Mitochondrial-associated impairments of temozolomide on neural stem/progenitor cells and hippocampal neurons
| Autor: | Diana C. Pearre, Kaijun Di, Naomi Lomeli, Daniela A. Bota, Tzu-Feng Chung |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transcription Genetic Mitochondrion Hippocampal formation Regenerative Medicine medicine.disease_cause Hippocampus 0302 clinical medicine Neural Stem Cells Stem Cell Research - Nonembryonic - Human Neural stem/progenitor cells Cells Cultured Cancer Cultured Neurogenesis Mitophagy Cytochromes b Mitochondria Hippocampal neurons Neurological Molecular Medicine Stem Cell Research - Nonembryonic - Non-Human Mental health Transcription medicine.drug DNA Replication Biochemistry & Molecular Biology Cell Survival Cells Spatial Learning Biology Article 03 medical and health sciences Rare Diseases Genetic Neurotoxicity Genetics medicine Temozolomide Chemotherapy Animals Humans Progenitor cell Molecular Biology Animal Neurosciences NADH Dehydrogenase Cell Biology Stem Cell Research medicine.disease Brain Disorders Rats Brain Cancer Disease Models Animal 030104 developmental biology nervous system Oxidative stress Apoptosis Disease Models Cancer research 030217 neurology & neurosurgery |
| Zdroj: | Mitochondrion |
| Popis: | Primary brain tumor patients often experience neurological, cognitive, and depressive symptoms that profoundly affect quality of life. The DNA alkylating agent, temozolomide (TMZ), along with radiation therapy forms the standard of care for glioblastoma (GBM) - the most common and aggressive of all brain cancers. Numerous studies have reported that TMZ disrupts hippocampal neurogenesis and causes spatial learning deficits in rodents; however, the effect of TMZ on mature hippocampal neurons has not been addressed. In this study, we examined the mitochondrial-mediated mechanisms involving TMZ-induced neural damage in primary rat neural stem/progenitor cells (NSC) and hippocampal neurons. TMZ inhibited mtDNA replication and transcription of mitochondrial genes (ND1 and Cyt b) in NSC by 24h, whereas the effect of TMZ on neuronal mtDNA transcription was less pronounced. Transmission electron microscopy imaging revealed mitochondrial degradation in TMZ-treated NSC. Acute TMZ exposure (4h) caused a rapid reduction in dendritic branching and loss of postsynaptic density-95 (PSD95) puncta on dendrites. Longer TMZ exposure impaired mitochondrial respiratory activity, increased oxidative stress, and induced apoptosis in hippocampal neurons. The presented findings suggest that NSC may be more vulnerable to TMZ than hippocampal neurons upon acute exposure; however long-term TMZ exposure results in neuronal mitochondrial respiratory dysfunction and dendritic damage, which may be associated with delayed cognitive impairments. |
| Databáze: | OpenAIRE |
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