Intermittent hypoxia and respiratory recovery in pre-clinical rodent models of incomplete cervical spinal cord injury

Gonzalez‐Rothi, Elisa J.; Lee, Kun‐Ze

doi:10.1016/j.expneurol.2021.113751

Cited by 11 publications

(5 citation statements)

References 143 publications

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“…Moreover, respiratory recovery after C2 injuries can be linked to cross-phrenic phenomena typical of C2 injury [32], whose existence is still debated in humans [33]. Hence, it may be relevant to use injury occurring at the phrenic motoneurons innervation level (C3-C5 in rodents) in a manner similar to that in previous publications [15,[34][35][36][37][38][39][40]. Furthermore, despite recent progress in the generation of transgenic rats, there is currently almost no alternative to mice for studying the roles of specific genes after SCI.…”

Section: Introductionmentioning

confidence: 93%

“…Nevertheless, a growing number of interventional studies using pharmacological strategies, such as the modulation of noradrenergic, serotonergic or dopaminergic neurotransmission, or neuromechanical devices, such as electrical stimulation, robotic assistance or even the brain-computer interface, are suggesting that respiratory neuroplasticity may be enhanced to improve spontaneous ventilation after SCI [13,14]. Moreover, few non-invasive therapeutics such as intermittent hypoxia protocols demonstrated their ability to induce substantial respiratory recovery in rodent preclinical models [15][16][17][18][19] of cervical injury as well as in human patients [20][21][22]. There is a need for more exploratory studies searching for a pharmacological agent, intervention or combinatorial approaches to further ameliorate the respiratory outcome following cervical SCI.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, most studies investigating respiratory physiopathology, the neuroplasticity of medullary spinal axonal regeneration and phrenic motoneurons nuclei reinnervation following high SCI use the C2 hemisection in rat [22][23][24][25] and mouse [26][27][28] models. These studies have unraveled fundamental concepts of respiratory physiopathology after SCI [23,27] and provided bases for putative therapeutics to cure SCI [15,24,29]. However, section models are not ideal for investigating SCI pathophysiology because transections are scarce in clinical settings [24,[29][30][31].…”

Section: Introductionmentioning

confidence: 99%

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Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Bajjig

Michel‐Flutot

Migevent

et al. 2022

Biology

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The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3–C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion—C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (−46% and −26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (−25% and −20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Bajjig

Michel‐Flutot

Migevent

et al. 2022

Biology

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“…Daily AIH protocols, therefore, appear to be a safe and non-invasive way to improve respiratory function following high SCIs, and this has been extensively reviewed [8,[118][119][120]. These preclinical studies demonstrated the feasibility and safety of repeated IH protocol application at low doses.…”

Section: Intermittent Hypoxiamentioning

confidence: 99%

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation

Michel‐Flutot

Lane

Lepore

et al. 2023

Cells

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High spinal cord injuries (SCIs) lead to permanent functional deficits, including respiratory dysfunction. Patients living with such conditions often rely on ventilatory assistance to survive, and even those that can be weaned continue to suffer life-threatening impairments. There is currently no treatment for SCI that is capable of providing complete recovery of diaphragm activity and respiratory function. The diaphragm is the main inspiratory muscle, and its activity is controlled by phrenic motoneurons (phMNs) located in the cervical (C3–C5) spinal cord. Preserving and/or restoring phMN activity following a high SCI is essential for achieving voluntary control of breathing. In this review, we will highlight (1) the current knowledge of inflammatory and spontaneous pro-regenerative processes occurring after SCI, (2) key therapeutics developed to date, and (3) how these can be harnessed to drive respiratory recovery following SCIs. These therapeutic approaches are typically first developed and tested in relevant preclinical models, with some of them having been translated into clinical studies. A better understanding of inflammatory and pro-regenerative processes, as well as how they can be therapeutically manipulated, will be the key to achieving optimal functional recovery following SCIs.

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“…Spinal cord injury (SCI) belongs to a serious disease resulting in specific neurological symptoms depending on the degree of injury, with high morbidity and mortality [4]. About 60% of SCI involves the cervical spinal cord, resulting in complete or incomplete quadriplegia, and the mortality rate is higher than that of thoracolumbar injuries [10]. Primary injury of the spinal cord is linked to the destruction of axons along with neurons, whereas secondary injury is resulted by neuroinflammation and can result in morphologic oedema, cavitation, as well as reactive gliosis [17].…”

Section: Introductionmentioning

confidence: 99%

Autophagy exerts a protective role in cervical spinal cord injury by microglia inhibition through the nuclear factor kappa-B pathway

Bai

Yang

2024

Folia Morphol

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Intermittent hypoxia and respiratory recovery in pre-clinical rodent models of incomplete cervical spinal cord injury

Cited by 11 publications

References 143 publications

Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation

Autophagy exerts a protective role in cervical spinal cord injury by microglia inhibition through the nuclear factor kappa-B pathway

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