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Increased Pro-Nerve Growth Factor and p75 Neurotrophin Receptor Levels in Developing Hypothyroid Rat Cerebral Cortex Are Associated with Enhanced Apoptosis

Departments of Endocrinology (A.K., R.A.S., M.T., A.S., R.S., K.K., S.K.G., M.M.G.) and Pathology (L.P.), Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India

Address all correspondence and requests for reprints to: Prof. Madan M. Godbole, Head, Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India. E-mail: madangodbole{at}yahoo.co.in.

Thyroid hormone insufficiency adversely affects cortical development; however, its effect on apoptosis modulation during cerebral cortex development is not understood. We investigated the effect of perinatal hypothyroidism on apoptosis and its mechanisms during rat cerebral cortex development. Primary hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant and lactating rats and continued until the animals were killed (hypothyroid group). Cerebral cortices from pups were harvested at different postnatal ages (postnatal d 0, 8, 16, and 24 and adult), and apoptosis was quantitated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling and cleaved caspase-3 immunoreactivity. Compared with the euthyroid, primary somatosensory cortex (S1) in the hypothyroid group exhibited enhanced apoptosis. In S1 of euthyroid rats, apoptotic cells were mostly found in cortical layers I–III and the proportion of apoptotic cells enhanced significantly in the hypothyroid group (P < 0.001). Most of the apoptotic cells were neurons, as assessed by double immunolabeling. A significantly increased activation of caspase-3 and -7, decreased levels of antiapoptotic proteins Bcl-2 and Bcl-x_L, and increased levels of proapoptotic protein Bax was observed in the developing cerebral cortex of hypothyroid rats, compared with the euthyroid (P < 0.001). In addition, hypothyroidism significantly elevated the levels of 53-kDa pro-nerve growth factor (P < 0.001) and p75 neurotrophin receptor (P < 0.001) and decreased TrkA expression. Taken together, we provide evidence for the possible contribution of pro-nerve growth factor/p75 neurotrophin receptor pathway in hypothyroidism-enhanced apoptosis during rat cortical development. Thus, the present study may help in explaining the mechanism of the deleterious effect of thyroid hormone deficiency on cerebral cortex development in children.

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