PMID- 10428835 OWN - NLM STAT- MEDLINE DCOM- 19990902 LR - 20220311 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 274 IP - 32 DP - 1999 Aug 6 TI - Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. PG - 22569-80 AB - Apoptosis is a form of programmed cell death that plays a pivotal role during development and in the homeostasis of the adult nervous systems. However, mechanisms that regulate neuronal apoptosis are not well defined. Here, we report that brain-derived neurotrophic factor (BDNF) protects cortical neurons against apoptosis induced by camptothecin or serum deprivation and activates the extracellular-signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI 3-kinase) pathways. Using pharmacological agents and transient transfection with dominant interfering or constitutive active components of the ERK or the PI 3-kinase pathway, we demonstrate that the ERK pathway plays a major role in BDNF neuroprotection against camptothecin. Furthermore, ERK is activated in cortical neurons during camptothecin-induced apoptosis, and inhibition of ERK increases apoptosis. In contrast, the PI 3-kinase pathway is the dominant survival mechanism for serum-dependent survival under normal culture conditions and for BDNF protection against serum withdrawal. These results suggest that the ERK pathway is one of several neuroprotective mechanisms that are activated by stress to counteract death signals in central nervous system neurons. Furthermore, the relative contribution of the ERK and PI 3-kinase pathways to neuronal survival may depend on the type of cellular injury. FAU - Hetman, M AU - Hetman M AD - Toxicology Program, Department of Environmental Health, the Graduate Program in Neurobiology and Behavior, the Graduate Program in Molecular and Cell Biology, University of Washington, Seattle, Washington 98195-7234, USA. FAU - Kanning, K AU - Kanning K FAU - Cavanaugh, J E AU - Cavanaugh JE FAU - Xia, Z AU - Xia Z LA - eng GR - 2 T32 AG00057-21/AG/NIA NIH HHS/United States GR - NS37359/NS/NINDS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Chromones) RN - 0 (Culture Media, Serum-Free) RN - 0 (Flavonoids) RN - 0 (Morpholines) RN - 0 (Neuroprotective Agents) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Topoisomerase I Inhibitors) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) RN - XT3Z54Z28A (Camptothecin) SB - IM MH - Animals MH - Apoptosis MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors/*metabolism MH - Camptothecin/pharmacology MH - Cells, Cultured MH - Cerebral Cortex/cytology/*metabolism MH - Chromones/pharmacology MH - Culture Media, Serum-Free/pharmacology MH - Flavonoids/pharmacology MH - Morpholines/pharmacology MH - Neurons/*drug effects MH - Neuroprotective Agents/pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - Topoisomerase I Inhibitors EDAT- 1999/07/31 00:00 MHDA- 1999/07/31 00:01 CRDT- 1999/07/31 00:00 PHST- 1999/07/31 00:00 [pubmed] PHST- 1999/07/31 00:01 [medline] PHST- 1999/07/31 00:00 [entrez] AID - S0021-9258(18)81578-2 [pii] AID - 10.1074/jbc.274.32.22569 [doi] PST - ppublish SO - J Biol Chem. 1999 Aug 6;274(32):22569-80. doi: 10.1074/jbc.274.32.22569.