Thyroid Hormones affect the Level and Activity of Nitric Oxide Synthase in Rat Cerebral Cortex during Postnatal Development

Serfözö, Zoltán; Kiss, P.; Kukor, Zoltán; Lontay, Beáta; Palatka, Károly; Varga, V.; Erdõdi, Ferenc; Elekes, Károly

doi:10.1007/s11064-007-9480-0

Cited by 22 publications

(15 citation statements)

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“…In contrast, PTU, which is a selective inhibitor of thyroid gland cell function, retards the developmental process, and decreases the density and intensity of nNOS-IR granule cell axon fibers, together with induction of the diminution of the cGMP level and abolishment of the cGMP-IR material in the cerebellum. Recently, similar to present findings, a positive correlation was observed between TH level and nNOS expression in the cerebral cortex at the same interval of postnatal ages [23]. In contrast, an inverse ratio was detected in 14- to 18-day-old embryos during maternal hypothyroidism [22], suggesting that the direction of nNOS regulation by TH is time dependent and may occur through different mechanisms during development.…”

Section: Discussionsupporting

confidence: 88%

“…The minimum level which can be detected by the method is 4 ng/l for T 3 and 1.8 µg/l for T 4 . Details of the measurement description can be found in our recent publication [23]. …”

Section: Methodsmentioning

confidence: 99%

“…Up to now, only a small number of studies have dealt with the possible interaction of TH and NO in the CNS, showing downregulation of nNOS expression in the embryonic cerebral cortex [22], but upregulation of nNOS expression in the postnatal cerebral cortex [23], in the adult hypothalamus [24], and enhanced nNOS activity in adult cortical synaptosomes [25] followed by the elevation of T 3 level. On the other hand, in recent non-neural studies, more attention was paid to hyperthyroidism-induced NOS-dependent vasodilatation [for review, see [26]].…”

Section: Introductionmentioning

confidence: 99%

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Thyroid Hormone Level Positively Regulates NOS and cGMP in the Developing Rat Cerebellum

2009

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Thyroid hormones and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling play a significant role in the structural development of the cerebellum, respectively. In the present study, the possible contribution of neuronal NO synthase (NOS) and cGMP in the thyroid hormone-induced structural changes was investigated in the cerebella of postnatal rats at different hormone levels. Animals were treated from postnatal day 4 until days 7, 14, and 21, by i.p. injection of 1 μg thyroxine (T₄)/10 g body weight/4 days, or p.o. with 100 μg 6-n-propyl-2-thyouracil (PTU)/10 g body weight/day. Control groups consisted of i.p. and p.o. vehicle controls and PTU/T₄-treated animals. Measurement of serum fT₄, TSH as well as total T₃ and T₄ concentration of the cerebellar tissue indicated the changed thyroid status. nNOS extensively expressed in growing parallel fibers revealed by quantitative Western blot and layer analysis of immunohistochemically labeled coronal sections. Simultaneously, the cGMP concentration increased and the distribution of cGMP-immunoreactive (cGMP-IR) material in Purkinje cell perikarya and in the molecular layer expanded during cerebellar development. T₄ increased nNOS and cGMP level, and accelerated the development of nNOS-IR parallel fibers and cGMP-IR molecular layer. In contrast, PTU retarded the development by decreasing nNOS and cGMP concentration and slowing down layer formation. A single dose of T₄ could rescue the PTU-induced changes. Results suggest that the contribution of nNOS- NO/cGMP signaling in thyroid hormone regulated structural maturation of the cerebellum. The possible involvement of neurotrophins, calcium, and apoptotic events in this process was discussed.

