Differential regional expression patterns of α-synuclein, TNF-α, and IL-1β; and variable status of dopaminergic neurotoxicity in mouse brain after Paraquat treatment

Journal of Neuroinflammation

Arindam Bhattacharyya¹  Nilkanta Chakrabarti²  Soham Mitra¹ 

[1] Immunology Lab, Department of Zoology, University of Calcutta, 35, Balygunge Circular Road. Kolkata-700019, India;Department of Physiology, University of Calcutta, 92, APC Ray Road, Kolkata-700009, India

关键词: frontal cortex, hippocampus;    substantia nigra;    interleukin-1β;    tumor necrosis factor-α;    tyrosine hydroxylase;    α-synuclein;    Paraquat;   

Others  :  1212994
DOI  :  10.1186/1742-2094-8-163

 received in 2011-03-25, accepted in 2011-11-24,  发布年份 2011

【 摘 要 】

Background

Paraquat (1, 1-dimethyl-4, 4-bipyridium dichloride; PQ) causes neurotoxicity, especially dopaminergic neurotoxicity, and is a supposed risk factor for Parkinson's disease (PD). However, the cellular and molecular mechanisms of PQ-induced neurodegeneration are far from clear. Previous studies have shown that PQ induces neuroinflammation and dopaminergic cell loss, but the prime cause of those events is still in debate.

Methods

We examined the neuropathological effects of PQ not only in substantia nigra (SN) but also in frontal cortex (FC) and hippocampus of the progressive mouse (adult Swiss albino) model of PD-like neurodegeneration, using immunohistochemistry, western blots, and histological and biochemical analyses.

Results

PQ caused differential patterns of changes in cellular morphology and expression of proteins related to PD and neuroinflammation in the three regions examined (SN, FC and hippocampus). Coincident with behavioral impairment and brain-specific ROS generation, there was differential immunolocalization and decreased expression levels of tyrosine hydroxylase (TH) in the three regions, whereas α-synuclein immunopositivity increased in hippocampus, increased in FC and decreased in SN. PQ-induced neuroinflammation was characterized by area-specific changes in localization and appearances of microglial cells with or without activation and increment in expression patterns of tumor necrosis factor-α in the three regions of mouse brain. Expression of interleukin-1β was increased in FC and hippocampus but not significantly changed in SN.

Conclusion

The present study demonstrates that PQ induces ROS production and differential α-synuclein expression that promotes neuroinflammation in microglia-dependent or -independent manners, and produces different patterns of dopaminergic neurotoxicity in three different regions of mouse brain.

【 授权许可】

   
2011 Mitra et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

Figure 12.

Figure 13.

