PMID- 10212287 OWN - NLM STAT- MEDLINE DCOM- 19990507 LR - 20191023 IS - 0270-6474 (Print) IS - 1529-2401 (Electronic) IS - 0270-6474 (Linking) VI - 19 IP - 9 DP - 1999 May 1 TI - Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascades and site of ethanol action. PG - 3277-86 AB - Cerebellar granule neurons cultured in medium containing a physiological concentration of KCl (5 mM) undergo apoptosis. The cells can be rescued by the in vitro addition of NMDA. The protective effect of NMDA is thought to reflect the in vivo innervation of developing cerebellar granule neurons by glutamatergic afferents. In the current work, we investigated the mechanism of the anti-apoptotic (protective) effect of NMDA. NMDA treatment reduced caspase-3-like activity in cerebellar granule neurons, and the time course and concentration dependence of the protective effect of NMDA mirrored the ability of NMDA to induce brain-derived neurotrophic factor (BDNF) expression. Furthermore, a Trk receptor antagonist, K252a, as well as a blocking antibody to BDNF, attenuated the protective effects of both NMDA and BDNF. These results suggest that NMDA-induced BDNF expression mediates the anti-apoptotic effect of NMDA. The protective effects of NMDA and BDNF were reduced by inhibitors of the phosphatidylinositol 3'-OH kinase (PI 3-kinase) signal transduction cascade (wortmannin and LY29004) but not by a MAP kinase kinase (MEK) inhibitor (PD98059) or a protein kinase A inhibitor (Rp-cAMPS). BDNF increased phosphorylation of Akt, a target of PI 3-kinase, and NMDA also induced Akt phosphorylation, but only after an exposure that was long enough to induce BDNF expression. Furthermore, ethanol, which interferes with NMDA receptor function, inhibited the NMDA-induced increase in BDNF levels but did not block the protective effect of BDNF. These findings further support the role of BDNF in the anti-apoptotic effect of NMDA in cerebellar granule neurons and suggest that the NMDA-BDNF interaction may play a key role in in vivo cerebellar granule neuron development, as well as in the deleterious effects of ethanol on the developing cerebellum. FAU - Bhave, S V AU - Bhave SV AD - Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. FAU - Ghoda, L AU - Ghoda L FAU - Hoffman, P L AU - Hoffman PL LA - eng GR - AA3527/AA/NIAAA NIH HHS/United States GR - AA9005/AA/NIAAA NIH HHS/United States 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 Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carbazoles) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Indole Alkaloids) RN - 0 (Morpholines) RN - 0 (Neuroprotective Agents) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 3K9958V90M (Ethanol) RN - 6384-92-5 (N-Methylaspartate) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 97161-97-2 (staurosporine aglycone) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.22.- (Caspases) SB - IM MH - Animals MH - Apoptosis/drug effects/physiology MH - Brain-Derived Neurotrophic Factor/genetics/pharmacology/*physiology MH - Carbazoles/pharmacology MH - Caspase 3 MH - Caspases/metabolism MH - Cells, Cultured MH - Cerebellum/*cytology/*physiology MH - Chromones/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Ethanol/*pharmacology MH - Indole Alkaloids MH - Insulin-Like Growth Factor I/pharmacology/physiology MH - Morpholines/pharmacology MH - N-Methylaspartate/*pharmacology/physiology MH - Neurons/*cytology/drug effects/*physiology MH - Neuroprotective Agents/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects/physiology PMC - PMC6782254 EDAT- 1999/04/23 00:00 MHDA- 1999/04/23 00:01 PMCR- 1999/11/01 CRDT- 1999/04/23 00:00 PHST- 1999/04/23 00:00 [pubmed] PHST- 1999/04/23 00:01 [medline] PHST- 1999/04/23 00:00 [entrez] PHST- 1999/11/01 00:00 [pmc-release] AID - 2952 [pii] AID - 10.1523/JNEUROSCI.19-09-03277.1999 [doi] PST - ppublish SO - J Neurosci. 1999 May 1;19(9):3277-86. doi: 10.1523/JNEUROSCI.19-09-03277.1999.