Department of Endocrinology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
J Neurosci Res. 2013 Feb;91(2):211-9. doi: 10.1002/jnr.23125. Epub 2012 Nov 14.
Protein kinase Cα (PKCα) has been implicated in the regulation of a variety of cellular functions, such as proliferation, differentiation, and apoptosis, in response to a diverse range of stimuli. Activated PKCα mediates oxidative stress, apoptosis, and inflammatory reaction. Thyroid hormone (TH) is essential for the proper development of the mammalian central nervous system. TH deficiency during critical periods of brain development results in permanent cognitive and neurological impairments. In the present study, we attempted to explore whether PKCα is involved in impaired brain function in developing hypothyroid rat brain. Severe perinatal hypothyroidism was obtained by administration of 30 mg/day propylthiouracil to dams. Brain PKC activity in hypothyroid pups was increased significantly in cytosol and membrane fractions. The change of membrane PKC activity was more marked than that of cytosol, and hypothyroidism led to a higher ratio of membrane PKC activity to that in cytosol, which means abnormal activation of PKC in developing hypothyroid rat brain. Thyroxine replacement partially corrected these changes. After being treated with bisindolmaleimide XI, a mainly selective inhibitor for PKCα, the hypothyroid pups showed improved place navigation test results, and further Western blot analysis showed that PKCα expression in cytosol fractions was increased in hypothyroid rat brain with or without bisindolmaleimide XI treatment, but, after treatment with bisindolmaleimide XI, PKCα content in membrane fractions decreased almost to normal. Therefore, we conclude that PKCα appears to be involved in the impaired brain development observed in perinatal hypothyroid rat brain.
蛋白激酶 Cα（PKCα）在各种刺激下参与调节多种细胞功能，如增殖、分化和凋亡。激活的 PKCα 介导氧化应激、细胞凋亡和炎症反应。甲状腺激素（TH）对哺乳动物中枢神经系统的正常发育至关重要。在大脑发育的关键时期，TH 缺乏会导致永久性的认知和神经损伤。在本研究中，我们试图探讨 PKCα 是否参与发育性甲状腺功能减退大鼠脑功能障碍。通过给予母鼠每天 30mg 的丙硫氧嘧啶来获得严重的围产期甲状腺功能减退症。甲状腺功能减退症幼鼠的脑胞质和膜部分的 PKC 活性显著增加。膜 PKC 活性的变化比胞质更明显，甲状腺功能减退症导致膜 PKC 活性与胞质 PKC 活性的比值升高，这意味着发育性甲状腺功能减退大鼠脑内 PKC 异常激活。甲状腺素替代治疗部分纠正了这些变化。在用主要选择性 PKCα抑制剂双吲哚马来酰亚胺 XI 处理后，甲状腺功能减退症幼鼠的位置导航测试结果得到改善，进一步的 Western blot 分析表明，甲状腺功能减退症大鼠脑胞质部分的 PKCα 表达增加，无论是否用双吲哚马来酰亚胺 XI 处理，但在用双吲哚马来酰亚胺 XI 处理后，膜部分的 PKCα 含量几乎降至正常。因此，我们得出结论，PKCα 似乎参与了围产期甲状腺功能减退大鼠脑发育受损的过程。
