Enprofylline protects motor neurons from in vitro excitotoxic challenge.
BACKGROUND
The death of motor neurons in amyotrophic lateral sclerosis (ALS) is believed to result, in part, from unrestrained activation of glutamate receptors (excitotoxicity). In some in vitro models, excitotoxic death only occurs if motor neurons develop in the presence of the growth factor, brain-derived neurotrophic factor (BDNF).


OBJECTIVE
Since the increased vulnerability of motor neurons evoked by BDNF is mediated by activation of TrkB, we sought to identify pharmacological agents that can block this pathway. Adenosine receptors are known to transactivate Trk receptors, leading us to examine the effects of manipulating of adenosine receptor signaling on Trk signaling and excitotoxic sensitivity.


METHODS
Spinal cord cultures were treated with adenosine receptor agonists and antagonists. The biochemical effects on Trk signaling and excitotoxic motor neuron death were examined.


RESULTS
We show here that adenosine A(2a) antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A(2a) receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge.


CONCLUSIONS
Selective, high-affinity adenosine A(2a) antagonists merit consideration as therapeutic agents for the treatment of ALS.
Mojsilovic-Petrovic
Jelena
J
Children's Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, PA 19104, USA.
Arneja
Amrita
A
Kalb
Robert G
RG
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D009046:Motor Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000187:drug effects / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D043683:Receptors, Adenosine A2; D014970:Xanthines; C034347:enprofylline; D020813:Receptor, trkB; D007608:Kainic Acid