Hypothyroidism Induces Interleukin-1-Dependent Autophagy Mechanism as a Key Mediator of Hippocampal Neuronal Apoptosis and Cognitive Decline in Postnatal Rats
Autor: | Jitendra Vishwakarma, Rukmani Pandey, Juhi Mishra, Shailendra Kumar Maurya, Manoj Kumar Shukla, Asmita Garg, Sanghamitra Bandyopadhyay, Naibedya Chattopadhyay, Keerti Gupta, Rafat Malik |
---|---|
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Autophagy Neuroscience (miscellaneous) Hippocampus Interleukin Hippocampal formation Biology 03 medical and health sciences Cellular and Molecular Neuroscience 030104 developmental biology 0302 clinical medicine Endocrinology Neurology Apoptosis Internal medicine medicine Cognitive decline 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway Neuroinflammation |
Zdroj: | Molecular Neurobiology. 58:1196-1211 |
ISSN: | 1559-1182 0893-7648 |
DOI: | 10.1007/s12035-020-02178-9 |
Popis: | Thyroid hormone (TH) is essential for brain development, and hypothyroidism induces cognitive deficits in children and young adults. However, the participating mechanisms remain less explored. Here, we examined the molecular mechanism, hypothesizing the involvement of a deregulated autophagy and apoptosis pathway in hippocampal neurons that regulate cognitive functions. Therefore, we used a rat model of developmental hypothyroidism, generated through methimazole treatment from gestation until young adulthood. We detected that methimazole stimulated the autophagy mechanism, characterized by increased LC3B-II, Beclin-1, ATG7, and ATG5-12 conjugate and decreased p-mTOR/mTOR and p-ULK1/ULK1 autophagy regulators in the hippocampus of developing and young adult rats. This methimazole-induced hippocampal autophagy could be inhibited by thyroxine treatment. Subsequently, probing the upstream mediators of autophagy revealed an increased hippocampal neuroinflammation, marked by upregulated interleukin (IL)-1alpha and beta and activated microglial marker, Iba1, promoting neuronal IL-1 receptor-1 expression. Hence, IL-1R-antagonist (IL-1Ra), which reduced hippocampal neuronal IL-1R1, also inhibited the enhanced autophagy in hypothyroid rats. We then linked these events with hypothyroidism-induced apoptosis and loss of hippocampal neurons, where we observed that like thyroxine, IL-1Ra and autophagy inhibitor, 3-methyladenine, reduced the cleaved caspase-3 and TUNEL-stained apoptotic neurons and enhanced Nissl-stained neuronal count in methimazole-treated rats. We further related these molecular results with cognition through Y-maze and passive avoidance tests, demonstrating an IL-1Ra and 3-methyladenine-mediated improvement in learning-memory performances of the hypothyroid rats. Taken together, our study enlightens the critical role of neuroinflammation-dependent autophagy mechanism in TH-regulated hippocampal functions, disrupted in developmental hypothyroidism. |
Databáze: | OpenAIRE |
Externí odkaz: |
načítá se...