Long‐term Delivery of “Low Dose” Repetitive Intermittent Hypoxia is Not Associated with Detectable Pathology

Abstract

Repetitive acute intermittent hypoxia (rAIH) is a promising therapeutic strategy to induce spinal plasticity and improve respiratory and non‐respiratory function after chronic, incomplete spinal cord injury. Although brief rAIH exposures (< 2 weeks) have proven safe in rodent models and humans with cSCI, the safety profile of prolonged rAIH exposures is unknown. This is an essential step in the translation of rAIH to treat humans with respiratory and non‐respiratory paralysis due to injury and/or disease. Here we report an absence of detectable respiratory, cardiovascular, neurological, renal, liver and osteological pathologies after prolonged rAIH (3 months) in rats. Beginning 8 weeks post‐injury spinally intact rats, or rats with C2 hemisections (C2Hx) were treated 4 times per week for 3 months with: 1) rAIH (10, 5 min episodes of 10.5% O2; 5 min normoxic intervals) versus 2) sham normoxia. Whole body plethysmography was conducted following the exposures to assess respiratory function in spontaneously breathing rats. To assess cardiovascular pathology: 1) arterial blood pressure was assessed in urethane anesthetized rats, and 2) the heart and aorta were processed for histological analyses. To assess neurological pathology, the cortex, hippocampus and cervical spinal cord were harvested and histology was used to assess possible gliosis and/or cell death. The liver and kidney were processed for histological analyses, and all tissues are being evaluated by a board certified veterinary pathologist. Lastly changes in bone density were evaluated in the left and right humerus bones using microcomputed tomography. No differences in respiratory or cardiovascular function were observed following rAIH exposures (n = 8–12 per group; all P > 0.50), nor did we observe any evidence of pathology in the heart, aorta, liver or kidney. We found no evidence of hippocampal cell death and/or reactive gliosis based on cressyl violet, NeuN, cd11b and GFAP staining. Bone density analyses are pending, but preliminary results indicate significant bone loss only as a result of C2Hx, but not rAIH. These results add to a building body of evidence that prolonged, “low dose” rAIH is a safe, simple and effective means to improve respiratory and non‐respiratory motor function after chronic spinal cord injury.Support or Funding InformationDoD SC130298 CDMRP; NIH R01 HL69064 and OT2OD023854 (SPARC); NIH T32 HD043730 (LLA), NIH K12 HD055929 (EGR); and the McKnight Brain Institute.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.