PMID- 10995840 OWN - NLM STAT- MEDLINE DCOM- 20001018 LR - 20211203 IS - 0270-6474 (Print) IS - 1529-2401 (Electronic) IS - 0270-6474 (Linking) VI - 20 IP - 18 DP - 2000 Sep 15 TI - Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3'-kinase/protein kinase B signaling. PG - 6962-7 AB - The neurotrophin brain-derived neurotrophic factor (BDNF) serves as a survival, mitogenic, and differentiation factor in both the developing and adult CNS and PNS. In an attempt to identify the molecular mechanisms underlying BDNF neuroprotection, we studied activation of two potentially neuroprotective signal transduction pathways by BDNF in a CNS trauma model. Transection of the optic nerve (ON) in the adult rat induces secondary death of retinal ganglion cells (RGCs). Repeated intraocular injections of BDNF prevent the degeneration of RGCs 14 d after ON lesion most likely by inhibition of apoptosis. Here, we report that BDNF activates both protein kinase B (PKB) via a phosphatidyl-inositol-3'-kinase (PI-3-K)-dependent mechanism and the mitogen-activated protein kinases extracellular signal-regulated kinase 1 (ERK1) and ERK2. Furthermore, we provide evidence that BDNF suppresses cleavage and enzymatic activity of the neuronal cell death effector caspase-3. Distinct from our recent study in which inhibition of the PI-3-K/PKB pathway attenuated the survival-promoting action of insulin-like growth factor-I on axotomized RGCs (Kermer et al., 2000), it does not in the case of BDNF. Thus, we assume that BDNF does not depend on a single signal transduction pathway exerting its neuroprotective effects on lesioned CNS neurons. FAU - Klocker, N AU - Klocker N AD - Department of Neurology, University of Tubingen, 72076 Tubingen, Germany. nikolaj.kloecker@uni-tuebingen.de FAU - Kermer, P AU - Kermer P FAU - Weishaupt, J H AU - Weishaupt JH FAU - Labes, M AU - Labes M FAU - Ankerhold, R AU - Ankerhold R FAU - Bahr, M AU - Bahr M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Caspase Inhibitors) RN - 0 (Enzyme Inhibitors) RN - 0 (Neuroprotective Agents) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - Animals MH - Axotomy MH - Brain-Derived Neurotrophic Factor/*metabolism/pharmacology MH - Caspase 3 MH - Caspase Inhibitors MH - Drug Administration Routes MH - Enzyme Inhibitors/administration & dosage MH - Female MH - MAP Kinase Signaling System/drug effects MH - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism MH - Neuroprotective Agents/*metabolism/pharmacology MH - Optic Nerve/physiology/surgery MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation/drug effects MH - *Protein Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*metabolism MH - Proto-Oncogene Proteins c-akt MH - Rats MH - Rats, Sprague-Dawley MH - Retinal Ganglion Cells/cytology/drug effects/*metabolism MH - Signal Transduction/drug effects PMC - PMC6772828 EDAT- 2000/09/21 11:00 MHDA- 2000/10/21 11:01 PMCR- 2001/03/15 CRDT- 2000/09/21 11:00 PHST- 2000/09/21 11:00 [pubmed] PHST- 2000/10/21 11:01 [medline] PHST- 2000/09/21 11:00 [entrez] PHST- 2001/03/15 00:00 [pmc-release] AID - 20/18/6962 [pii] AID - 4537 [pii] AID - 10.1523/JNEUROSCI.20-18-06962.2000 [doi] PST - ppublish SO - J Neurosci. 2000 Sep 15;20(18):6962-7. doi: 10.1523/JNEUROSCI.20-18-06962.2000.