Abstract
Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and widely-used animal model of human inflammatory demyelinating polyradiculoneuropathies. Doxycycline is a well-known antibiotic and has been reported to have neuroprotective and anti-inflammatory effects. Here we investigated the effects of doxycycline on rat EAN. Therapeutic treatment with doxycycline (40 mg/kg body weight daily from the Day 9 to Day 14 post immunization) significantly attenuated the severity of EAN, decreased inflammatory infiltration of macrophages, B- and T-cells and demyelination in sciatic nerves of EAN rats. Pro-inflammatory molecules including matrixmetalloproteinase-9, inducible nitric oxide synthase and interleukin-17 were greatly decreased in sciatic nerves by administration of doxycycline as well. Taken together, our data showed that doxycycline could effectively suppress the peripheral inflammation to improve outcome of EAN, which suggests that doxycycline may be considered as a potential candidate of pharmacological treatment for neuropathies.
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References
Hughes RA, Cornblath DR (2005) Guillain-Barré syndrome. Lancet 366:1653–1666
Milner P, Lovelidge CA, Taylor WA et al (1987) P0 myelin protein produces experimental allergic neuritis in Lewis rats. J Neurol Sci 79:275–285
Yrjanheikki J, Keinanen R, Pellikka M et al (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774
Yrjanheikki J, Tikka T, Keinanen R et al (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500
Popovic N, Schubart A, Goetz BD et al (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–223
Wu DC, Jackson-Lewis V, Vila M et al (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771
Griffin MO, Fricovsky E, Ceballos G et al (2010) Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Am J Physiol Cell Physiol 299:539–548
Paemen L, Martens E, Norga K et al (1996) The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors. Biochem Pharmacol 52:105–111
Golub LM, Ramamurthy NS, McNamara TF et al (1991) Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2:297–321
Gabler WL, Creamer HR (1991) Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 26:52–58
Jantzie LL, Cheung PY, Todd KG (2005) Doxycycline reduces cleaved caspase-3 and microglial activation in an animal model of neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 25:314–324
Jantzie LL, Rauw GA, Todd KG (2006) The effects of doxycycline administration on amino acid neurotransmitters in an animal model of neonatal hypoxia-ischemia. Neurochem Int 49:717–728
Zouboulis CC, Piquero-Martin J (2003) Update and future of systemic acne treatment. Dermatology 206:37–53
Stirling DP, Koochesfahani KM, Steeves JD et al (2005) Minocycline as a neuroprotective agent. Neuroscientist 11:308–322
Hartung HP, Schäfer B, Heininger K et al (1988) The role of macrophages and eicosanoids in the pathogenesis of experimental allergic neuritis Serial clinical, electrophysiological, biochemical and morphological observations. Brain 111:1039–1059
Leifeld L, Fielenbach M, Dumoulin FL et al (2002) Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression in fulminant hepatic failure. J Hepatol 37:613–619
Schabet M, Whitaker JN, Schott K et al (1991) The use of protease inhibitors in experimental allergic neuritis. J Neuroimmunol 31:265–272
Hughes PM, Wells GM, Clements JM (1998) Matrix metalloproteinase expression during experimental autoimmune neuritis. Brain 121:481–494
Kieseier BC, Clements JM, Pischel HB et al (1998) Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome. Ann Neurol 43:427–434
Brundula V, Rewcastle NB, Metz LM et al (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125:1297–1308
Newman JP, Verity AN, Hawatmeh S et al (1996) Ciliary neurotrophic factors enhances peripheral nerve regeneration. Arch Otolaryngol Head Neck Surg 122:399–403
Opdenakker G, Van Damme J (1994) Cytokine-regulated proteases in autoimmune diseases. Immunol Today 15:103–107
Curci JA, Mao D, Bohner DG et al (2001) Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms. J Vasc Surg 31:325–342
Saliba E, Henrot A (2001) Inflammatory mediators and neonatal brain damage. Biol Neonate 79:224–227
Bettelli E, Korn T, Oukka M et al (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057
Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348
Lee Y, Shin T (2002) Expression of constitutive endothelial and inducible nitric oxide synthase in the sciatic nerve of Lewis rats with experimental autoimmune neuritis. J Neuroimmunol 126:78–85
Zhu J, Mix E, Link H (1998) Cytokine production and the pathogenesis of experimental autoimmune neuritis and Guillain-Barré syndrome. J Neuroimmunol 84:40–52
Abramson SB, Amin AR, Clancy RM et al (2001) The role of nitric oxide in tissue destruction. Best Pract Res Clin Rheumatol 15:831–845
Conti G, Rostami A, Scarpini E et al (2004) Inducible nitric oxide synthase (iNOS) in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system. Exp Neurol 187:350–358
Zhang ZY, Zhang ZR, Fauser U et al (2009) Improved outcome of EAN, an animal model of GBS, through amelioration of peripheral and central inflammation by minocycline. J Cell Mol Med 13:341–351
Cunha BA (2006) New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited. Med Clin North Am 90:1089–1107
NINDS NET-PD Investigators (2008) A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. Clin Neuropharmacol 31:141–150
Toth A, Lesser ML, Naus G et al (1988) Effect of doxycycline on pre-menstrual syndrome: a double-blind randomized clinical trial. J Int Med Res 16:270–279
Fox C, Dingman A, Derugin N et al (2005) Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 25:1138–1149
Kraus RL, Pasieczny R, Lariosa-Willingham K et al (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 94:819–827
Yao JS, Shen F, Young WL et al (2007) Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int 50:524–530
Acknowledgments
Chenju Yi gratefully acknowledged China Scholarship Council. This investigation was partly supported by National Nature Science Foundation of China (No: 81070954).
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C. Yi and Z. Zhang contributed equally to this work.
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Yi, C., Zhang, Z., Wang, W. et al. Doxycycline Attenuates Peripheral Inflammation in Rat Experimental Autoimmune Neuritis. Neurochem Res 36, 1984–1990 (2011). https://doi.org/10.1007/s11064-011-0522-2
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DOI: https://doi.org/10.1007/s11064-011-0522-2