Adrenoleukodystrophy: Molecular Pathogenesis and Development of Therapeutic Agents

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  • MORITA Masashi
    Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

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Other Title
  • 副腎白質ジストロフィーの分子病態の解明と治療薬開発
  • フクジン ハクシツ ジストロフィー ノ ブンシ ビョウタイ ノ カイメイ ト チリョウヤク カイハツ

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Abstract

  Adrenoleukodystrophy (ALD) is an inherited disorder characterized by progressive demyelination of the central nervous system and adrenal dysfunction. The biochemical characterization is made based on the accumulation of pathgnomonic amounts of saturated very long chain fatty acid (VLCFA, >22) in all tissues, including brain white matter and adrenal glands. The accumulation of VLCFA is linked to a mutation in the ABCD1 gene that encodes ABCD1/ALDP, a peroxisomal ABC protein. ABCD1/ALDP is thought to be involved in the active ATP-driven transport of VLCFA-CoA from the cytoplasm into the peroxisomes. However, the precise function of ABCD1/ALDP is still unclear. The accumulation of VLCFA is caused by reducing peroxisomal VLCFA β-oxidation and/or increasing fatty acid elongation. Since the reduction of accumulated VLCFA in the brain is thought to be crucial for preventing the progression of neurologic symptoms in X-ALD, compounds that can cross the blood-brain barrier and decrease the VLCFA levels in the brain would be a highly attractive candidate for effective treatment of ALD patients. We found that baicalein 5,6,7-trimethyl ether, a flavonoid derivative, decreased the VLCFA level in X-ALD fibroblasts, possibly by activating peroxisomal fatty acid β-oxidation. Continued pharmacologic studies of flavonoids and chemically modified derivatives may lead to major advances in the pharmacologic therapy for X-ALD.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 127 (7), 1059-1064, 2007-07-01

    The Pharmaceutical Society of Japan

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