Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
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DOI：
10.1093/hmg/ddq082
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Pujol, Aurora
中科院分区：
文献类型：
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作者：
Fourcade, Stephane;Ruiz, Montserrat;Pujol, Aurora
X连锁肾上腺脑白质营养不良（X-ALD）是一种致命的轴突脱髓鞘性神经代谢疾病。它是由过氧化物酶体ATP结合盒转运蛋白亚家族D（ABCD 1）的一个成员的功能丧失引起的，该亚家族参与极长链脂肪酸（VLCFA）的代谢。由过量的二十六烷酸（在X-ALD中积累的最普遍的VLCFA）引起的蛋白质的氧化损伤是神经退行性级联反应中的早期事件。我们在这里证明，丙戊酸（VPA），一种广泛使用的抗癫痫药物与组蛋白去乙酰化酶抑制剂的性能，诱导功能重叠ABCD 2过氧化物酶体转运蛋白的表达。VPA纠正了氧化损伤，降低了单不饱和VLCFA（C26：1 n-9）的水平，但不饱和VLCFA。在X-ALD小鼠模型中，ABCD 2单独过表达可防止蛋白质的氧化损伤。在X-ALD患者中进行的一项为期6个月的VPA初步试验导致外周血单核细胞中蛋白质的氧化损伤逆转。因此，我们建议VPA作为一种有前途的新的治疗方法，值得在X-ALD的进一步临床研究。
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.