The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphate level in the brain of prenatally stressed rats.
The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphate level in the brain of prenatally stressed rats.
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发表时间：
2010-04
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通讯作者：
B. Budziszewska;Magdalena Szymanska;M. Leśkiewicz;A. Basta-Kaim;L. Jaworska-Feil;M. Kubera;D. Jantas;W. Lasoń
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作者：
B. Budziszewska;Magdalena Szymanska;M. Leśkiewicz;A. Basta-Kaim;L. Jaworska-Feil;M. Kubera;D. Jantas;W. Lasoń
我们前期的研究表明，在产前应激抑郁模型中，成年大鼠糖皮质激素受体（GR）功能增强。然而，长期的后果，压力，抑郁症的一个因果因素，对细胞内的元素参与调节GR功能的检查很差。有丝分裂原活化蛋白激酶（MAPK）是GR作用的重要调节因子，其活性在抑郁症中受到干扰，因此它们可以介导应激对GR功能的影响。因此，本研究的目的是调查的水平的活性磷酸化形式的细胞外信号调节激酶（ERK），Jun N-末端激酶（JNK）和p38激酶在海马和额叶皮质在大鼠产前应激。还测定了MAP激酶磷酸酶（MKP-1，MKP-2）和蛋白磷酸酶-2A（PP 2A）的浓度，这些磷酸酶使所有形式的MAP激酶脱磷酸化。在验证应用模型的抑郁症，我们发现，产前强调大鼠显示高水平的不动性在Porsolt测试和丙咪嗪，氟西汀，米氮平和噻奈普汀的管理21天正常化这个参数。Western blot结果显示，产前应激组大鼠海马p-JNK 1和p-JNK 2以及额叶皮层p-p38表达水平降低，而p-ERK 1和p-ERK 2表达水平无明显变化。丙咪嗪长期治疗抑制应激诱导的p-JNK 1/2下降，而丙咪嗪，氟西汀和米氮平阻断p-p38的变化。PP 2A磷酸酶水平在产前应激动物的海马和额叶皮质高于对照组。抗抑郁药物的慢性治疗减弱了这种磷酸酶水平的应激诱导的增加，但对对照动物的浓度没有影响。对照组和产前应激组大鼠的两种脑结构中MKP-1和MKP-2水平无显著差异。结果表明，产前应激降低了JNK和p38活性形式的水平，但增加了PP 2A磷酸酶的表达，这些变化大多被抗抑郁药物逆转。由于已知p-JNK和p-p38抑制GR功能，因此其降低的水平可增强糖皮质激素的作用。此外，PP 2A浓度的增加可能不仅通过抑制JNK和p38磷酸化，而且还通过直接影响GR易位过程来增强GR作用。
Our previous study suggests that in prenatal stress model of depression glucocorticoid receptor (GR) function in adult rats is enhanced. However, the long-term consequences of stress, a causal factor in depression, on intracellular elements involved into the regulation of GR function is poorly examined. Mitogen-activated protein kinases (MAPKs), activity of which is disturbed in depression, are important regulators of GR action, so they can mediate the effect of stress on GR function. Therefore, the aim of the present study was to investigate the levels of active phosphorylated forms of extracellular signal-regulated kinases (ERK), Jun N-terminal kinases (JNK) and the p38 kinase in the hippocampus and frontal cortex in rats subjected to prenatal stress. The concentration of MAP kinase phosphatase (MKP-1, MKP-2) and protein phosphatase-2A (PP2A), which dephosphorylate all forms of MAP kinases, were also determined. During verification of the applied model of depression, we found that prenatally stressed rats displayed high level of immobility in the Porsolt test and that the administration of imipramine, fluoxetine, mirtazapine and tianeptine for 21 days normalized this parameter. Western blot study revealed that rats subjected to prenatal stress had decreased levels of p-JNK1 and p-JNK2 in the hippocampus and p-p38 in the frontal cortex, but the concentrations of p-ERK1 and p-ERK2 were not changed. Chronic treatment with imipramine inhibited the stress-induced decrease in p-JNK1/2, while imipramine, fluoxetine and mirtazapine blocked changes in p-p38. PP2A phosphatase level was higher in the hippocampus and frontal cortex in prenatally stressed animals than in control rats. Chronic treatment with antidepressant drugs attenuated the stress-induced increase in the level of this phosphatase, but had no effect on its concentration in control animals. There was no significant difference in MKP-1 and in MKP-2 levels in both brain structures between control and prenatally stressed rats. The obtained results showed that prenatal stress decreased the levels of active form of JNK and p38, but enhanced PP2A phosphatase expression and most of these changes were reversed by antidepressant drugs. Since p-JNK and p-p38 are known to inhibit GR function their lowered levels may enhance glucocorticoid action. Furthermore, the increased PP2A concentration may intensify GR action not only by inhibition of JNK and p38 phosphorylation, but also by a direct influence on the process of GR translocation.