부신백질형성장애증 섬유모세포에서 발프로산의 항산화능
Valproic Acid Reduces Reactive Oxygen Species in Fibroblast of X-linked Adrenoleukodystrophy
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목적: X-ALD는 Xq28에 위치한 ABCD1 유전자의 돌연변이로 긴사슬지방산이 신경 조직과 부신에 축적되어 일어나는 퇴행 뇌질환이며, 소아기 대뇌형의 경우 빠르고 심한 임상 경과를 보인다. 이 과정에서산화스트레스도 조직 손상에 영향을 주는 것으로 알려져 있다. 골수이식이나 로렌조 기름 등이 치료 방법으로 이용되나 치료의 위험성과효과에서 한계를 보이는 실정이다. 이에 저자들은 X-ALD 환자에게채취한 섬유모세포를 이용하여, X-ALD의 치료 가능성을 알아보기위하여 VPA의 효과를 연구해보고자 하였다. 방법: X-ALD 환자의 피부에서 채취한 섬유모세포와 정상인의 피부에서 채취한 섬유모세포를 배양하였다. 배양된 섬유모세포에 VPA 를 처리한 후 RNA발현 정도를 통해 ABCD2 발현을 확인하고 유동세포계측법으로 활성산소종을 측정하였다. 결과: VPA을 처리한 후 정상과 X-ALD 섬유모세포 모두에서ABCD2의 mRNA 발현이 증가하였다. 특히 X-ALD 섬유모세포에서ABCD2 유전자 mRNA 발현이 2.22배로 정상의 1.76배보다 더 증가하였다. 유동세포계측법으로 활성산소종을 확인한 결과 대조군에서13.7, VPA를 처리한 군에서는 각각 0.25 mM에서 8.67, 0.5 mM에서9.37, 1 mM에서 5.83을 나타내었다. 결론: X-ALD 환자에서 VPA의 항산화능을 이용하여 신경손상을막을 수 있는 가능성이 있을 것으로 보이며, 이를 실제 환자에 적용하는 연구가 필요할 것이다.
Abstract
Purpose: X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurodegenerative disease, and is caused by mutations the in ABCD1 (ATP-binding cassette transporter subfamily D member 1). Oxidative damage of proteins caused by very long chain fatty acid accumulating in X-ALD, is an early event in the neuro degenerative cascade. We evaluated valproic acid (VPA) as a possible option for oxidative damage in X-ALD. Method: We generated fibroblast of the childhood cerebral ALD from patient. We evaluated mRNA (ribonucleic acid) level of ABCD2 by real-time polymerase chain reaction, and reactive oxygen species (ROS) levels by flow cytometry. Results: VPA increased expression of ABCD2 in both control and ALD fibroblast. ABCD2 gene mRNA expression was increased 1.76 fold in normal fibroblasts, and 2.22 fold in the X-ALD fibroblasts. ROS levels were decreased in VPA treated X-ALD fibroblast, especially in treated with 1 mM of VPA. ROS levels revealed 13.7 in control fibroblast, on the other hand, 5.83 in X-ALD fibroblast treated with 1 mM of VPA. Conclusion: We propose VPA as a promising novel therapeutic approach in oxidant damage that warrants further clinical investigation in X-ALD.
