Nöroprotektif tedavide yeni bir ilaç hedefi: İkinci jenerasyon tetrasiklinler

Year 2007, Volume: 14 Issue: 1, 47 - 52, 30.04.2009

İsmail Yılmaz

Abstract

SüleymanDemirel Üniversitesi
TIP FAKÜLTESİ DERGİSİ: 2007 Mart; 14(1)












Nöroprotektif tedavide yeni bir ilaç hedefi: İkinci jenerasyon tetrasiklinler



İsmail Yılmaz



İzmir Eğitim ve Uygulama Hastanesi, Bozyaka\ İzmir



Özet



Minosiklin ve doksisiklin yüksek lipofilik özellikli ikinci jenerasyon tetrasiklinlerdir ve her iki ilaç da kan-beyin engelini kolayca geçebilir. Bu ilaçların antimikrobiyal özelliklerinden tamamen ayrı bir şekilde anti-inflamatuar özellliklerinin de bulunduğu belirlenmiştir. Yakın zaman önce yapılan çalışmalar minosiklinde daha belirgin olmak üzere ikinci jenerasyon tetrasiklinlerin global ve fokal beyin iskemisinde, Huntington hastalığında, amyotrofik lateral sklerozda, Parkinson hastalığında, multiple sklerozda, travmatik beyin hasarı ve medulla spinalis zedelenmesinde nöroprotektif etkileri olduğunu ortaya koymuştur. Nöroprotektif özellikte başta mikrogliyal aktivasyonun inhibisyonu olmak üzere anti-apopitotik ve anti-inflamatuar etkinliğin önemli rolü vardır. Bu bilgilerin daha fazla sayıda deneysel ve klinik çalışmalarla desteklenmesi, nöronal ölümle giden bir çok serebral hastalıkta başta minosiklin olmak üzere bu ilaçların güvenli bir şekilde kullanımına ışık tutacaktır.



Anahtar kelimeler: Minosiklin, doksisiklin, nöroprotektif tedavi





Abstract



Second generation tetracyclines:A novel drug target for the neuroprotective therapy



Minocycline and doxycycline are second generation tetracyclines that have high lipophilic properties and degree of access to brain. These drugs have antiinflammatory properties independent of their antimicrobial activities. Recently, it has been shown that these drugs (especially minocycline) display neuroprotective activity in animal models of global and focal cerebral ischemia, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, traumatic brain injury and spinal cord injury. Mainly microglial activation's inhibition, then, antiapoptotic activity and antiinflammatory activity play an important role on neuroprotection's features. To support these information by more clinical and experimental studies light the way for second generation tetracyclines, especially minocycline in cerebral diseases with neuronal death.



Key words: Minocycline, doxycycline, neuroprotection

Keywords

Minosiklin, doksisiklin, nöroprotektif tedavi

References

• Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clinical Pharmacokinetics 1988;15:355-66.
• Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998; 95(26):15769-74.
• Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999; 96(23):13496-500.
• Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington’s disease. Nat Med 2000; 6(7):797-801.
• Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M et al. Minocycline inhibits cytochrom-c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002; 417(6884):74-8.
• He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6- hydroxydopamine injection into mouse striatum. Brain Res 2001; 909(1-2):187-93.
• Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002; 51(2):215-23.
• Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001; 48(6):1393-9.
• Wells EAJ, Hulbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003; 126:1628-37.
• Patel RN, Attur MG, Dave MN, Patel IV, Stuchin SA, Abramson SB et al. A novel mechanism of action of chemically modified tetracyclines: inhibition of COX- 2-mediated prostaglandin E2 production. The Journal of Immunology 1999; 163: 3459-67.
• Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN et al. A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc. Natl. Acad. Sci. 1996; 93:14014-9.
• Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125 (6):1297-1308.
• Clark WM, Calcagno FA, Gabler WL, Smith JR, Coull BM. Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment. Stroke 1994; 25(7):1411-15.
• Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. The Journal of Neuroscience 2001; 21(8): 2580-88.
• Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. The Journal of Immunol 2001; 166(12):7527-33.
• Tikka T, Usenius T, Tenhunen M, Keinanen R, Koistinaho J. Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation. J Neurochem 2001; 78(6):1409-14.
• Zhang C, Lei B, Lam TT, Yang F, Sinha D, Tso MOM. Neuroprotection of photoreceptors by minocycline in light-induced retinal degeneration. Invest Opthalmol Vis Sci 2004; 45 (8): 2753-59.
• Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol. 2004; 3(12):744-51.
• Gonzalez-Scarano F, Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 1999; 22:201-40.
• Kim SS, Kong PJ, Kim BS, Sheen DH, Nam SY, Chun W. Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch Pharm Res 2004; 27(3):314-8.
• Baptiste DC, Hartwick ATE, Jollimore CAB, Baldridge WH, Seigel GM, Kelly MEM. An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. Molecular Pharmacology 2004; 66 (5):1113-22.
• Munzar P, Li H, Nicholson KL, Wiley JL, Balster RL. Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats. Psychopharmacology 2002;160:331-6.
• Pi R, Li W, Lee NTK, Chan HHN, Pu Y, Chan LN et al. Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. Journal of Neurochemistry 2004; 91:1219-30.
• Dommergues MA, Plaisant F, Verney C, Gressens P. Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience 2003; 121:619-28.
• Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. European Journal of Neurscience 2004; 19:3305-16.26. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA 2001; 98(25):14669-74.
• Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002; 22(5):1763-71.
• Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett 2001; 315(1- 2):61-4.
• Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 2002; 52(1):54-61.
• Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S et al. Minocycline inhibits contusion-triggered mitochondrial cytochrome-c release and mitigates functional deficits after spinal cord injury. PNAS 2004; 101(9): 3071-76.
• Reasoner DK, Hindman BJ, Dexter F, Subieta A, Cutkomp J, Smith T. Doxycycline reduces early neurologic impairment after cerebral arterial air embolism in the rabbit. Anesthesiology 1997; 87:569- 76.
• Wang C, Yang T, Noor R, Shuaib A. Delayed minocycline but not delayed mild hypothermia protects against embolic stroke. BMC Neurol 2002; 2(1):1-4.
• Tsuji M, Wilson MA, Lange MS, Johnston MV. Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Experimental Neurology 2004; 189:58-65.
• Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 2003; 53:731-42.
• Yang L, Sugama S, Chirichigno JW, Gregorio J, Lorenzl S, Shin DH et al. Minocycline enhances MPTP toxicity to dopaminergic neurons. Journal of Neuroscience Research 2003; 74:278-85.
• Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD et al. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci. 2004; 24(9):2182-90.
• Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol 2003; 53:267-70.
• Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiology of Disease 2002; 10:268- 78.
• Kriz J, Gowing G, Julien JP. Efficient three-drug cocktail for disease induced by mutant superoxide dismutase. Ann Neurol 2003; 53:429-36.
• Gordon PH, Moore DH, Gelinas DF, Qualls C, Meister ME, Werner J et al. Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 2004; 62 (10):1845-47.
• Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PAS, et al. Minocycline and doxycycline are not beneficial in a model of Huntington’s disease. Ann Neurol 2003; 4:186-96.
• Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington's disease: a pilot study. Mov Disord. 2004;19(6):692-5.
• Bonelli RM, Hödl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 2004; 19:337-42.
• Giuliani F, Metz LM, Wilson T, Fan Y, Bar-Or A, Yong VW. Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J Neuroimmunol. 2005; 158(1-2): 213-21.