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Published on: November 20, 2015
Protein kinase Cα is involved in impaired perinatal hypothyroid rat brain development
Hong-Mei Zhang1, Ning Lin, Yan Dong
1Department of Endocrinology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Abstract:
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.
Insights
Thyroid hormone deficiency impairs brain development in rats by abnormally activating Protein Kinase C alpha (PKCα). Treatment with a PKCα inhibitor improved cognitive function, suggesting PKCα
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Thyroid hormone (TH) is critical for mammalian central nervous system development.
- TH deficiency during development causes irreversible cognitive and neurological deficits.
- Protein Kinase C alpha (PKCα) regulates cellular functions including proliferation, differentiation, and apoptosis.
Purpose of the Study:
- To investigate the role of PKCα in impaired brain function in developing hypothyroid rat models.
- To determine if PKCα is abnormally activated in perinatal hypothyroidism.
- To assess the therapeutic potential of targeting PKCα in hypothyroid-induced brain dysfunction.
Main Methods:
- Induction of severe perinatal hypothyroidism in rats using propylthiouracil.
- Measurement of brain Protein Kinase C (PKC) activity in cytosol and membrane fractions.
- Assessment of cognitive function using the place navigation test.
- Western blot analysis to evaluate PKCα expression levels.
- Pharmacological inhibition of PKCα using bisindolmaleimide XI.
Main Results:
- Hypothyroid rat pups exhibited significantly increased PKC activity in both cytosol and membrane fractions, with a marked increase in membrane-associated activity.
- Thyroxine replacement partially reversed these PKC activity changes.
- Inhibition of PKCα with bisindolmaleimide XI improved performance in the place navigation test.
- PKCα expression increased in the cytosol of hypothyroid rat brains, while membrane-bound PKCα decreased to near-normal levels after bisindolmaleimide XI treatment.
Conclusions:
- PKCα is abnormally activated in the developing rat brain during perinatal hypothyroidism.
- PKCα plays a significant role in the cognitive and neurological impairments associated with hypothyroidism.
- Targeting PKCα may offer a therapeutic strategy for mitigating brain dysfunction in congenital hypothyroidism.
