Weekly Acute Intermittent Hypoxia as a Strategy to Restore Spontaneous Micturition Patterns in Awake Rats with Moderate Contusion SCI: Therapeutic Efficacy and Time Course

Abstract

Both daily and weekly exposures to neuroplasticity‐inducing acute intermittent hypoxia (AIH) have been proposed as non‐invasive therapeutic paradigms to improve respiratory and motor function following spinal cord injury (SCI). SCI can also lead to bladder dysfunction that results in inefficient voiding and urine retention that are associated with a high degree of morbidity and a poor quality of life. Our ongoing preclinical studies have been investigating the therapeutic potential of AIH as a strategy to promote restoration of lower urinary tract (LUT; bladder) function in SCI. We have found that in rats with moderate contusion SCI, exposure to a single episode of AIH results in an immediate short‐term reduction in non‐voiding bladder contractions and induction of more efficient voiding while exposure to daily AIH for 7 consecutive days leads to sustained beneficial improvements in both spontaneous voiding pattern and reflex bladder function that persist for at least 2 weeks following completion of therapy. Here, we investigated the impact of weekly AIH (wAIH) exposures composed of five alternating 3‐min episodes of 12% O2 and 21% O2 on micturition patterns in adult female SD rats with mid‐thoracic moderate contusion SCI; weekly normoxia (wNx; 21% O2) exposures in a separate group of SCI rats served as a control. Overnight (awake) micturition chamber (MC) measurements were used to evaluate voiding patterns weekly before and for 10 weeks after SCI, with wAIH and wNx exposures being administered 3x per week for 4 weeks beginning at 4 weeks after SCI. Data acquired between 9:00 PM and 6:00 AM were used to quantify voiding pattern features (i.e., number of voids (#); inter‐void interval (IVI)) and voiding volumes (total volume; volume per void), with weekly pre‐SCI MC measurements averaged and set to 100% for each rat. To evaluate the magnitudes of the deficits and progression of recovery of micturition pattern behaviors, weekly post‐SCI MC measurements were compared to their pre‐SCI level. For both groups of rats, the voiding pattern at 1‐week post‐SCI was characterized by infrequent voiding events with large volumes (~50% decrease in number of voids; ~100% increase in IVI; ~4 fold increase in volume per void), and by 4‐weeks post‐SCI, similar limited partial spontaneous recovery of voiding pattern was noted in both groups, albeit deficits were still present. Subsequent wAIH treatment led to further improvements in voiding pattern, such that following 2‐weeks of wAIH treatment, the number of voids and IVI were restored to pre‐SCI levels, but with a sustained elevation in volume per void. The restoration of voiding pattern and elevated volume per void persisted for the remaining MC measurements, including those obtained at 2‐weeks following completion of wAIH treatment. In contrast, no further recovery of any voiding pattern features was observed in wNx‐treated rats. These observations suggest that wAIH therapy improves SCI‐induced bladder dysfunction, leading to restoration of spontaneous micturition patterns in awake rats with SCI.