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Section: Discussionsupporting

confidence: 88%

“…The minimum level which can be detected by the method is 4 ng/l for T 3 and 1.8 µg/l for T 4 . Details of the measurement description can be found in our recent publication [23]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thyroid Hormone Level Positively Regulates NOS and cGMP in the Developing Rat Cerebellum

2009

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“…The relationship between nNOS and poor survival of neurons and thyroid hormone deprivation has also been suggested 67. It has been shown that even a moderate and transient decrease in maternal thyroxine significantly increases nNOS expression, which is reversible by hormone replacement 67,72. In contrast, another report showed that propylthiouracil (PTU)-treated animals exhibited reduced NOS activity that could be rescued by T4 administration 72.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth

Hosseini

Dastghaib

Rafatpanah

et al. 2010

Clinics

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INTRODUCTION:Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period. The role of nitric oxide (NO) in learning and memory has been widely investigated.METHODS:This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory. Animals were divided into two groups and treated for 60 days from the first day of lactation. The control group received regular water, whereas animals in a separate group were given water supplemented with 0.03% methimazole to induce hypothyroidism. Male offspring were selected and tested in the Morris water maze. Samples of blood were collected to measure the metabolites of NO, NO2, NO3 and thyroxine. The animals were then sacrificed, and their hippocampi were removed to measure the tissue concentrations of NO2 and NO3.DISCUSSION:Compared to the control group's offspring, serum thyroxine levels in the methimazole group's offspring were significantly lower (P<0.01). In addition, the swim distance and time latency were significantly higher in the methimazole group (P<0.001), and the time spent by this group in the target quadrant (Q1) during the probe trial was significantly lower (P<0.001). There was no significant difference in the plasma levels of NO metabolites between the two groups; however, significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls (P<0.05).CONCLUSION:These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism; however, the precise underlying mechanism(s) remains to be elucidated.

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“…One of the major players in this process is a neurotransmitter known as nitric oxide (NO) produced by an enzyme neuronal nitric oxide synthase (nNOS) expressed in newly generated neurons. Although nNOS expression is modulated by steroid and THs during postnatal development (14,15), its modulation by TH during the embryonic period lacks definite evidence. Therefore, the present study has been performed to understand the effect of maternal TH deficiency on the expression of nNOS, and its consequent impact on generation and survival of neocortical neurons.…”

mentioning

confidence: 99%

Maternal Thyroid Hormone: A Strong Repressor of Neuronal Nitric Oxide Synthase in Rat Embryonic Neocortex

et al. 2008

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Understanding of how maternal thyroid inadequacy during early gestation poses a risk for developmental outcomes is still a challenge for the neuroendocrine community. Early neocortical neurogenesis is accompanied by maternal thyroid hormone (TH) transfer to fetal brain, appearance of TH receptors, and absence of antineurogenesis signals, followed by optimization of neuronal numbers through apoptosis. However, the effects of TH deprivation on neurogenesis and neuronal cell death before the onset of fetal thyroid are still not clear. We show that maternal TH deficiency during early gestational period causes massive premature elevation in the expression of neuronal nitric oxide synthase (nNOS) with an associated neuronal death in embryonic rat neocortex. Maternal hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant Sprague Dawley rats from embryonic d 6. Cerebral cortices from fetuses were harvested at different embryonic stages (embryonic d 14, 16, and 18) of hypothyroid and euthyroid groups. Immunoblotting and real-time PCR results showed that both protein and RNA levels of nNOS were prematurely increased under maternal hypothyroidism, and showed reversibility upon T4 administration. Immunohistochemistry revealed an increased nNOS immunoreactivity in both the cortical plate and proliferative zone of neocortex along with a corroborative decrease in the microtubule associated protein-2 positive neurons under maternal TH insufficiency. Results combined, put forth nNOS as a novel target of maternal TH action in embryonic neocortex, and underscore the importance of prenatal screening and timely rectification of maternal TH insufficiency, even of a moderate degree.

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Thyroid Hormones affect the Level and Activity of Nitric Oxide Synthase in Rat Cerebral Cortex during Postnatal Development

Cited by 22 publications

References 42 publications

Thyroid Hormone Level Positively Regulates NOS and cGMP in the Developing Rat Cerebellum

Thyroid Hormone Level Positively Regulates NOS and cGMP in the Developing Rat Cerebellum

Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth

Maternal Thyroid Hormone: A Strong Repressor of Neuronal Nitric Oxide Synthase in Rat Embryonic Neocortex

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