  CAS  PubMed  Google Scholar 

  60. Li D, Song T, Yang L et al (2016) Neuroprotective actions of pterostilbene on hypoxic-ischemic brain damage in neonatal rats through upregulation of heme oxygenase-1. Int J Dev Neurosci 54:22–31. https://doi.org/10.1016/J.IJDEVNEU.2016.08.005

    Article  CAS  PubMed  Google Scholar 

  61. Venkateshappa C, Harish G, Mythri RB et al (2012) Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson’s disease. Neurochem Res 37:358–369. https://doi.org/10.1007/s11064-011-0619-7

    Article  CAS  PubMed  Google Scholar 

  62. Colín-González AL, Orozco-Ibarra M, Chánez-Cárdenas ME et al (2013) Heme oxygenase-1 (HO-1) upregulation delays morphological and oxidative damage induced in an excitotoxic/pro-oxidant model in the rat striatum. Neuroscience 231:91–101. https://doi.org/10.1016/j.neuroscience.2012.11.031

    Article  CAS  PubMed  Google Scholar 

  63. Hunter RL, Dragicevic N, Seifert K et al (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386. https://doi.org/10.1111/j.1471-4159.2006.04327.x

    Article  CAS  PubMed  Google Scholar 

  64. Hong JM, Lee SM (2018) Heme oxygenase-1 protects liver against ischemia/reperfusion injury via phosphoglycerate mutase family member 5-mediated mitochondrial quality control. Life Sci 200:94–104. https://doi.org/10.1016/j.lfs.2018.03.017

    Article  CAS  PubMed  Google Scholar 

  65. Schulz S, Wong RJ, Vreman HJ, Stevenson DK (2012) Metalloporphyrins—an update. Front Pharmacol 3:68. https://doi.org/10.3389/fphar.2012.00068

    Article  PubMed  PubMed Central  Google Scholar 

  66. Fan J, Xu G, Jiang T, Qin Y (2012) Pharmacologic induction of heme oxygenase-1 plays a protective role in diabetic retinopathy in rats. Invest Ophthalmol Vis Sci 53:6541–6556. https://doi.org/10.1167/iovs.11-9241

    Article  CAS  PubMed  Google Scholar 

  67. Choi MJ, Lee EJ, Park JS et al (2017) Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: critical role of PPAR-γ signaling pathway. Biochem Pharmacol 144:120–131. https://doi.org/10.1016/j.bcp.2017.07.021

    Article  CAS  PubMed  Google Scholar 

  68. Lin C-C, Yang C-C, Chen Y-W et al (2018) Arachidonic Acid induces ARE/Nrf2-dependent heme oxygenase-1 transcription in rat brain astrocytes. Mol Neurobiol 55:3328–3343. https://doi.org/10.1007/s12035-017-0590-7

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pharmacology and Toxicology, German University in Cairo (GUC), New Cairo, Egypt

    Aya Zakaria & Laila Mahran

  2. Department of Microbiology and Immunology, German University in Cairo (GUC), New Cairo, Egypt

    Mona Rady & Khaled Abou-Aisha

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  1. Aya Zakaria
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AZ conceived of the presented idea, preformed the experimental work and wrote the manuscript; MR contributed in the experimental work; LM co- supervised the study; KAA contributed in the experimental work, conceived the presented idea and supervised the study. All the authors discussed the results and contributed in the manuscript.

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Correspondence to Aya Zakaria or Khaled Abou-Aisha.

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Fig. 1: Histology of H&E stained substantia nigra. Reduction in neurons, and increase in astrocytic gliosis in LPS and ZnPPIX-injected mice, these findings were attenuated with administration of pioglitazone for 7 days (scale bar: 20 µm)

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Zakaria, A., Rady, M., Mahran, L. et al. Pioglitazone Attenuates Lipopolysaccharide-Induced Oxidative Stress, Dopaminergic Neuronal Loss and Neurobehavioral Impairment by Activating Nrf2/ARE/HO-1. Neurochem Res 44, 2856–2868 (2019). https://doi.org/10.1007/s11064-019-02907-0

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