Neurotrophins protect against cytosine arabinoside-induced apoptosis of immature rat cerebellar neurons
| Autor: | Y. Leng, E. Chalecka-Franaszek, P. Leeds, De-Maw Chuang |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
Programmed cell death Antimetabolites Antineoplastic Cell Survival Blotting Western Apoptosis DNA Fragmentation Pharmacology Biology Protein Serine-Threonine Kinases Cytoplasmic Granules Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Phosphatidylinositol 3-Kinases Neurotrophic factors Cerebellum Proto-Oncogene Proteins Animals Nerve Growth Factors Protein kinase B Protein kinase C Protein Kinase C Neurons Kinase Brain-Derived Neurotrophic Factor Cytarabine Cell Biology MAP Kinase Kinase Kinases Rats carbohydrates (lipids) nervous system Biochemistry chemistry Trk receptor K252a Proto-Oncogene Proteins c-akt |
| Zdroj: | Neurochemistry international. 46(1) |
| ISSN: | 0197-0186 |
| Popis: | Neurotrophin-induced neuroprotection against apoptosis was investigated using immature cultured cerebellar granule cells (CGC) from newborn rat pups. Apoptotic cell death induced by treatment with cytosine arabinoside (AraC) was confirmed by DNA fragmentation and quantified by cell survival assays. AraC was most effective in inducing apoptosis when added to CGC on the day of culture preparation, while less or no effect was observed when added at 24 or 48 h after plating, respectively. Pretreatment of CGC cultures for 24 h with brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3), robustly protected against AraC neurotoxicity. K252a, an inhibitor of the tropomyosin-related kinase (Trk) tyrosine kinase receptor family which showed no toxicity by itself, blocked BDNF protection of AraC-induced apoptosis in a concentration-dependent manner. Neither protein kinase C activation nor inhibition mimicked or affected BDNF protection against AraC neurotoxicity. BDNF, but not NT-3, treatment of immature CGC caused a marked, but transient activation of Akt through phosphatidylinositol (PI) 3-kinase. The neuroprotective effects of BDNF were suppressed by pretreatment with LY 294002 (a PI 3-kinase inhibitor). BDNF neuroprotection was also preceded by activation of mitogen activated protein kinase (MAPK) and suppressed by two MAPK/ERK (MEK)-selective inhibitors, PD 98059 and U-0126. Moreover, inhibitors of PI 3-kinase and MEK potentiated AraC-induced neurotoxicity. These results show that neurotrophins protect against AraC-induced apoptosis, at least in part, through TrkB-mediated activation of the PI 3-kinase/Akt and MEK signaling pathways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect