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Adenosine 2A Receptor Antagonism in Acute Cervical Contusion/Compression Injury Preserves Serotonin‐Dependent Phrenic Motor Plasticity
Author(s) -
Seven Yasin B.,
Allen Latoya L.,
Tadjalli Arash,
Zwick Amanda,
ElChami Mohamad,
Perim Raphael R.,
GonzalezRothi Elisa J.,
Mitchell Gordon S.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.843.8
Subject(s) - serotonergic , medicine , anesthesia , adenosine , neuroscience , serotonin , receptor , biology
Cervical spinal cord injury (cSCI) disrupts descending respiratory neural pathways, causing respiratory muscle paralysis and decreased breathing capacity. Immediately following acute trauma, a suite of pathogenic mechanisms contributes to secondary degeneration and respiratory failure including spinal ischemia, excitotoxicity and inflammation. These events are accompanied by increased extracellular adenosine that activates adenosine receptor signaling cascades. Adenosine 2A receptor (A2AR) antagonism is shown to preserve neurons in neurodegenerative diseases and ischemic injury, likely due to reduced excitotoxicity and inflammation. However, little is known concerning how A2AR activation immediately following cSCI impacts the respiratory control system and its neuromodulatory inputs. Thus, the fundamental hypothesis guiding this study is that A2ARs exert pathogenic effects on respiratory function and plasticity immediately following cSCI. Serotonergic plasticity plays a significant role in the respiratory control network. For example, the phrenic motor system exhibits phrenic long‐term facilitation (pLTF) following moderate acute intermittent hypoxia (AIH), a form of phrenic motor plasticity that requires raphe serotonergic neuron activation. Spinal trauma induces neurodegeneration in descending raphe serotonergic axons, undermining the capacity for pLTF following cSCI. Here, we tested the hypothesis that A2AR antagonism in acute cSCI preserves serotonin‐dependent, AIH‐induced pLTF in adult male Sprague‐Dawley rats with mid‐cervical spinal contusion with compression (cSCC). Addition of a brief compression with dwell time exacerbated the impact of C4/5 contusion as demonstrated by: 1) high death rates (~50% vs <10% without compression); 2) severe paralysis in all limbs for up to 5 days; 3) delays in regaining of the righting reflex; 4) ventilatory deficits when challenged with 7% CO2 + 10.5% O2; and 5) profound neurodegeneration extending rostrally to the brainstem. One week post‐cSCC, pLTF is abolished, consistent with degeneration in raphe serotonergic neurons. However, even a single administration of istradefylline 1‐hour post‐cSCC preserved and even augmented pLTF 1‐week post‐cSCC. Respiratory and locomotor functional studies are in progress. These exciting preliminary data suggest that plasticity outcomes are improved by A2AR antagonism in acute cSCC. Support or Funding Information NIH OT2OD023854 (SPARC), HL69064, and K12 HD055929 (EGR), and the McKnight Brain Institute. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .