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Enprofylline Protects Motor Neurons from in vitro Excitotoxic Challenge

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<sub>2a</sub> antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A<sub>2a</sub> receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge. Conclusion: Selective, high-affinity adenosine A<sub>2a</sub> antagonists merit consideration as therapeutic agents for the treatment of ALS. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurodegenerative Diseases Karger

Enprofylline Protects Motor Neurons from in vitro Excitotoxic Challenge

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Publisher
Karger
Copyright
© 2005 S. Karger AG, Basel
ISSN
1660-2854
eISSN
1660-2862
DOI
10.1159/000089621
Publisher site
See Article on Publisher Site

Abstract

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<sub>2a</sub> antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A<sub>2a</sub> receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge. Conclusion: Selective, high-affinity adenosine A<sub>2a</sub> antagonists merit consideration as therapeutic agents for the treatment of ALS.

Journal

Neurodegenerative Diseases – Karger

Published: Jan 1, 2006

Keywords: Transactivation; Amyotrophic lateral sclerosis; Adenosine A 2a receptor; Brain-derived neurotrophic factor; Trk receptor

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