【 参考文献 】

• [1]González-Polo RA, Rodríguez-Martín A, Morán JM, Niso M, Soler G, Fuentes JM: Paraquat-induced apoptotic cell death in cerebellar granule cells. Brain Res 2004, 1011:170-176.
• [2]Chinta SJ, Rane A, Poksay KS, Bredesen DE, Andersen JK, Rao RV: Coupling endoplasmic reticulum stress to the cell death program in dopaminergic cells: effect of paraquat. Neuromol Med 2008, 10:333-342.
• [3]Niso-Santano M, González-Polo RA, Bravo-San Pedro JM, Gómez-Sánchez R, Lastres-Becker I, Ortiz-Ortiz MA, Soler G, Morán JM, Cuadrado A, Fuentes JM: Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death: Modulation by the Nrf2/Trx axis. Free Rad Biol Med 2010, 48:1370-1381.
• [4]Franco R, Li S, Rodriguez-Rocha H, Burns M, Panayiotidis MI: Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson's disease. Chem Biol Interact 2010, 188:289-300.
• [5]Chanyachukul T, Yoovathaworn K, Thongsaard W, Chongthammakun S, Navasumrit P, Satayavivad J: Attenuation of paraquat-induced motor behavior and neurochemical disturbances by l-valine in vivo. Toxicol Lett 2004, 150:259-269.
• [6]Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, Suno M, Ogawa K, Hayase N, Kimura K, Shiono H: Carrier-mediated processes in blood--brain barrier penetration and neural uptake of paraquat. Brain Res 2001, 906:135-142.
• [7]Bartlett RM, Holden JE, Jerome Nickles R, Murali D, Barbee DL, Barnhart TE, Christian BT, DeJesus OT: Paraquat is excluded by the blood brain barrier in rhesus macaque: An in vivo pet study. Brain Res 2009, 1259:74-79.
• [8]Hisahara S, Shimohama S: Toxin-Induced and Genetic Animal Models of Parkinson's Disease. Parkinsons Dis 2010, 22:2011.
• [9]Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA: The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice - Paraquat and alpha-synuclein. J Biol Chem 2002, 277:1641-1644.
• [10]Berry C, Vecchia CL, Nicotera P: Paraquat and Parkinson's disease. Cell Death Differ 2010, 17:1115-1125.
• [11]McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA: Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochem 2005, 93:1030-1037.
• [12]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.
• [13]Klintwortha H, Gardenb G, Xia Z: Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neurosci Lett 2009, 462:1-5.
• [14]McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, CorySlechta DA, Di Mont DA: Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 2002, 10:119-127.
• [15]Wu XF, Block ML, Zhang W, Qin L, Wilson B, Zhang WQ, Veronesi B, Hong JS: The role of microglia in paraquat induced dopaminergic neurotoxicity. Antioxid Redox Signal 2005, 7:654-661.
• [16]McCormack AL, Atienza JG, Langston JW, Di Monte DA: Decreased susceptibility to oxidative stress underlies the resistance of specific dopaminergic cell populations to paraquat-induced degeneration. Neurosci 2006, 141:929-937.
• [17]Tansey MG, Goldberg MS: Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 2010, 37:510-518.
• [18]Chen Q, Niu Y, Zhang R, Guo H, Gao Y, Li Y, Liu R: The toxic influence of paraquat on hippocampus of mice: Involvement of oxidative stress. Neurotoxicol 2010, 31:310-316.
• [19]Fernagut PO, Hutson CB, Fleming SM, Tetreaut NA, Salcedo J, Masliah E, Chesselet MF: Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse 2007, 61:991-1001.
• [20]Kim SJ, Kim JE, Moon IS: Paraquat induces apoptosis of cultured rat cortical cells. 2004, 17:102-7.
• [21]Bove´ J, Prou D, Perier C, Przedborski S: Toxin-induced models of Parkinson's disease. NeuroRx 2005, 2:484-494.
• [22]Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhou Y, Hong JS, Zhang J: Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 2005, 19:533-542.
• [23]Kim YS, Joh TH: Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 2006, 38:333-347.
• [24]Zhou C, Huang Y, Przedborski S: Oxidative Stress in Parkinson's Disease: A Mechanism of Pathogenic and Therapeutic Significance. Ann N Y Acad Sci 2008, 1147:93-104.
• [25]Winklhofer KF, Haass C: Mitochondrial dysfunction in Parkinson's disease. Biochim Biophys Acta 2010, 1802:29-44.
• [26]Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T: Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brain. J Neural Transm 2000, 107:335-341.
• [27]Pierre SR, Lemmens MAM, Figueiredo-Pereira ME: Subchronic infusion of the product of inflammation prostaglandin J2 models sporadic Parkinson's disease in mice. J Neuroinflam 2009, 6:18. BioMed Central Full Text
• [28]Paxinos G, Franklin KBJ: The mouse brain in stereotaxic coordinates. San Diego: Elsevier Academic Press; 2001.
• [29]Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J Neuroinflam 2011, 8:9. BioMed Central Full Text
• [30]Weil A, Davenport HA: Staining of oligodendroglia and microglia in celloidin sections. Arch Neurol Psychiat 1933, 30:175-178.
• [31]Sinha AK: Colorimetric assay of catalase. Anal Chem 1972, 47:389-394.
• [32]Pabst JM, Habig WH, Jakoby WB: Glutathione-S-transferase. A J Biol Chem 1974, 249:7140-7150.
• [33]Kakkar P, Das B, Vishwanathan PN: A modified spectrophotometric assay of superoxide dismutase. I J Biochem Biophys 1984, 21:130-132.
