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

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 2 weeks 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; 7 days) 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 4 weeks. 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 4 weeks. 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.

Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation

“…; Navarrete‐Opazo et al . ). This shift likely arises from serotonergic reinnervation below the injury; shifting expression patterns of A 2A receptors could also contribute to these complex results.…”

Physiological and Biological Responses to Short-Term Intermittent Hypobaric Hypoxia Exposure: From Sports and Mountain Medicine to New Biomedical Applications

“…Complete or incomplete spinal cord injuries are characterized by spared synaptic pathways below the level of the injury. Intermittent hypoxia elicits plasticity in the spinal cord and strengthens these spared synaptic pathways, expressed as respiratory and somatic functional recovery in both experimental animals and humans with traumatic spinal cord injury (Navarrete-Opazo et al, 2015 , 2017a , b ; Dougherty et al, 2017 ; Trumbower et al, 2017 ). Table 5 lists studies reporting beneficial neurological impact after a wide range of intermittent hypoxia exposure protocols.…”

Acute intermittent hypoxia enhances corticospinal synaptic plasticity in humans

“…Brief exposures to hypoxic air interspersed with periods of breathing ambient room air, known as acute intermittent hypoxia (AIH), impacts the respiratory, cardiovascular, immune, metabolic, bone and nervous systems ( Dale et al, 2014 ; Gonzalez-Rothi et al, 2015 ). During recent years, an increasing number of studies support the view that AIH also affects the damaged central nervous system, triggering recovery of motor function in humans with partial paralysis due to spinal cord injury ( Trumbower et al, 2012 ; Lynch et al, 2017 ; Navarrete-Opazo et al, 2017a , b ). AIH represents a promising and safe strategy to supplement conventional neurorehabilitation ( Navarrete-Opazo and Mitchell, 2014 ).…”