Effects of Repetitive Intermittent Hypoxia after Acute and Chronic Spinal Cord Injury

Abstract

Acute intermittent hypoxia (AIH – brief exposure to hypoxia alternating with normal O2 levels) is a promising potential therapy for spinal cord injury (SCI), which enhances spinal plasticity resulting in improved functional recovery. In this thesis, I assessed the effect of AIH on motor functional recovery, markers of spinal plasticity within spinal motor neurons, inflammation within the lesion site, and muscle atrophy in the forelimb after in a rat model of acute and chronic SCI. I found that 7 days of AIH in the acute SCI model did not have a significant effect on functional recovery. In rats with a chronic SCI, 12 weeks of AIH treatment resulted in improved performance in reaching when compared to normoxia controls. I next assessed the expression of plasticity- and hypoxia-associated proteins within spinal motor neurons after both acute and chronic SCI and found no significant effect on expression of these proteins in any of the experimental groups studied. At the lesion site, there was no change in markers of macrophage or astrocyte phenotype after acute SCI. After chronic SCI there was increased CD206, a pro-repair M2 macrophage marker after 7 days of AIH treatment which did not persist after 12 weeks of treatment. There was also a non-significant trend towards elevated C3, a marker of the A1 astrocyte phenotype, after both 7 days and 12 weeks of AIH treatment. In limb muscles after acute SCI, normoxia controls had decreased pAkt in the ipsilateral limb compared to the contralateral limb, while in AIH treated rats pAkt expression was restored. In rats with a chronic SCI there was an increase in muscle fibre size variability in one forelimb muscle in AIH treated animals compared to normoxia controls after 4 weeks of AIH treatment. This thesis provides the first evidence that prolonged AIH treatment can elicit sustained functional recovery in a motor task in a rat model of SCI, and provides evidence that AIH has potentially beneficial effects beyond the spinal motor neurons by altering inflammation at the lesion site after chronic SCI, as well as eliciting changes within muscles after both acute and chronic SCI.