Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats:: Relation to neurofilament phosphorylation
Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats:: Relation to neurofilament phosphorylation
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DOI：
10.1038/sj.npp.1300095
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发表时间：
2003-05-01
影响因子：
7.6
通讯作者：
García-Sevilla, JA
中科院分区：
文献类型：
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作者：
Ferrer-Alcón, M;La Harpe, R;García-Sevilla, JA
神经元细胞周期蛋白依赖性激酶-5(CDK5)及其神经元特异性激活物p35在调节细胞骨架动力学中起着重要作用。由于阿片成瘾与人死后脑内神经细丝(NF)的过度磷酸化有关，本研究旨在探讨慢性阿片滥用者脑内CDK5/p35复合体的状态及其与NF-H磷酸化的关系。与对照组相比，阿片依赖者前水平皮质CDK5(18%)和p35(26-44%)的免疫密度降低。在同一脑中，p25(一种截短的神经毒性形式的p35)、磷酸酶PP2Ac和p-calain的密度没有变化。急性吗啡(30 mg/kg，2 h)使大脑皮层中CDK5的密度增加(35%)，但不增加p35的密度。而慢性吗啡(10-100 mg/kg，连续5天)可引起大鼠脑内CDK5(40%)和p35(47%)表达显著下降。在阿片成瘾者的脑中，磷酸化的NF-H的密度增加了43%，磷酸化的和非磷酸化的NF-H的比例增加了一倍。在这些脑组织中，磷酸化的核因子-H与p35显著相关(r=0.58)，而与CDK5无关(r=0.03)。结果表明，阿片成瘾与大脑中CDK5/p35水平的下调有关。这种下调和NF-H蛋白的异常过度磷酸化可能在人类与阿片成瘾相关的神经可塑性的发展中有重要的后果。
Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefirontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and p-calpain were found unaltered, Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to noriphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r = 0.58) but not with cdk5 (r = 0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.