Assessment of combined neuroprotective minocycline and neuroplasticity-inducing intermittent hypoxia as a strategy to promote improvements in bladder function in rats with SCI

Abstract

Spinal cord injury (SCI) causes significant damage to neural tissue that results in disruption of ascending and descending motor, sensory, and autonomic connections between the brain and spinal cord. SCI above the lumbosacral level can severely impact bladder function, leading to detrusor overactivity, decreased voiding efficiency, and urine retention. The initial SCI trauma is followed by a secondary wave of damage, which includes multiple vascular, inflammatory, and biochemical processes that further disrupt neuronal function and repair at the lesion site albeit spontaneous axon growth/sprouting/regeneration and synaptic remodeling across a lesion may lead to some restoration of function. As such, strategies aimed at reducing the extent of secondary SCI-induced inflammation and tissue damage/loss are being pursued. To this end, administration of the antibiotic minocycline (MIN) has been shown to decrease multiple processes mediating tissue loss and development of secondary injury, resulting in reduced lesion size and improved hindlimb motor function in SCI. Previous studies in our laboratory have been focused on the use of neuroplasticity-inducing acute intermittent hypoxia (AIH) as a therapeutic strategy to improve bladder function in SCI. While this work shows that a single AIH treatment results in reductions in bladder overactivity ( i.e., non-voiding bladder contractions, NVCs) and more efficient voiding, combining this approach with prior MIN administration could increase the neural substrate available to respond to AIH treatment. Therefore, we investigated the effects of 7-day MIN administration initiated at 24-hr after moderate contusion SCI on spontaneous and reflex micturition and on AIH-induced improvements in reflex micturition; the antibiotic Baytril (BAY) was used in a separate group of rats as a control. Assessment of spontaneous overnight awake micturition patterns before and at weekly intervals for 4-weeks after SCI shows that both MIN- and BAY-treated rats exhibit similar partial recovery of voiding behaviors but with increased volume per void. Assessment of reflex bladder function at 4-weeks post-SCI in urethane-anesthetized rats shows that while both MIN- and BAY-treated rats exhibit voiding contractions (VCs) and NVCs, VC behaviors ( e.g., peak BP-minimum BP, contraction duration, and contraction area) in MIN-treated rats are improved, resulting in an ~27% improvement in dynamic voiding efficiency (P=0.06). Subsequent AIH treatment in both MIN- and BAY-treated rats decreased NVCs and elicited more efficient voiding (as expected), and these improvements appeared to be slightly more robust in MIN-treated rats. Our preliminary findings indicate that MIN may exert beneficial effects on bladder function in SCI but combining MIN and AIH treatment may exert a greater impact. Additional experiments are needed to more fully characterize the beneficial improvements noted. NYS DOH SCIRB C35598GG 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.