Enprofyllline protects neurons

Enprofyllline - Toxicity Pathways in ALS Neurodegenerative Dis 2005;2:160165 DOI 10.1159/000089621 Diseases Enprofylline Protects Motor Neurons

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Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Toxicity Pathways in ALS Neurodegenerative Dis 2005;2:160–165 DOI: 10.1159/000089621 Enprofylline Protects Motor Neurons from in vitro Excitotoxic Challenge Jelena Mojsilovic-Petrovic Amrita Arneja Robert G. Kalb Children’s Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, Philadelphia, Pa. , USA motor neurons vulnerable to excitotoxic challenge. Con- clusion: Selective, high-afF nity adenosine A 2a antago- nists merit consideration as therapeutic agents for the treatment of ALS. Copyright © 2005 S. Karger AG, Basel Introduction The excessive activation of cell surface glutamate re- ceptors can cause neuronal death [1] . This process, termed excitotoxicity, is believed to be a central event in a variety of pathological situations such as stroke, traumatic injury and epilepsy [2] . Excitotoxicity is also believed to par- ticipate in neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), for example, higher-than-normal levels of extracellular glutamate have been linked to de- fects in re-uptake mechanism and by virtue of the persis- tent activation of glutamate receptors initiate cell death [3–5] . The character of motor neuron glutamate receptors may underlie the cell type speci± city seen in this disease [6, 7] . Excitotoxic insult of motor neurons has been modeled in a variety of ways in vitro, including cultures of organ- otypic spinal cord slices, mixed dissociated spinal cord cells and puri± ed motor neurons [8–12] . Such models sys- tems have yielded important insights into the role of spe- Key Words Adenosine A 2a receptor ? Brain-derived neurotrophic factor Trk receptor Transactivation Amyotrophic lateral sclerosis Abstract Background: The death of motor neurons in amyotrophic lateral sclerosis (ALS) is believed to result, in part, from unrestrained activation of glutamate receptors (excito- toxicity). In some in vitro models, excitotoxic death only occurs if motor neurons develop in the presence of the growth factor, brain-derived neurotrophic factor (BDN±). Objective: Since the increased vulnerability of motor neurons evoked by BDN± 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 recep- tor 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 BDN± signaling makes Diseases Robert G. Kalb Children’s Hospital of Philadelphia/ARC #814 3615 Civic Center Boulevard, Philadelphia, PA 19104 (USA) Tel. +1 215 590 0691, Fax +1 267 426 5134 E-Mail [email protected] © 2005 S. Karger AG, Basel 1660–2854/05/0024–0160$22.00/0 Accessible online at: www.karger.com/ndd
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This note was uploaded on 01/07/2011 for the course BIPN BIPN 144 taught by Professor Bier during the Spring '10 term at UCSD.

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Enprofyllline - Toxicity Pathways in ALS Neurodegenerative Dis 2005;2:160165 DOI 10.1159/000089621 Diseases Enprofylline Protects Motor Neurons

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