Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Journal of Neuroinflammation

Anumantha G Kanthasamy¹  Balaraman Kalyanaraman²  Brian P Dranka²  Pallavi Srivastava¹  Vellareddy Anantharam¹  Joy Joseph²  Arthi Kanthasamy¹  Anamitra Ghosh¹ 

[1] Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA;Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

关键词: Astrocytes;    Diapocynin;    Microglia;    Dopamine;    Neuroprotection;    Neuroinflammation;    Oxidative stress;    Parkinson’s disease;   

Others  :  1160189
DOI  :  10.1186/1742-2094-9-241

 received in 2012-07-25, accepted in 2012-10-06,  发布年份 2012

【 摘 要 】

Background

Parkinson’s disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.

Methods

Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin.

Results

Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD.

Conclusions

Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.

【 授权许可】

   
2012 Ghosh et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Vila M, Przedborski S: Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 2004, Suppl 10:58-62.
• [2]Dauer W, Przedborski S: Parkinson's disease: mechanisms and models. Neuron 2003, 39:889-909.
• [3]Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K: Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease. J Neurosci 2009, 29:13543-13556.
• [4]Gao HM, Liu B, Hong JS: Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 2003, 23:6181-6187.
• [5]McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988, 38:1285-1291.
• [6]Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC: Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 1996, 72:355-363.
• [7]Dehmer T, Lindenau J, Haid S, Dichgans J, Schulz JB: Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 2000, 74:2213-2216.
• [8]Bokoch GM, Knaus UG: NADPH oxidases: not just for leukocytes anymore! Trends Biochem Sci 2003, 28:502-508.
• [9]Awasthi YC, Sharma R, Sharma A, Yadav S, Singhal SS, Chaudhary P, Awasthi S: Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death. Free Radic Biol Med 2008, 45:111-118.
• [10]Anantharam V, Kaul S, Song C, Kanthasamy A, Kanthasamy AG: Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells. Neurotoxicology 2007, 28:988-997.
• [11]Lafeber FP, Beukelman CJ, van den Worm E, van Roy JL, Vianen ME, van Roon JA, van Dijk H, Bijlsma JW: Apocynin, a plant-derived, cartilage-saving drug, might be useful in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 1999, 38:1088-1093.
• [12]Zhang Y, Chan MM, Andrews MC, Mori TA, Croft KD, McKenzie KU, Schyvens CG, Whitworth JA: Apocynin but not allopurinol prevents and reverses adrenocorticotropic hormone-induced hypertension in the rat. Am J Hypertens 2005, 18:910-916.
• [13]Johnson DK, Schillinger KJ, Kwait DM, Hughes CV, McNamara EJ, Ishmael F, O'Donnell RW, Chang MM, Hogg MG, Dordick JS, Santhanam L, Ziegler LM, Holland JA: Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols. Endothelium 2002, 9:191-203.
• [14]Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schoneich C, Engelhardt JF: SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 2008, 118:659-670.
• [15]Zhang D, Anantharam V, Kanthasamy A, Kanthasamy AG: Neuroprotective effect of protein kinase C delta inhibitor rottlerin in cell culture and animal models of Parkinson's disease. J Pharmacol Exp Ther 2007, 322:913-922.
• [16]Ghosh A, Chandran K, Kalivendi SV, Joseph J, Antholine WE, Hillard CJ, Kanthasamy A, Kanthasamy A, Kalyanaraman B: Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model. Free Radic Biol Med 2010, 49:1674-1684.
• [17]Jin H, Kanthasamy A, Ghosh A, Yang Y, Anantharam V: Kanthasamy AG: α-Synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J Neurosci 2011, 31:2035-2051.
• [18]Roy A, Ghosh A, Jana A, Liu X, Brahmachari S, Gendelman HE, Pahan K: Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease. PLoS One 2012.
• [19]Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K: Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2007, 104:18754-18759.
• [20]Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A 2003, 100:6145-6150.
