Mucopolysaccharidosis Stem Cell Research Group, Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
PLoS One. 2010 Dec 1;5(12):e14192. doi: 10.1371/journal.pone.0014192.
Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein.
METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed.
CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.
神经退行性代谢紊乱，如 IIIB 型黏多糖贮积症（MPSIIIB 或 Sanfilippo 病），会导致未降解的底物在大脑中积累，并且由于血脑屏障对酶的不渗透性，往往对酶替代治疗没有反应。MPSIIIB 的特征是行为困难、认知和随后的运动能力下降，最终在生命的第二个十年死亡。这些神经退行性溶酶体贮积病大多数缺乏有效的治疗方法。我们最近描述了使用酪氨酸激酶抑制剂染料木黄酮可显著减少 MPSIIIB 小鼠肝脏中累积的硫酸乙酰肝素底物。
方法/主要发现：我们在此报告，连续 9 个月给予 MPSIIIB 小鼠高剂量的染料木黄酮苷元可显著减少溶酶体贮积、硫酸乙酰肝素底物和大脑皮质和海马中的神经炎症，从而纠正观察到的行为缺陷。还观察到大脑皮质中突触小泡蛋白表达和继发性贮存的改善。
结论/意义：染料木黄酮可能被证明是一种有用的底物减少剂，可延迟 MPSIIIB 的临床发病，并且由于其多模式作用，可能为几种其他神经退行性代谢疾病提供治疗辅助。
