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The Journal of Neuroscience, September 15, 2000, 20(18):6962-6967
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
Nikolaj Klöcker1, 2, Pawel Kermer1, 3, Jochen H. Weishaupt1, Monika Labes1, Richard Ankerhold1, and Mathias Bähr1 Departments of 1 Neurology and 2 Physiology, University of Tübingen, 72076 Tübingen, Germany, and 3 The Burnham Institute, Program on Cell Death and Apoptosis Research, San Diego, California 92037
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.
Key words: retinal ganglion cell; axotomy; caspase-3; brain-derived neurotrophic factor (BDNF); neuroprotection; mitogen-activated protein kinase (MAPK); protein kinase B (PKB)
Copyright © 2000 Society for Neuroscience 0270-6474/00/20186962-06$05.00/0
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