Abstract
Aspirin (ASA) is one of the most widely used nonsteroidal anti-inflammatory drugs. ASA has primarily been used to treat headaches, rheumatic pain, and inflammation, but its therapeutic effects have recently been demonstrated on a range of disorders, including those of the central nervous system. In this study, we investigated whether ASA is neuroprotective in inflammation-mediated neurodegenerative diseases. Pretreatment with ASA reduced the lipopolysaccharide (LPS)-induced degeneration of dopaminergic (DA) neurons in mesencephalic neuron–glia cultures in a dose-dependent manner. The neuroprotective effect of ASA was attributed to the inhibition of microglial activation because of its observed inhibitory effects on LPS-stimulated nitric oxide, tumor necrosis factor-α, and superoxide production by microglial cells. Moreover, ASA increased the production of the anti-inflammatory cytokines transforming growth factor beta-1 and interleukin-10 in neuron–glia cultures after stimulation with LPS. Mechanistic studies revealed that the neuroprotective effects of ASA were mediated through the inhibition of nicotinamide adenine dinucleotide phosphate oxidase (PHOX), a key enzyme for superoxide production in microglia. These results suggest that ASA protects DA neurodegeneration by inhibiting the microglial-mediated oxidative stress/inflammatory response and by regulating the production of anti-inflammatory cytokines.
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References
Akiyama H, McGeer PL (1989) Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res 489:247–253
Ariza D, Lima MM, Moreira CG et al (2010) Intranigral LPS administration produces dopamine, glutathione but not behavioral impairment in comparison to MPTP and 6-OHDA neurotoxin models of Parkinson’s disease. Neurochem Res 35:1620–1627
Brochard V, Combadiere B, Prigent A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Investig 119:182–192
DeLeo FR, Quinn MT (1996) Assembly of the phagocyte NADPH oxidase: molecular interaction of oxidase proteins. J Leukoc Biol 60:677–691
Di Matteo V, Benigno A, Pierucci M et al (2006a) 7-Nitroindazole protects striatal dopaminergic neurons against MPP+−induced degeneration: an in vivo microdialysis study. Ann NY Acad Sci 1089:462–471
Di Matteo V, Pierucci M, Di Giovanni G et al (2006b) Aspirin protects striatal dopaminergic neurons from neurotoxin-induced degeneration: an in vivo microdialysis study. Brain Res 1095:167–177
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81:1285–1297
Gao HM, Hong JS, Zhang W, Liu B (2003a) Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson’s disease. J Neurosci 23:1228–1236
Gao HM, Liu B, Zhang W, Hong JS (2003b) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. FASEB J 17:1954–1956
Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934
Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105
Grili M, Pizzi M, Memo M, Spano P (1996) Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 274:1383–1385, New York, N.Y
Hams AS, Barnum CJ, Ruhn KA et al (2011) Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol Ther 19:46–52
Ishida Y, Nagai A, Kobayashi S, Kim SU (2006) Upregulation of protease-activated receptor-1 in astrocytes in Parkinson’s disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J Neuropathol Exp Neurol 65:66–77
Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347
Lavigne MC, Malech HL, Holland SM, Leto TL (2001) Genetic requirement of p47phox for superoxide production by murine microglia. FASEB J 15:285–287
Li JM, Mullen AM, Yun S et al (2002) Essential role of the NADPH oxidase subunit p47 (phox) in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-alpha. Circ Res 90:143–150
Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7
Maharaj DS, Saravanan KS, Maharaj H, Mohanakumar KP, Daya S (2004) Acetaminophen and aspirin inhibit superoxide anion generation and lipid peroxidation, and protect against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. Neurochem Int 44:355–360
McCoy MK, Martinez TN, Ruhn KA et al (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative TNF inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26:9365–9375
Miller R, Sun G, Sun A (2007) Cytotoxicity of paraquat in microglial cells: involvement of the PKC delta- and ERK1/2-dependent NADPH oxidase. Brain Res 1167:129–139
Qian L, Block ML, Wei SJ et al (2006) Interleukin-10 protects lipopolysaccharide induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. J Pharmacol Exp Ther 319:44–52
Qian L, Wei SJ, Zhang D et al (2008) Potent anti-inflammatory and neuroprotective of TGF-beta1 are mediated through the inhibition of ERK and P47phox-Ser345 phosphorylation and translocation in microglia. J Immunol 181:660–668
Qin L, Liu Y, Wang T et al (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421
Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38:227–301
Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson’s disease: molecules to medicine. J Clin Investig 116:1744–1754
Wang JY, Shum AY, Ho YJ, Wang JY (2003) Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of P38 mitogen-activated protein kinase and caspase-3. J Neurosci Res 72:508–519
Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucicus R (2007) Inflammation in Parkinson’s disease and other neurodegenerative disease: cause and therapeutic implications. Curr Pharm Des 13:1925–1928
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This study was supported by the Natural Science Foundation of China (No. 30900448) and Excellent Youth Scholars Foundation of Ministry of Education of China (NO. 20090142120047).
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Wang, F., Zhai, H., Huang, L. et al. Aspirin Protects Dopaminergic Neurons Against Lipopolysaccharide-Induced Neurotoxicity in Primary Midbrain Cultures. J Mol Neurosci 46, 153–161 (2012). https://doi.org/10.1007/s12031-011-9541-3
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DOI: https://doi.org/10.1007/s12031-011-9541-3