PMID- 16957081
OWN - NLM
STAT- MEDLINE
DCOM- 20060926
LR  - 20220309
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 26
IP  - 36
DP  - 2006 Sep 6
TI  - Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk 
      receptors.
PG  - 9250-63
AB  - The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to 
      result from the interaction of a variety of factors including excitotoxicity, 
      accumulation of toxic proteins, and abnormal axonal transport. Previously, we 
      found that the susceptibility of motor neurons to excitotoxic insults can be 
      limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) 
      activation of the receptor tyrosine kinase B (TrkB). Here we show that this can 
      be achieved by direct kinase inhibition or by blockade of a transactivation 
      pathway that uses adenosine A2a receptors and src-family kinases (SFKs). 
      Downstream signaling cascades (such as mitogen-activated protein kinase and 
      phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to 
      protecting motor neurons from excitotoxic insult, these agents also prevent 
      toxicity that follows from the expression of mutant proteins (G85R superoxide 
      dismutase 1; G59S p150(glued)) that cause familial motor neuron disease. TrkB, 
      adenosine A2a receptors, and SFKs associate into complexes in lipid raft and 
      nonlipid raft membranes and the signaling from lipids rafts may be particularly 
      important because their disruption by cholesterol depletion blocks the ability of 
      BDNF to render motor neurons vulnerable to insult. The neuroprotective 
      versatility of Trk antagonism suggests that it may have broad utility in the 
      treatment of ALS patients.
FAU - Mojsilovic-Petrovic, Jelena
AU  - Mojsilovic-Petrovic J
AD  - Department of Neurology, Children's Hospital of Philadelphia, Joseph Stokes Jr. 
      Research Institute, Philadelphia, Pennsylvania 19104, USA.
FAU - Jeong, Goo-Bo
AU  - Jeong GB
FAU - Crocker, Amanda
AU  - Crocker A
FAU - Arneja, Amrita
AU  - Arneja A
FAU - David, Samuel
AU  - David S
FAU - Russell, David S
AU  - Russell DS
FAU - Kalb, Robert G
AU  - Kalb RG
LA  - eng
GR  - K08 DA000302-05/DA/NIDA NIH HHS/United States
GR  - R01 NS052325/NS/NINDS NIH HHS/United States
GR  - NS 52325/NS/NINDS NIH HHS/United States
GR  - R01 NS029837/NS/NINDS NIH HHS/United States
GR  - NS 29837/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  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Adenosine A2 Receptor Antagonists)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptor, Adenosine A2A)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - SIV03811UC (Kainic Acid)
SB  - IM
EIN - J Neurosci. 2006 Oct 4;26(40):10079. Russell, David [corrected to Russell, David 
      S]
MH  - *Adenosine A2 Receptor Antagonists
MH  - Amyotrophic Lateral Sclerosis/chemically induced/*metabolism/pathology/prevention 
      & control
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cells, Cultured
MH  - Kainic Acid
MH  - Motor Neurons/drug effects/*metabolism/*pathology
MH  - Neuroprotective Agents/administration & dosage
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Receptor, Adenosine A2A/metabolism
PMC - PMC6674510
EDAT- 2006/09/08 09:00
MHDA- 2006/09/27 09:00
PMCR- 2007/03/06
CRDT- 2006/09/08 09:00
PHST- 2006/09/08 09:00 [pubmed]
PHST- 2006/09/27 09:00 [medline]
PHST- 2006/09/08 09:00 [entrez]
PHST- 2007/03/06 00:00 [pmc-release]
AID - 26/36/9250 [pii]
AID - 3147352 [pii]
AID - 10.1523/JNEUROSCI.1856-06.2006 [doi]
PST - ppublish
SO  - J Neurosci. 2006 Sep 6;26(36):9250-63. doi: 10.1523/JNEUROSCI.1856-06.2006.