PMID- 19136940
OWN - NLM
STAT- MEDLINE
DCOM- 20090522
LR  - 20141120
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Linking)
VI  - 16
IP  - 4
DP  - 2009 Apr
TI  - GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA 
      receptor modulator S18986.
PG  - 624-37
LID - 10.1038/cdd.2008.188 [doi]
AB  - Positive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor 
      modulators include benzamide compounds that allosterically modulate AMPA 
      glutamate receptors. These small molecules that cross the blood-brain barrier 
      have been shown to act as a neuroprotectant by increasing the levels of 
      endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor 
      modulators have also been shown to increase the levels of growth-associated 
      protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal 
      function in vertebrates. The goal of this study was to determine whether GAP-43 
      was important in mediating the actions of positive AMPA receptor modulator 
      (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, 
      we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control 
      cultures; (2) this upregulation of GAP-43 is essential for mediating the 
      neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF 
      leads to an increase in the expression of the glutamate transporters GLT-1 and 
      GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 
      and GLAST expression is completely blocked in the absence of GAP-43. Taken 
      together this study concludes that GAP-43 is an important mediator of the 
      neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and 
      is essential for the success of positive AMPA receptor modulator-BDNF-based 
      neurotrophin therapy.
FAU - Gupta, S K
AU  - Gupta SK
AD  - National Brain Research Center, Manesar, Haryana, India.
FAU - Mishra, R
AU  - Mishra R
FAU - Kusum, S
AU  - Kusum S
FAU - Spedding, M
AU  - Spedding M
FAU - Meiri, K F
AU  - Meiri KF
FAU - Gressens, P
AU  - Gressens P
FAU - Mani, S
AU  - Mani S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090109
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Benzothiadiazines)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (GAP-43 Protein)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, AMPA)
RN  - 0 (S18986-1)
SB  - IM
MH  - Animals
MH  - Benzothiadiazines/*pharmacology
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Cell Death/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/*drug effects
MH  - GAP-43 Protein/genetics/*metabolism
MH  - Gene Expression Regulation/*drug effects
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - In Vitro Techniques
MH  - Mice
MH  - Mice, Knockout
MH  - Neuroprotective Agents/*pharmacology
MH  - Polymerase Chain Reaction
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, AMPA/*agonists
EDAT- 2009/01/13 09:00
MHDA- 2009/05/23 09:00
CRDT- 2009/01/13 09:00
PHST- 2009/01/13 09:00 [entrez]
PHST- 2009/01/13 09:00 [pubmed]
PHST- 2009/05/23 09:00 [medline]
AID - cdd2008188 [pii]
AID - 10.1038/cdd.2008.188 [doi]
PST - ppublish
SO  - Cell Death Differ. 2009 Apr;16(4):624-37. doi: 10.1038/cdd.2008.188. Epub 2009 
      Jan 9.