title: Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats.
abstract: Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively. Moreover, hyperphosphorylation of the cytoskeletal proteins was not reversed by T3 and poorly reversed by T4. In addition, congenital hypothyroidism is associated with downregulation of astrocyte glutamate transporters (GLAST and GLT-1) leading to decreased glutamate uptake and subsequent influx of Ca(2+) through N-methyl-D-aspartate (NMDA) receptors. The Na(+)-coupled (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation into hippocampal cells also might cause an increase in the intracellular Ca(2+) concentration by opening voltage-dependent calcium channels (VDCC). The excessive influx of Ca(2+) through NMDA receptors and VDCCs might lead to an overload of Ca(2+) within the cells, which set off glutamate excitotoxicity and oxidative stress. The inhibited acetylcholinesterase (AChE) activity might also induce Ca(2+) influx. The inhibited glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyl transferase (GGT) activities, associated with altered glutamate and neutral amino acids uptake could somehow affect the GSH turnover, the antioxidant defense system, as well as the glutamate-glutamine cycle. Reduced levels of S100B and glial fibrillary acidic protein (GFAP) take part of the hypothyroid condition, suggesting a compromised astroglial/neuronal neurometabolic coupling which is probably related to the neurotoxic damage in hypothyroid brain.
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Daiane
authors.initials: D
authors.lastname: Cattani
authors.forename: Paola Bez
authors.initials: PB
authors.lastname: Goulart
authors.forename: Vera Lúcia de Liz Oliveira
authors.initials: VL
authors.lastname: Cavalli
authors.forename: Elisa
authors.initials: E
authors.lastname: Winkelmann-Duarte
authors.forename: André Quincozes
authors.initials: AQ
authors.lastname: Dos Santos
authors.forename: Paula
authors.initials: P
authors.lastname: Pierozan
authors.forename: Daniela Fraga
authors.initials: DF
authors.lastname: de Souza
authors.forename: Viviane Mara
authors.initials: VM
authors.lastname: Woehl
authors.forename: Marilda C
authors.initials: MC
authors.lastname: Fernandes
authors.forename: Fátima Regina Mena Barreto
authors.initials: FR
authors.lastname: Silva
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.forename: Regina
authors.initials: R
authors.lastname: Pessoa-Pureur
authors.forename: Ariane
authors.initials: A
authors.lastname: Zamoner
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002452:Cell Count; D003409:Congenital Hypothyroidism / Q000201:enzymology* / Q000473:pathology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D008297:Male; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; C579158:S100b protein, rat; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D013963:Thyroid Hormones; D018698:Glutamic Acid; D000110:Acetylcholinesterase; C548246:Ache protein, rat