Hypoxia-Evoked Spinal Adenosine Kinetics in Rats with Chronic Spinal Cord Injury

Abstract

Therapeutic acute intermittent hypoxia (tAIH) is emerging as a simple and effective means of improving motor function after spinal cord injury (SCI) and ALS. For example, daily AIH applied one-week after C2 spinal hemisection (C2Hx) improves breathing in rats. Unfortunately, studies using the same protocol with chronic cSCI (>8 weeks) report less robust recovery, except when the rats are pretreated with an adenosine 2A receptor antagonist. Pro-inflammatory conditions, such as those experienced after SCI, increase CNS extracellular adenosine concentrations. Guided by increased understanding of adenosinergic signaling mechanisms constraining AIH-induced phrenic motor plasticity, we aimed to determine real-time in vivo dynamics of extracellular adenosine in response to hypoxia in the ventral cervical spinal cord in intact and spinally injured rats. We used enzyme-immobilized micro-biosensors for real time enzymatic detection of extracellular adenosine in the mid-cervical spinal cord of intact rats and rats with chronic C2Hx (>8 weeks post-injury) during 5-min 13% O2, 1-min 9% O2 and 1-min 9% O2 + 4% CO2. Extracellular adenosine exhibits rapid kinetics with a time-constant of seconds, regardless of condition. Rats with chronic C2Hx were classified post hoc into 2 groups: normotensive (systolic blood pressure > 120 mmHg) and hypotensive (systolic blood pressure < 120 mmHg). Normotensive C2Hx rats had baseline adenosine levels comparable to intact rats; hypoxia-induced increases in adenosine were slightly reduced versus intact rats. On the other hand, hypotensive C2Hx rats had elevated baseline adenosine levels and almost completely diminished hypoxia-evoked adenosine increases. Hypercapnic hypoxia had minimal impact on adenosine levels during exposures, but lowered adenosine following each hypercapnic hypoxic episode. These results suggest that changes in cardiovascular hemodynamics in chronic SCI rats can alter basal tissue adenosine levels, possibly undermining the therapeutic efficacy of tAIH in the condition of chronic SCI. Further, hypercapnic hypoxia appears to minimize inhibitory effects of adenosine on tAIH-induced phrenic/diaphragm motor plasticity. Supported by: NIH HL147554, HL148030 & OT2OD023854 and the University of Florida McKnight Brain Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.