The maintenance of hippocampal pyramidal neuron populations is dependent on the modulation of specific cell cycle regulators by thyroid hormones.
The onset of adult hypothyroidism causes neuronal damage in the CA3 hippocampal region, which is attenuated by T(4) administration. We analyzed the expression of molecular proliferation markers (Cyclin D1 and PCNA), cellular damage-arrest (p53 and p21), and apoptosis (Bax/Bcl-2 index) in the hippocampus of hypothyroid (methimazole; 60 mg/kg) or thyroid replaced (T(4), 20 microg/kg; MMI+T(4) or T(3), 20 microg/kg; MMI+T(3)) adult male rats. Histological analysis showed that hypothyroid animals exhibit significant neuronal damage in all regions of the hippocampus accompanied by the triggering of the apoptotic pathway (increases in p53, p21 and the Bax/Bcl-2 index) and no changes in proliferation (Cyclin D1 and PCNA). MMI+T(4) replaced animals were completely protected with no changes in molecular markers. In contrast, MMI+T(3) replaced animals showed partial protection in which, although pro-apoptotic effects remained (increase in the Bax/Bcl-2), proliferative mechanisms were triggered (increase in p53, Cyclin D1 and PCNA expression). Our results indicate that thyroid hormones participate in the maintenance of the hippocampal neuronal population even in adulthood, suggesting that THs have different physiological roles as neuronal survival factors: T(4) prevents the activation of apoptotic pathways, whereas T(3) activates cell differentiation and proliferation mechanisms.
Alva-Sánchez
Claudia
C
Departamento de Fisiología Mauricio Russek, Escuela Nacional de Ciencias Biológicas-IPN, Prol. de Carpio y Plan de Ayala, C.P. 11340, D.F. México, Mexico.
Sánchez-Huerta
Karla
K
Arroyo-Helguera
Omar
O
Anguiano
Brenda
B
Aceves
Carmen
C
Pacheco-Rosado
Jorge
J
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D013956:Antithyroid Agents; C530106:Ccnd1 protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D013963:Thyroid Hormones; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D008713:Methimazole