• [34]Thiruchelvam M, McCormack A, Richfield EK, Baggs RB, Tank AW, Di Monte DA, Cory-Slechta DA: Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. Eur J Neurosci 2003, 18:589-600.
• [35]Wegener T, Sandhagen B, Chan KW, Saldeen T: N-acetylcysteine in paraquat toxicity: toxicological and histological evaluation in rats. Ups J Med Sci 1988, 93:81-9.
• [36]Lee J, Kwon W, Jo Y, Suh G, Youn Y: Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats. Hum Exp Toxicol 2008, 27:49-54.
• [37]Loeffler DA, DeMaggio AJ, Juneau PL, Havaich MK, LeWitt PA: Effects of enhanced striatal dopamine turnover in vivo on glutathione oxidation. Clin Neuropharmacol 1994, 17:370-379.
• [38]Somayajulu-Niţu M, Sandhu JK, Cohen J, Sikorska M, Sridhar TS, Matei A, Borowy-Borowski H, Pandey S: Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10. BMC Neurosci 2009, 10:88. BioMed Central Full Text
• [39]Choi WS, Abel G, Klintworth H, Flavell RA, Xia Z: JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death. J Neuropathol Exp Neurol 2010, 69:511-520.
• [40]Bhatnagar M, Dutt Shukla S: Unilateral degeneration in hippocampus of female rat. Neuroanat 2008, 7:1-5.
• [41]Tanibuchi I, Kitano H, Jinnai K: Substantia Nigra Output to Prefrontal Cortex Via Thalamus in Monkeys. II Activity of Thalamic Relay Neurons in Delayed Conditional Go/No-Go Discrimination Task. J Neurophysiol 2009, 102:2946-2954.
• [42]Prasad K, Tarasewicz E, Mathew J, Strickland PA, Buckley B, Richardson JR, Richfield EK: Toxicokinetics and toxicodynamics of paraquat accumulation in mouse brain. Exp Neurol 2009, 215:358-367.
• [43]Prasad K, Winnik B, Thiruchelvam MJ, Buckley B, Mirochnitchenko O, Richfield EK: Prolonged toxicokinetics and toxicodynamics of paraquat in mouse brain. Environ Health Perspect 2007, 115:1448-1453.
• [44]Kuter K, Nowak P, Gołembiowska K, Ossowska K: Increased reactive oxygen species production in the brain after repeated low-dose pesticide paraquat exposure in rats. a comparison with peripheral tissues. Neurochem Res 2010, 35:1121-1130.
• [45]Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA: Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 2003, 23:3095-3099.
• [46]Siebert H, Kahle PJ, Kramer ML, Isik T, Schlüter OM, Schulz-Schaeffer WJ, Brück W: Over-expression of alpha-synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion in a transgenic mouse strain. J Neurochem 2010, 114:1007-1018.
• [47]Westerlund M, Belin AC, Anvret A, Håkansson A, Nissbrandt H, Lind C, Sydow O, Olson L, Galter D: Cerebellar α-synuclein levels are decreased in Parkinson's disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. FASEB J 2008, 22:3509-3514.
• [48]Reis DJ, Gilad G, Pickel VM, Joh TH: Reversible changes in the activities and amounts of tyrosine hydroxylase in dopamine neurons of the substantia nigra in response to axonal injury as studied by immunochemical and immunocytochemical methods. Brain Res 1978, 144:325-342.
• [49]Hansson E, Ronnback L: Glial neuronal signaling in the central nervous system. FASEB J 2003, 17:341-348.
• [50]Gomes FCA, Spohr TCLS, Martinez R, Moura Neto V: Cross-talk between neurons and glia: highlights on soluble factors. Volume 34. Brazilian Journal of Medical and Biological Research; 2001::611-620.
• [51]Neumann H, Kotter MR, Franklin RJM: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009, 132:288-295.
• [52]Luo XG, Ding JQ, Chen SD: Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegen 2010, 5:12. BioMed Central Full Text
• [53]McGeer PL, Yasojima K, McGeer EG: Association of interleukin-1 beta polymorphisms with idiopathic Parkinson's disease. Neurosci Lett 2002, 326:67-69.
• [54]Dheen ST, Kaur C, Ling EA: Microglial Activation and its Implications in the Brain Diseases. CurMed Chem 2007, 14:1189-1197.
• [55]Fendrick SE, Xue QS, Streit WJ: Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J Neuroinflamm 2007, 4:9. BioMed Central Full Text
• [56]Yang MS, Ji KA, Jeon SB, Jin BK, Kim SU, Jou I, Joe E: Interleukin-13 enhances cyclooxygenase-2 expression in activated rat brain microglia: implications for death of activated microglia. J Immunol 2006, 177:1323-1329.
• [57]Boehme SA, Lio FM, Maciejewski-Lenoir D, Bacon KB, Conlon PJ: The Chemokine Fractalkine Inhibits Fas-Mediated Cell Death of Brain Microglia. J Immunol 2000, 165:397-403.
• [58]Whitton PS: Inflammation as a causative factor in the aetiology of Parkinson's disease Brain. J Pharmacol 2007, 150:963-976.
• [59]Schmid CD, Melchior B, Masek K, Puntambekar SS, Danielson PE, Lo DD, Sutcliffe JG, Carson MJ: Differential gene expression in LPS/IFNgamma activated microglia and macrophages: in vitro versus in vivo. J Neurochem 2009, 109:117-125.
• [60]Kortekaas R, Leenders KL, Van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH: Blood--brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005, 57:176-179.
• [61]Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M: Peripheral cytokines profile in Parkinson's disease. Brain Behav Immunol 2009, 23:55-63.