Enhanced recovery of breathing capacity from combined adenosine 2A receptor inhibition and daily acute intermittent hypoxia after chronic cervical spinal injury

Exp Neurol. 2017 Jan;287(Pt 2):93-101. doi: 10.1016/j.expneurol.2016.03.026. Epub 2016 Apr 11.

Abstract

Daily acute intermittent hypoxia (dAIH) improves breathing capacity after C2 spinal hemisection (C2HS) in rats. Since C2HS disrupts spinal serotonergic innervation below the injury, adenosine-dependent mechanisms underlie dAIH-induced functional recovery 2weeks post-injury. We hypothesized that dAIH-induced functional recovery converts from an adenosine-dependent to a serotonin-dependent, adenosine-constrained mechanism with chronic injury. Eight weeks post-C2HS, rats began dAIH (10, 5-min episodes, 10.5% O2; 5-min intervals; 7days) followed by AIH 3× per week (3×wAIH) for 8 additional weeks with/without systemic A2A receptor inhibition (KW6002) on each AIH exposure day. Tidal volume (VT) and bilateral diaphragm (Dia) and T2 external intercostal motor activity were assessed in unanesthetized rats breathing air and during maximum chemoreflex stimulation (MCS: 7% CO2, 10.5% O2). Nine weeks post-C2HS, dAIH increased VT versus time controls (p<0.05), an effect enhanced by KW6002 (p<0.05). dAIH increased bilateral Dia activity (p<0.05), and KW6002 enhanced this effect in contralateral (p<0.05) and ipsilateral Dia activity (p<0.001), but not T2 inspiratory activity. Functional benefits of combined AIH plus systemic A2A receptor inhibition were maintained for 4weeks. Thus, in rats with chronic injuries: 1) dAIH improves VT and bilateral diaphragm activity; 2) VT recovery is enhanced by A2A receptor inhibition; and 3) functional recovery with A2A receptor inhibition and AIH "reminders" last 4weeks. Combined dAIH and A2A receptor inhibition may be a simple, safe, and effective strategy to accelerate/enhance functional recovery of breathing capacity in patients with respiratory impairment from chronic spinal injury.

Keywords: Adenosine receptors; Breathing; Cervical; Chronic; Functional recovery; Hemisection; Intermittent hypoxia; Rehabilitation; Spinal cord injury; Spinal plasticity.

MeSH terms

  • Adenosine A2 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Antagonists / therapeutic use
  • Animals
  • Cervical Vertebrae*
  • Diaphragm / drug effects
  • Disease Models, Animal
  • Functional Laterality / drug effects
  • Functional Laterality / physiology
  • Hypercapnia / physiopathology
  • Hypoxia*
  • Male
  • Maximal Voluntary Ventilation / drug effects
  • Maximal Voluntary Ventilation / physiology*
  • Motor Activity / drug effects
  • Muscle Contraction / drug effects
  • Purines / pharmacology
  • Purines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adenosine A2 / metabolism*
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*
  • Respiration Disorders / etiology*
  • Respiration Disorders / therapy*
  • Spinal Cord Injuries / complications*
  • Time Factors
  • Vital Capacity / drug effects
  • Vital Capacity / physiology

Substances

  • Adenosine A2 Receptor Antagonists
  • Purines
  • Receptors, Adenosine A2
  • istradefylline