Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).
Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).
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DOI：
10.1002/ana.24815
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发表时间：
2016-12
影响因子：
11.2
通讯作者：
Kielian, Tammy
中科院分区：
文献类型：
--
作者：
Aldrich, Amy;Bosch, Megan E.;Fallet, Rachel;Odvody, Jessica;Burkovetskaya, Maria;Rao, Kakulavarapu V. Rama;Cooper, Jonathan D.;Drack, Arlene V.;Kielian, Tammy
幼年神经性ceroid lipofuscinosis (JNCL)，或称幼年Batten病，是一种由CLN3常染色体隐性突变引起的儿童溶酶体贮积病，典型表现为失明、癫痫发作、进行性认知和运动能力下降以及过早死亡。目前，没有治疗JNCL的方法可以减缓疾病进展，这突出表明需要探索新的策略来延长患病儿童的生存和生活质量。环腺苷一磷酸（cAMP）是具有多效作用的第二信使，包括调节神经炎症和神经元存活。在这里，我们研究了3种磷酸二酯酶- 4 （PDE4）抑制剂（罗利普兰，罗氟司特和PF - 06266047）是否可以减轻Cln3Δex7/8小鼠JNCL模型中的行为缺陷和细胞特异性病理。在一项随机、盲法研究中，野生型（WT）和Cln3Δex7/8小鼠从1或3个月大开始每天接受PDE4抑制剂治疗，持续6至9个月，通过加速旋转测试评估运动缺陷。我们还在WT和Cln3Δex7/8动物中检测了PDE4抑制剂对cAMP水平、星形胶质细胞和小胶质细胞活化（分别为胶质纤维酸性蛋白和CD68）、溶酶体病理（溶酶体相关膜蛋白1）和星形胶质细胞谷氨酸转运蛋白表达（谷氨酸/天冬氨酸转运蛋白）的影响。cAMP水平在Cln3Δex7/8大脑中显著降低，并通过PF‐06266047恢复。PDE4抑制剂显著改善Cln3Δex7/8小鼠的运动功能，减弱神经胶质活化和溶酶体病理，并将谷氨酸转运蛋白表达恢复到WT动物的水平，血液化学分析显示无毒性证据。这些研究揭示了PDE4抑制剂在Cln3Δex7/8小鼠中的神经保护作用，并支持其在JNCL患者中的治疗潜力。Ann Neurol 2016；80:909 - 923
Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase‐4 (PDE4) inhibitors (rolipram, roflumilast, and PF‐06266047) could mitigate behavioral deficits and cell‐specific pathology in the Cln3Δex7/8 mouse model of JNCL. In a randomized, blinded study, wild‐type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal‐associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3Δex7/8 animals. cAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF‐06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis. These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923
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