PMID- 12356841
OWN - NLM
STAT- MEDLINE
DCOM- 20021108
LR  - 20211203
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 43
IP  - 10
DP  - 2002 Oct
TI  - Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death 
      through MAPK and PI3K signaling pathways.
PG  - 3319-26
AB  - PURPOSE: Brain-derived neurotrophic factor (BDNF) has a potential neuroprotective 
      effect on axotomized retinal ganglion cells (RGCs); however, the mechanism, in 
      regard to intracellular signaling, of BDNF-induced neuroprotection of RGCs is 
      largely unknown. Intracellular signaling was investigated, by using axotomized 
      RGCs and the relative contribution of the two major downstream signaling routes 
      of TrkB determined--that is, mitogen-activated protein kinase (MAPK) and 
      phosphatidylinositol 3 kinase (PI3K)-Akt routes, mediated by BDNF. METHODS: 
      Neuroprotective effects of BDNF were determined by quantifying the surviving RGCs 
      after axotomy, by retrograde labeling. The MAPK and Akt levels were determined by 
      Western blot analysis and activity assays. Quantification of the relative 
      contribution of the two signaling pathways was performed by use of specific 
      inhibitors for MAPK and PI3K (i.e., U0126 and LY294002, respectively). RESULTS: 
      Intravitreous administration of BDNF had the most profound neuroprotective 
      effects on axotomized RGCs among the neurotrophins. Burst phosphorylation of MAPK 
      and Akt was induced by BDNF within 1 hour and was sustained over 2 weeks in the 
      whole retina. Immunohistochemistry revealed that phosphorylated MAPK was detected 
      in the RGCs and retinal Muller cells, and Akt was in the RGCs. BDNF-induced 
      phosphorylation of MAPK and Akt was suppressed by their specific inhibitors. 
      Moreover, administration of U0126 and LY294002 decreased significantly, but only 
      partially, the neuroprotective effect of BDNF on the axotomized RGCs. 
      CONCLUSIONS: BDNF-mediated signaling involves activation of both MAPK and Akt on 
      the axotomized adult rat retina, and the collaboration of both MAPK and PI3K-Akt 
      pathways seems to be necessary in neuroprotective signaling in axotomized RGCs.
FAU - Nakazawa, Toru
AU  - Nakazawa T
AD  - Department of Molecular Genetics, National Institute for Longevity Sciences, 
      Aichi Japan.
FAU - Tamai, Makoto
AU  - Tamai M
FAU - Mori, Nozomu
AU  - Mori N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - *Axotomy
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Cell Death/drug effects/physiology
MH  - Enzyme Activation/physiology
MH  - Male
MH  - Mitogen-Activated Protein Kinases/*physiology
MH  - Neuroprotective Agents/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/*physiology
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/physiology
MH  - Proto-Oncogene Proteins c-akt
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Retina/physiology
MH  - Retinal Ganglion Cells/drug effects/*physiology
MH  - Signal Transduction/*physiology
EDAT- 2002/10/03 04:00
MHDA- 2002/11/26 04:00
CRDT- 2002/10/03 04:00
PHST- 2002/10/03 04:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/10/03 04:00 [entrez]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2002 Oct;43(10):3319-26.