Daily administration of ketoprofen restores AIH‐induced phrenic long term facilitation with prolonged chronic intermittent hypoxia

Abstract

Acute intermittent hypoxia (AIH) elicits a form of spinal, respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Preconditioning with a single day of chronic intermittent hypoxia (8 hours, 2 min hypoxic episodes with 2 min intervals) abolishes AIH-induced pLTF through a mechanism that requires systemic inflammation and spinal p38 MAP kinase activation (Huxtable et al., 2015). pLTF is restored by high-dose, systemic administration of the non-steroidal anti-inflammatory drug, ketoprofen, or spinal p38 MAP kinase inhibition. Similarly, preconditioning with 7 days of CIH (8 hours per day, 2 min episodes, 2 min intervals) abolishes pLTF, but we observed that phospho-p38 within phrenic motor neurons is unchanged from control rats (Gonzalez-Rothi and colleagues, unpublished). Thus, mechanisms whereby 7 days of CIH undermines AIH-induced pLTF are unclear. Since CIH induces time-dependent spinal inflammatory gene expression profiles over time (Smith et al., 2013), we hypothesize that prolonged CIH (versus a single day) blunts LTF through an inflammation-dependent mechanism that is independent of p-38MAP kinase. Thus, in ongoing experiments, the impact of anti-inflammatory drugs on AIH-induced pLTF in rats preconditioned with prolonged CIH (7 days). pLTF was restored when ketoprofen was administered each day just prior to the IH7 exposure (70% increase, p=.0013 vs. vehicle), but not when a single dose of ketoprofen was delivered just prior to assessment of pLTF (19% increase, p=0.9975 vs. vehicle). Upcoming experiments will explore the role of p38 MAP kinase with prolonged CIH exposure. These experiments are the first to explore shifting mechanisms whereby prolonged CIH and associated inflammation undermine phrenic motor plasticity. Such experiments are essential since chronic intermittent hypoxia is a hallmark of sleep apnea, a condition highly prevalent in individuals living with neurological disorders (spinal cord injury, ALS, etc.). It is therefore important to identify and mitigate factors which may undermine the potential for therapeutic interventions (i.e., repetitive AIH) to harness endogenous plasticity and ultimately improve breathing.