4.5 Article

Mitochondrial-associated impairments of temozolomide on neural stem/progenitor cells and hippocampal neurons

期刊

MITOCHONDRION
卷 52, 期 -, 页码 56-66

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.mito.2020.02.001

关键词

Chemotherapy; Mitochondria; Neural stem/progenitor cells; Hippocampal neurons; Oxidative stress; Neurotoxicity; Temozolomide

资金

  1. NCATS NIH HHS [UL1 TR001414] Funding Source: Medline
  2. NCI NIH HHS [T32 CA060396, P30 CA062203] Funding Source: Medline
  3. NIGMS NIH HHS [R25 GM055246] Funding Source: Medline
  4. NINDS NIH HHS [K08 NS072234, T32 NS082174] Funding Source: Medline

向作者/读者索取更多资源

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 24 h, 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 (4 h) 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.

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