Inflammation Differentially Impacts Phrenic Long‐term Facilitation (pLTF) in Rats with Motor Neuron Death Induced by Intrapleural CTB‐saporin Injections

Abstract

Intrapleural injection of cholera toxin B fragment conjugated to saporin (CTB‐SAP) selectively kills respiratory motor neurons, and mimics aspects of neuromuscular disorders and neurodegenerative diseases including phrenic motor neuron death, decreased phrenic motor output, and increased microglial cell number. Our previous results demonstrated unexpectedly that respiratory plasticity is not only observed 7 days (d) after CTB‐SAP delivery, but that it is actually enhanced compared to control treatments. At 28d, however, respiratory plasticity is comparable to control levels, suggesting that the underlying mechanisms of plasticity at both time points may differ. Because inflammation is a hallmark of all neurodegenerative diseases, and it is known to prevent the development of acute intermittent hypoxia‐induced phrenic long‐term facilitation (pLTF), we predicted that inflammation would impair pLTF in CTB‐SAP‐treated rats and thus, anti‐inflammatory drugs would enhance pLTF at both time points. Using anesthetized, paralyzed and ventilated CTB‐SAP‐treated adult Sprague Dawley rats, we studied acute intermittent hypoxia (AIH; 3, 5 min bouts of 10.5% O2) induced pLTF following intrathecal C4 delivery of the nonsteroidal anti‐inflammatory drug ketoprofen to rats that received bilateral, intrapleural injections of: 1) CTB‐SAP (25μg), or 2) un‐conjugated CTB and SAP (control) in rats treated 7d or 28d prior. Surprisingly, preliminary results indicate that ketoprofen attenuates pLTF in 7d CTB‐SAP‐treated rats, but enhances it in the 28d CTB‐SAP‐treated rats. These observations suggest that inflammation potentially contributes to pLTF in 7d CTB‐SAP‐treated rats, whereas it may undermine pLTF in 28d CTB‐SAP‐treated rats. Studies are underway to assess cervical spinal levels of both pro‐inflammatory and anti‐inflammatory and neurotrophic molecules at both time points, and their cellular source. Future studies will investigate the potential contributions of microglia to the mechanisms whereby inflammation differentially impacts pLTF in CTB‐SAP‐treated rats. Results from this project will increase our understanding of how inflammation and microglial activities influence respiratory plasticity following motor neuron death, and will have broad implications for therapies restoring ventilatory function in many disorders in which motor neuron death is associated.Support or Funding InformationNIH K99/R00 HL119606This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.