Commentary

Thyroid Hormones (THs) regulate the development of all biological systems, particularly CNS [1-30], neuronal excitability and the ionic gradient [6,8]. The fetal hypothyroidism diminished the levels of nucleotides, ATPases (Na+, K+-ATPase, Ca2+-ATPase and Mg2+-ATPase) activities, and total adenylate; however, the adenylate energy charges displayed a tendency to an increase in cerebrum and cerebellum at gestation days 15 and 20 [25]. The synthesis of ATP delays considerably during hypothyroidism state [31] and changed the hydrolysis of adenine nucleotide in synaptosomes from hippocampus and cerebral cortex of rats [32]. The alterations in fetal ATPases might disrupt the neurotransmitter roles in the CNS [6]. The neonatal hypothyroidism alters the activity of these enzymes [33] and impairs the metabolic process, ionic transportation and neuronal functions [34-36].

On the other hand, perinatal hyperthyroidism stimulates the activities of ATPases and causes a maldevelopment and pathophysiological state [3]. However, Bruno, et al. [37] reported that hyperthyroidism during development inhibits the hydrolysis of AMP, ADP and ATP in synaptosomes from hippocampus and cerebral cortex of rats. This inhibition can disrupt the brain excitability [6]. Generally, both hypo- or hyper-thyroidism disordered the activities of ATPase in the frontal cortex and the hippocampus of rat [38]. Thus, hyperthyroidism changes the hydrolysis of ATP to adenosine, while hypothyroidism appears to delay the production of adenosine [6,32,37]. Thus, any thyroid disorders might alter the activities of ATPases and hydrolysis of nucleotides during the development. This can inhibit the nerve transmission and delay the cognitive functions. Further studies are needed to explore the non-genomic mechanisms of THs and developmental adenosinergic axis.

1. El-Bakry AM, El-Gareib AW, Ahmed RG. Comparative study of the effects of experimentally-induced hypothyroidism and hyperthyroidism in some brain regions in albino rats.  Int J Dev Neurosci. 2010; 28: 371-89. https://goo.gl/E7jehd
2. Ahmed RG, El-Gareib AW, Incerpi S. Lactating PTU exposure: II- Alter’s thyroid-axis and prooxidant-antioxidant balance in neonatal cerebellum. Int. Res. J. of Natural Sciences. 2014; 2: 1-20. https://goo.gl/Gw7Nmf
3. Ahmed OM, Abd El-Tawab SM, Ahmed RG. Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: I- The development of the thyroid hormones-neurotransmitters and adenosinergic system interactions. Int J Dev Neurosci. 2010; 28: 437-54. https://goo.gl/vF5mkE
4. Ahmed OM, Ahmed RG. Hypothyroidism. In A New Look At Hypothyroidism. Dr. D. Springer (Ed.), ISBN: 978-953-51-0020-1), In Tech Open Access Publisher. 2012; Chapter 1: pp. 1-20. https://goo.gl/SUfGhq
5. Ahmed OM, Ahmed RG, El-Gareib AW, El-Bakry AM, Abd El-Tawab SM. Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: II-The developmental pattern of neurons in relation to oxidative stress and antioxidant defense system. Int J Dev Neurosci. 2012; 30: 517-37. https://goo.gl/MY3Dbe
6. Ahmed OM, El-Gareib AW, El-Bakry AM, Abd El-Tawab SM, Ahmed RG. Thyroid hormones states and brain development interactions. Int J Dev Neurosci. 2008; 26: 147-209. https://goo.gl/ykazPD
7. Ahmed RG. Perinatal 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin exposure alters developmental neuroendocrine system. Food Chem Toxicol. 2011; 49: 1276-84. https://goo.gl/M9YgVa
8. Ahmed, R.G., 2012a. Maternal-newborn thyroid dysfunction. In the Developmental Neuroendocrinology, pp. 1-369. Ed R.G. Ahmed. Germany: LAP LAMBERT Academic Publishing GmbH & Co KG.
9. Ahmed RG. Maternal-Fetal Thyroid Interactions, Thyroid Hormone, Dr. NK. Agrawal (Ed.), ISBN: 978-953-51-0678-4. In Tech Open Access Publisher. Chapter 5; 2012b: pp. 125-156. https://goo.gl/ysH3x9
10. Ahmed RG. Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction. J Endocrinol. 2013; 219: 205-15. https://goo.gl/mqG6LC
11. Ahmed RG. Editorial: Do PCBs modify the thyroid-adipokine axis during development? Annals Thyroid Res. 2014; 1: 11-12. https://goo.gl/1KSBSq
12. Ahmed, R.G., 2015a. Chapter 1: Hypothyroidism and brain development. In Advances in Hypothyroidism Treatment. Avid Science Borsigstr. 9, 10115 Berlin, Berlin, Germany. Avid Science Publications level 6, Melange Towers, Wing a, Hitec City, Hyderabad, Telangana, India. pp. 1-40.
13. Ahme RG. Hypothyroidism and brain developmental players. Thyroid Research J. 2015: 8: 1-12. https://goo.gl/na1QxJ
14. Ahmed RG. Editorials and Commentary: Maternofetal thyroid action and brain development. Jounal of Advances in Biology. 2015; 7: 1207-1213. https://goo.gl/7SHztq
15. Ahmed RG. Gestational dexamethasone alters fetal neuroendocrine axis. Toxicology Letters. 2016; 258: 46–54. https://goo.gl/a3CMtj
16. Ahmed RG. Neonatal polychlorinated biphenyls-induced endocrine dysfunction. Ann. Thyroid Res. 2016; 2: 34-35. https://goo.gl/VQKdsA
17. Ahmed RG. Maternal iodine deficiency and brain disorders. Endocrinol. Metab. Syndr. 2016; 5: 223.  https://goo.gl/h72CjA
18. Ahmed RG. Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction. Food Chem. Toxicology. 2016; 95: 168-174. https://goo.gl/HEpimq
19. Ahmed RG, Abdel-Latif M, Ahmed F. Protective effects of GM-CSF in experimental neonatal hypothyroidism. Int Immunopharmacol. 2015; 29: 538-543. https://goo.gl/AxnGC2
20. Ahmed RG, Abdel-Latif M, Mahdi E, El-Nesr K. Immune stimulation improves endocrine and neural fetal outcomes in a model of maternofetal thyrotoxicosis. Int. Immunopharmacol. 2015; 29: 714-721. https://goo.gl/sosg5V
21. Ahmed RG, Davis PJ, Davis FB, De Vito P, Farias RN, Luly P, Pedersen, et al.  Nongenomic actions of thyroid hormones: from basic research to clinical applications. An update.  Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry. 2013; 13: 46-59. https://goo.gl/uKp73D
22. Van Herck SL, Geysens S, Bald E, Chwatko G, Delezie E, Dianati E. Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues. J Endocrinol. 2013; 218: 105-15. https://goo.gl/DBbFDf
23. Ahmed RG, El-Gareib AW. Lactating PTU exposure: I- Alters thyroid-neural axis in neonatal cerebellum. Eur J of Biol and Medical Sci. Res. 2014; 2: 1-16. https://goo.gl/afxxrq
24. Ahmed RG, El-Gareib AW. Maternal carbamazepine alters fetal neuroendocrine-cytokines axis. Toxicology. 2017; 382: 59-66. https://goo.gl/13BcX9
25. Ahmed RG, Incerpi S. Gestational doxorubicin alters fetal thyroid–brain axis. Int J Dev Neurosci. 2013; 31: 96-104. https://goo.gl/qbLL4x
26. Ahmed RG, Incerpi S, Ahmed F, Gaber A. The developmental and physiological interactions between free radicals and antioxidant: Effect of environmental pollutants. J of Natural Sci. Res. 2013; 3: 74-110. https://goo.gl/Hf6qXh
27. Candelotti E, De Vito P, Ahmed RG, Luly P, Davis P.J, Pedersen J.Z, et al. Thyroid hormones crosstalk with growth factors: Old facts and new hypotheses. Immun, Endoc. & Metab. Agents in Med. Chem. 2015; 15: 71-85. https://goo.gl/84pVS1
28. De Paolo De Vito, Elena Candelotti, Ragab G. Ahmed, Paolo Luly, Paul J. Davis, et al. Role of thyroid hormones in insulin resistance and diabetes. Immun. Endoc. &Metab. Agents in Med. Chem. 2015; 15: 86-93. https://goo.gl/xG1QJP
29. El-Ghareeb AA, El-Bakry AM, Ahmed RG, Gaber A. Effects of zinc supplementation in neonatal hypothyroidism and cerebellar distortion induced by maternal carbimazole. Asian Journal of Applied Sciences. 2016; 4: 1030-1040. https://goo.gl/FcMKMA
30. Incerpi S, Hsieh MT, Lin HY, Cheng GY, De Vito P, Fiore AM, et al. Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: new roles for integrin αvβ3. Am J Physiol Cell Physiol. 2014; 307: C150-C161. https://goo.gl/vBMzQt
31. Dave BN, Katyare SS, Billimoria FR. Effect of neonatal hypothyroidism on Ca2+-ATPase activity in the rat brain. Neuroscience Letters. 2006; 395: 33-36. https://goo.gl/h6Y5Bo
32. Bruno AN, Ricachenevsky FK, Pochmann D, Bonan CD, Battastini AM, Barreto-Chaves ML, et al. Hypothyroidism changes adenine nucleotide hydrolysis in synaptosomes from hippocampus and cerebral cortex of rats in different phases of development. Int J Dev Neurosci. 2005; 23: 37-44. https://goo.gl/Xkpv1i
33. Billimoria FR, Dave BN, Katyare SS. Neonatal hypothyroidism alters the kinetic properties of Na+, K+-ATPase in synaptic plasma membranes from rat brain. Brain Res Bull. 2006; 70: 55-61. https://goo.gl/Zmi9Qy
34. Gerges NZ, Alkadhi KA. Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. Hippocampus. 2004; 14: 40-45. https://goo.gl/uSKhhY
35. Mussa GC, Mussa F, Bretto R, Zambelli MC, Silvestro L. Influence of thyroid in nervous system growth. Minerva Pediatr. 2001; 53: 325-353. https://goo.gl/jHekWw
36. Sui L, Gilbert ME. Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology. 2003; 144: 4195-4203. https://goo.gl/SRXnxt
37. Bruno AN, Da Silva RS, Bonan CD, Battastini AM, Barreto-chaves ML, Sarkis JJ. Hyperthyroidism modifies ecto-nucleotidase activities in synaptosomes from hippocampus and cerebral cortex of rats in different phases of development. Int J Dev Neurosci. 2003; 21: 401-408. https://goo.gl/9Ezju1
38. Carageorgiou H, Pantos C, Zarros A, Stolakis V, Mourouzis I, Cokkinos D, et al. Changes in acetylcholinesterase, Na+, K+-ATPase, and Mg2+-ATPase activities in the frontal cortex and the hippocampus of hyper-and hypothyroid adult rats. Metabolism. 2007; 56: 1104-1110. https://goo.gl/c87Nn2