Therapeutic Potential of Intermittent Hypoxia-Induced Plasticity on Bladder and Respiratory Function Following Thoracic Spinal Cord Injury
Abstract
Rationale and Objective: Injury to the spinal cord produces significant loss of sensory, motor, and autonomic function below the site of injury and a profound long-term negative impact on health and quality of life. Spontaneous functional recovery does occur as a result of intrinsic neuronal plasticity; however, this recovery is rarely complete, and deficits persist. Thus, research efforts aimed at enhancing intrinsic neuronal plasticity in order to improve recovery of function in individuals living with spinal cord injury (SCI) is desirable. With this in mind, the rationale for the proposed study is based on the idea that neuronal plasticity is required for recovery of function following SCI and that implementation of an intervention that promotes neuronal plasticity will enhance functional recovery. Specifically, we propose to utilize acute intermittent hypoxia (AIH), which is a well-established non-invasive experimental approach for inducing respiratory spinal motor plasticity, as a therapeutic intervention following SCI. Since AIH has been shown to elicit functional improvements in both respiratory and non-respiratory (somatic) motor spinal systems in both rats and humans, including humans with incomplete SCI, this approach has a therapeutic potential for clinical use. The primary objective of the proposed studies is to quantitatively assess the efficacy of AIH in improving bladder and respiratory function in a rat model with moderate contusion (incomplete) and SHAM mid-thoracic SCI. We propose to optimize the timing and number of hypoxic episodes of the AIH gas delivery protocol (Specific Aim 1) and then investigate the therapeutic efficacy of this optimized gas delivery protocol using repetitive AIH (rAIH) gas treatment three times per week for up to 8 weeks (Specific Aim 2) on both bladder and respiratory function following SCI. Both single bout AIH and rAIH protocols are designed to induce spinal motor plasticity, and our experiments are designed to measure both bladder and respiratory function in awake unrestrained rats using metabolic and plethysmography chambers, respectively, and under anesthesia using bladder cystometry and electrical recording from bladder- and respiratory-related muscles. Applicability of the Research/Potential Clinical Applications, Benefits, and Risks: The level of hypoxia for the AIH stimulus proposed in our experiments consists of brief repeated exposures to a mild level of hypoxic gas interspersed with breathing normoxic air. This hypoxic stimulus has been reported to be well tolerated by humans (including those with SCI), and no deleterious side effects have been reported in response to such protocols. Moreover, studies and clinical applications of single bout and/or repeated bouts of AIH in humans with SCI have been and continue to be performed, and results from these studies/applications indicate that this is a promising therapeutic approach to facilitate recovery in SCI patients. Projected Time to Person-Related Outcome: While the proposed studies will be conducted in rats, it is anticipated that positive results could be quickly transferred to the clinic. Both single bout and repeated bout of AIH protocols are straightforward, and gas delivery systems capable of administering these types of protocols are widely available; therefore, clinical studies and application of AIH protocols to elicit improvements in bladder and respiratory function following (mid-thoracic) SCI could be initiated with minimal delay. Contributions of the Proposed Research to Advancing the Field of SCI research, Quality of Life and Patient Care: The proposed study is the first to implement single and repetitive bout AIH as a therapeutic approach for simultaneously improving bladder and respiratory function following mid-thoracic SCI. Since AIH is a non-invasive therapeutic strategy, it could be implemented in SCI patients in various settings (e.g., hospital, rehabilitation center, home)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710260
Entities
People
- Irene Solomon
Organizations
- Stony Brook University
- United States Army