참고문헌 (36)
- Moser HW, "Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy", Brain, 120(Pt 8), pp.1485~1508 (1997)
- Kemp S, "X-linked adrenoleukodystrophy : clinical, metabolic, genetic and pathophysiological aspects", Biochim Biophys Acta, 1822, pp.1465~1474 (2012)
- Shimozawa N, "X-linked adrenoleukodystrophy : diagnostic and follow-up system in Japan", J Hum Genet, 56, pp.106~109 (2011)
- Siddiqui S, "MRI in X-linked adrenoleukodystrophy", Neurology, 84, pp.211~ (2015)
- Engelen M, "X-linked adrenoleukodystrophy(X-ALD) : clinical presentation and guidelines for diagnosis, follow-up and management", Orphanet J Rare Dis, 7, pp.51~ (2012)
- Deon M, "The effect of Lorenzo's oil on oxidative stress in X-linked adrenoleukodystrophy", J Neurol Sci, 247, pp.157~164 (2006)
- Miller WP, "Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy : the largest single-institution cohort report", Blood, 118, pp.1971~1978 (2011)
- Moser HW, "Therapy of X-linked adrenoleukodystrophy", NeuroRx, 3, pp.246~253 (2006)
- Potic A, "Childhood cerebral X-linked adrenoleukodystrophy more than 5 years after hematopoietic cell transplantation : the first case from Serbia and southeastern Europe", J Child Neurol, 25, pp.1542~1547 (2010)
- Semmler A, "Therapy of X-linked adrenoleukodystrophy", Expert Rev Neurother, 8, pp.1367~1379 (2008)
- van Geel BM, "Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy : a retrospective study", J Inherit Metab Dis, 38, pp.359~361 (2015)
- Baarine M, "Evidence of oxidative stress in very long chain fatty acid--treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins", Neuroscience, 213, pp.1~18 (2012)
- Deon M, "Oxidative stress is induced in female carriers of X-linked adrenoleukodystrophy", J Neurol Sci, 266, pp.79~83 (2008)
- Uto T, "Oxidative imbalance in nonstimulated X-adrenoleukodystrophy-derived lymphoblasts", Dev Neurosci, 30, pp.410~418 (2008)
- Kernochan LE, "The role of histone acetylation in SMN gene expression", Hum Mol Genet, 14, pp.1171~1182 (2005)
- Labiner DM, "DP-VPA D-Pharm", Curr Opin Investig Drugs, 3, pp.921~923 (2002)
- Leng Y, "Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity", J Neurosci, 26, pp.7502~7512 (2006)
- van Bergeijk J, "Valproic acid promotes neurite outgrowth in PC12 cells independent from regulation of the survival of motoneuron protein", Chem Biol Drug Des, 67, pp.244~247 (2006)
- Swoboda KJ, "Sorenson SL, et al. Phase II open label study of valproic acid in spinal muscular atrophy", PLoS One, 4, pp.e5268~ (2009)
- Tsai LK, "Valproic acid treatment in six patients with spinal muscular atrophy", Eur J Neurol, 14, pp.e8~e9 (2007)
- Weihl CC, "Valproate may improve strength and function in patients with type III", IV spinal muscle atrophy, 2006, pp.67, 500~501
- Rothstein JD., "Current hypotheses for the underlying biology of amyotrophic lateral sclerosis", Ann Neurol, 65(Suppl 1), pp.S3~S9 (2009)
- Zhou C, "Oxidative stress in Parkinson's disease : a mechanism of pathogenic and therapeutic significance", Ann N Y Acad Sci, 1147, pp.93~104 (2008)
- Fourcade S, "Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy", Hum Mol Genet, 17, pp.1762~1773 (2008)
- Powers JM, "Adreno-leukodystrophy : oxidative stress of mice and men", J Neuropathol Exp Neurol, 64, pp.1067~1079 (2005)
- Vargas CR, "Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy", Biochim Biophys Acta, 1688, pp.26~32 (2004)
- Aubourg P, "A two-year trial of oleic and erucic acids("Lorenzo's oil")as treatment for adrenomyeloneuropathy", N Engl J Med, 329, pp.745~752 (1993)
- Kemp S, "Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy", Mol Genet Metab, 84, pp.144~151 (2005)
- Muneer Z, "Abcd2 is a strong modifier of the metabolic impairments in peritoneal macrophages of ABCD1-deficient mice", PLoS One, 25, pp.e108655~ (2014)
- Singh J, "Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation : implication for X-adrenoleukodystrophy", J Lipid Res, 50, pp.135~147 (2009)
- Pujol A, "Functional overlap between ABCD1(ALD)and ABCD2(ALDR)transporters : a therapeutic target for X-adrenoleukodystrophy", Hum Mol Genet, 13, pp.2997~3006 (2004)
- Bachmann RF, "Common effects of lithium and valproate on mitochondrial functions : protection against methamphetamine-induced mitochondrial damage", Int J Neuropsychopharmacol, 12, pp.805~822 (2009)
- Cui J, "Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate", Neuroscience, 144, pp.1447~1453 (2007)
- Lai JS, "Cytoprotection by lithium and valproate varies between cell types and cellular stresses", Eur J Pharmacol, 539, pp.18~26 (2006)
- Chang TK, "Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity", Drug Metab Rev, 38, pp.627~639 (2006)
- Lheureux PE, "Carnitine in the treatment of valproic acid-induced toxicity", Clin Toxicol(Phila), 47, pp.101~111 (2009)