• [21]Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, Ischiropoulos H: Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci U S A 1998, 95:7659-7663.
• [22]Luchtefeld R, Luo R, Stine K, Alt ML, Chernovitz PA, Smith RE: Dose formulation and analysis of diapocynin. J Agric Food Chem 2008, 56:301-306.
• [23]Bedard K, Krause KH: The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007, 87:245-313.
• [24]Impellizzeri D, Esposito E, Mazzon E, Paterniti I, Di Paola R, Bramanti P, Cuzzocrea S: Effect of apocynin, a NADPH oxidase inhibitor, on acute lung inflammation. Biochem Pharmacol 2011, 81:636-648.
• [25]Impellizzeri D, Mazzon E, Esposito E, Paterniti I, Bramanti P, Cuzzocrea S: Effect of Apocynin, an inhibitor of NADPH oxidase, in the inflammatory process induced by an experimental model of spinal cord injury. Free Radic Res 2010, 45:221-236.
• [26]Hougee S, Hartog A, Sanders A, Graus YM, Hoijer MA, Garssen J, van den Berg WB, van Beuningen HM, Smit HF: Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice. Eur J Pharmacol 2006, 531:264-269.
• [27]Wang Q, Tompkins KD, Simonyi A, Korthuis RJ, Sun AY, Sun GY: Apocynin protects against global cerebral ischemia-reperfusion-induced oxidative stress and injury in the gerbil hippocampus. Brain Res 2006, 1090:182-189.
• [28]Dumont M, Stack C, Elipenhali C, Calingasan NY, Wille E, Beal MF: Apocynin administration does not improve behavioral and neuropathological deficits in a transgenic mouse model of Alzheimer's disease. Neurosci Lett 2011, 492:150-154.
• [29]Trumbull KA, McAllister D, Gandelman MM, Fung WY, Lew T, Brennan L, Lopez N, Morre J, Kalyanaraman B, Beckman JS: Diapocynin and apocynin administration fails to significantly extend survival in G93A SOD1 ALS mice. Neurobiol Dis 2012, 45:137-144.
• [30]Gao HM, Liu B, Zhang W, Hong JS: Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson's disease. FASEB J 2003, 17:1954-1956.
• [31]Vejrazka M, Micek R, Stipek S: Apocynin inhibits NADPH oxidase in phagocytes but stimulates ROS production in non-phagocytic cells. Biochim Biophys Acta 2005, 1722:143-147.
• [32]Galea E, Feinstein DL, Reis DJ: Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci U S A 1992, 89:10945-10949.
• [33]Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S: Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999, 5:1403-1409.
• [34]Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS: NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 2004, 279:1415-1421.
• [35]Blanchard-Fillion B, Souza JM, Friel T, Jiang GC, Vrana K, Sharov V, Barron L, Schoneich C, Quijano C, Alvarez B, Radi R, Przedborski S, Fernando GS, Horwitz J, Ischiropoulos H: Nitration and inactivation of tyrosine hydroxylase by peroxynitrite. J Biol Chem 2001, 276:46017-46023.
• [36]Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y: Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A 1996, 93:2696-2701.
• [37]Picklo MJ, Amarnath V, McIntyre JO, Graham DG, Montine TJ: 4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial respiration at multiple sites. J Neurochem 1999, 72:1617-1624.
• [38]Liu W, Kato M, Akhand AA, Hayakawa A, Suzuki H, Miyata T, Kurokawa K, Hotta Y, Ishikawa N, Nakashima I: 4-hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death. J Cell Sci 2000, 113:635-641.
• [39]Date I, Yoshimoto Y, Imaoka T, Miyoshi Y, Gohda Y, Furuta T, Asari S, Ohmoto T: Enhanced recovery of the nigrostriatal dopaminergic system in MPTP-treated mice following intrastriatal injection of basic fibroblast growth factor in relation to aging. Brain Res 1993, 621:150-154.
• [40]Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen EY, Palfi S, Roitberg BZ, Brown WD, Holden JE, Pyzalski R, Taylor MD, Carvey P, Ling Z, Trono D, Hantraye P, Déglon N, Aebischer P: Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000, 290:767-773.
• [41]Wang Q, Smith RE, Luchtefeld R, Sun AY, Simonyi A, Luo R, Sun GY: Bioavailability of apocynin through its conversion to glycoconjugate but not to diapocynin. Phytomedicine 2008, 15:493-503.