PMID- 18384166
OWN - NLM
STAT- MEDLINE
DCOM- 20080610
LR  - 20180315
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Linking)
VI  - 63
IP  - 5
DP  - 2008 May
TI  - Activated Src kinases interact with the N-methyl-D-aspartate receptor after 
      neonatal brain ischemia.
PG  - 632-41
LID - 10.1002/ana.21365 [doi]
AB  - OBJECTIVE: Neonatal stroke is associated with the N-methyl-D-aspartate receptor 
      (NMDAR)-mediated excitotoxic brain injury. Src family kinases (SFKs) are 
      considered to be the molecular hub for NMDAR regulation. We determined the 
      relationship between SFKs activation and NMDAR tyrosine phosphorylation after 
      neonatal hypoxia-ischemia (HI) and investigated the neuroprotective potential of 
      a selective SFKs inhibitor, PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo 
      [3, 4-d] pyramidine), against neonatal brain ischemic injury. METHODS: The 
      Rice-Vannucci model was adapted for neonatal HI injury in postnatal day 7 CD1 
      mice. SFKs activity in the postsynaptic densities was measured by Western blot. 
      NMDAR tyrosine phosphorylation and their association with SFKs were determined by 
      coimmunoprecipitation. Brains from animals treated with PP2 or its inactive 
      analog, PP3, were examined histologically with cresyl violet and iron stain to 
      assess the degree of damage. RESULTS: Neonatal HI resulted in a rapid and 
      transient increase in tyrosine phosphorylation of NMDAR subunits NR2A and NR2B. 
      This upregulation correlated with the enhanced association of Fyn and Src with 
      NR2A and NR2B. SFKs were activated in the postsynaptic densities after HI. 
      Inhibition of SFKs with PP2 attenuated brain injury after neonatal HI, whereas 
      PP3 did not protect the brain from the HI insult. INTERPRETATION: SFKs may play 
      an important role in NMDAR-mediated excitotoxicity and downstream events leading 
      to neuronal death after neonatal HI. Inhibition of SFKs may provide protection 
      against neonatal stroke. Rather than blockade of NMDAR after HI in the developing 
      brain, it may be safer and more beneficial to manipulate components of the NMDAR 
      signaling complex at the postsynaptic density.
FAU - Jiang, Xiangning
AU  - Jiang X
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA 94143-0663, USA. xiangning.jiang@ucsf.edu
FAU - Mu, Dezhi
AU  - Mu D
FAU - Biran, Valerie
AU  - Biran V
FAU - Faustino, Joel
AU  - Faustino J
FAU - Chang, Shengjun
AU  - Chang S
FAU - Rincon, Christina M
AU  - Rincon CM
FAU - Sheldon, R Ann
AU  - Sheldon RA
FAU - Ferriero, Donna M
AU  - Ferriero DM
LA  - eng
GR  - 3R01 NS 33997/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (AG 1879)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain Ischemia/*drug therapy/*metabolism/pathology
MH  - Enzyme Activation/drug effects
MH  - Mice
MH  - Neuroprotective Agents/administration & dosage
MH  - Pyrimidines/*administration & dosage
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Signal Transduction/drug effects
MH  - Treatment Outcome
MH  - src-Family Kinases/*administration & dosage/*antagonists & inhibitors
EDAT- 2008/04/04 09:00
MHDA- 2008/06/11 09:00
CRDT- 2008/04/04 09:00
PHST- 2008/04/04 09:00 [pubmed]
PHST- 2008/06/11 09:00 [medline]
PHST- 2008/04/04 09:00 [entrez]
AID - 10.1002/ana.21365 [doi]
PST - ppublish
SO  - Ann Neurol. 2008 May;63(5):632-41. doi: 10.1002/ana.21365.