Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury

Navarrete‐Opazo, Angela; Vinit, Stéphane; Dougherty, Brendan J.; Mitchell, Gordon S.

doi:10.1016/j.expneurol.2015.02.007

Cited by 73 publications

(68 citation statements)

References 57 publications

(100 reference statements)

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“…In spite of the limitations of the present model, our findings are consistent with previous human studies showing augmented hypoxic ventilatory responses and oxidative stress in patients with obstructive sleep apnea (Lavie, 2009; Narkiewicz et al, 1999) and healthy humans exposed to CIH (Pialoux et al, 2009). We emphasize that our findings do not apply to other patterns of exposure intended to mimic sleep apnea or to “therapeutic” intermittent hypoxia paradigms (Navarrete-Opazo et al, 2015). …”

Section: Discussionmentioning

confidence: 77%

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

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Section: Discussionmentioning

confidence: 77%

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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“…If the precise mechanisms implied in spinal cord plasticity following exposure to intermittent hypoxia remain to be determined, 39,40 these preclinical results are encouraging and support their translation in clinical studies to induce respiratory and motor plasticity in humans.…”

Section: Hypoxic Conditioning In Animal Models Of Brainstem and Spinamentioning

confidence: 92%

Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries?

Baillieul

Chacaroun

Doutreleau

et al. 2017

Exp Biol Med (Maywood)

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Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation. Hypoxic conditioning may represent a harmless and efficient non-pharmacological new therapeutic modality in the field of neuroprotection and neuroplasticity, as supported by many preclinical data. Animal studies provide clear evidence for neuroprotection and neuroplasticity induced by hypoxic conditioning in several models of neurological disorders. These studies show improved functional outcomes when hypoxic conditioning is applied and provides important information to translate this intervention to clinical practice. Some studies in humans provide encouraging data regarding the tolerance and therapeutic effects of hypoxic conditioning strategies. The main issues to address in future research include the definition of the appropriate hypoxic dose and pattern of exposure, the determination of relevant physiological biomarkers to assess the effects of the treatment and the evaluation of combined strategies involving hypoxic conditioning and other pharmacological or non-pharmacological treatments. AbstractCentral nervous system diseases are among the most disabling in the world. Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation as pharmacology treatments are often insufficiently effective. Conditioning the central nervous system has been proposed as a potential non-pharmacological neuro-therapeutic. Conditioning refers to a procedure by which a potentially deleterious stimulus is applied near to but below the threshold of damage to the organism to increase resistance to the same or even different noxious stimuli given above the threshold of damage. Hypoxic conditioning has been investigated in several cellular and preclinical models and is now recognized as inducing endogenous mechanisms of neuroprotection. Ischemic, traumatic, or chronic neurodegenerative diseases can benefit from hypoxic conditioning strategies aiming at preventing the deleterious consequences or reducing the severity of the pathological condition (preconditioning) or aiming at inducing neuroplasticity and recovery (postconditioning) following central nervous system injury. Hypoxic conditioning can consist in single (sustained) or cyclical (intermittent, interspersed by short period of normoxia) hypoxia stimuli which duration range from few minutes to several hours and that can be repeated over several days or weeks. This mini-review addresses the existing evidence regarding the use of hypoxic conditioning as a potential innovating neuro-therapeutic modality to induce neuroprotection, neuroplasticity and brain recovery. This mini-review also emphasizes issues which remain to be clarified and future researches to be performed in the field.

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“…Telemetry implantation and C2 cervical hemisection were performed under sterile conditions as described previously (Navarrete-Opazo et al, 2014, 2015). Rats were pre-medicated with subcutaneous buprenorphine (0.03 mg/kg), carprofen (Rimadyl, 5 mg/kg) and enrofloxacin (Baytril, 4 mg/kg); additional injections were made every 12 h for 2 days post-surgery to minimize post-operative pain and infection.…”

Section: Methodsmentioning

confidence: 99%

“…Intermittent hypoxia (IH) elicits spinal, respiratory motor plasticity, strengthening synaptic pathways to respiratory motor neurons (Fuller et al, 2003; Golder and Mitchell, 2005; Lovett-Barr et al, 2012). For example, repetitive IH improves phrenic nerve/diaphragm muscle activity after C2 cervical hemisection (C2HS) (Fuller et al, 2003; Navarrete-Opazo and Mitchell, 2014), at least partially restoring breathing capacity (Fuller et al, 2006; Lovett-Barr et al, 2012; Navarrete-Opazo et al, 2015). To date, studies attempting to harness IH as a therapeutic tool to restore breathing capacity have been performed in rats with sub-acute SCI (<4 weeks).…”

Section: Introductionmentioning

confidence: 99%

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

Navarrete‐Opazo

Dougherty

Mitchell

2017

Experimental Neurology

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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.

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Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury

Cited by 73 publications

References 57 publications

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries?

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

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