Respiratory Abnormalities Resulting from Midcervical Spinal Cord Injury and their Reversal by Serotonin 1A Agonists in Conscious Rats

Choi, Howard; Liao, Wei-Lee; Newton, Kimberly M.; Onario, Renna C.; King, Allyson M.; Desilets, Federico C.; Woodard, Eric J.; Eichler, Marc E.; Frontera, Walter R.; Sabharwal, Sunil; Teng, Yang D.

doi:10.1523/jneurosci.5135-04.2005

Cited by 70 publications

(84 citation statements)

References 62 publications

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“…22,23 Our findings are in accordance with experimental data previously reported in unilateral C5 contusion 8 and bilateral cervical contusion 9,10 paradigms. Most of these studies demonstrated transient changes in respiratory rate and tidal volume under normoxic conditions, but no effects on global minute ventilation.…”

Section: Discussionsupporting

confidence: 92%

“…It has been demonstrated that respiratory abnormalities could be detected up to 4 weeks following C5 SCI under hypercapnic conditions (although this response ultimately recovered), whereas under normocapnia, the abnormality only lasted for 2 weeks. 8 Collectively, these data suggest that animal models of midcervical hemicontusion manifest subacute respiratory abnormalities. To date, none of the existing cervical contusion SCI models are able to induce persistent ventilatory deficits during both resting breathing and respiratory challenge.…”

Section: Discussionmentioning

confidence: 94%

“…To date, none of the existing cervical contusion SCI models are able to induce persistent ventilatory deficits during both resting breathing and respiratory challenge. [8][9][10] As suggested by Lane and colleagues from a translational point of view, 10 current cervical contusion paradigms seem to model incomplete cervical SCI (as defined by the American Spinal Injury Association [ASIA] Impairment Scale) or SCI patients weaned from mechanical ventilation, as breathing deficits are observed when the cardiorespiratory system is challenged (i.e., during exercise or hypercapnia). [24][25][26][27][28] A noteworthy ventilatory parameter is peak inspiratory flow, which reflects inspiratory muscle strength in the absence of airway pathology.…”

Section: Discussionmentioning

confidence: 99%

“…The chamber temperature, pressure, and air flows were measured and integrated in the Drorbaugh and Fenn equation to calculate tidal volume, respiratory frequency, minute ventilation, and peak inspiratory flow. [8][9][10] Tidal volume and minute ventilation were further normalized to body weight. Recordings were averaged over 5 min once quiet breathing was reached.…”

Section: Wbpmentioning

confidence: 99%

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Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

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Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Wbpmentioning

confidence: 99%

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Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

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“…2. Preliminary plethysmography experiments in spinal intact rats indicated that breathing patterns could be affected by body weight, even if respiratory volumes are normalized to body mass (Choi et al, 2005;Fuller et al, 2006). In particular, we compared the pattern of breathing in two groups of age-matched, uninjured male Sprague-Dawley rats of differing body weights as follows: group 1, age=103±1 days, weight=354±3 g, n=7; group 2, age=104±1 days, weight=450±2 g, n=9.…”

Section: Ventilation In C2hs Rats Relative To Weight-matched Control mentioning

confidence: 99%

Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats

Fuller

Doperalski

Dougherty

et al. 2008

Experimental Neurology

114

167

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Following C2 spinal hemisection (C2HS) in adult rats, ipsilateral phrenic motoneuron (PhMN) recovery occurs through a time-dependent activation of latent, crossed-spinal collaterals (i.e., spontaneous crossed phrenic phenomenon; sCPP) from contralateral bulbospinal axons. Ventilation is maintained during quiet breathing after C2HS, but the ability to increase ventilation during a respiratory stimulation (e.g. hypercapnia) is impaired. We hypothesized that long-term expression of the sCPP would correspond to a progressive normalization in ventilatory patterns during respiratory challenge. Breathing was assessed via plethsymography in unanesthetized animals and phrenic motor output was measured in urethane-anesthetized, paralyzed and vagotomized rats. At 2-week post-C2HS, minute ventilation (VE) was maintained during baseline (room air) conditions as expected but was substantially blunted during hypercapnic challenge (68±3% of VE in uninjured, weight-matched rats). However, by 12 weeks the spinal-lesioned rats achieved a hypercapnic VE response that was 85±7% of control (p = 0.017 vs. 2 wks). These rats also exhibited augmented breaths (AB's) or "sighs" more frequently (p<0.05) than controls; however, total AB volume was significantly less than control at 2-and 12-week post-injury (69±4% and 80±5%, p<0.05, respectively). We also noted that phrenic neurograms demonstrated a consistent delay in onset of the ipsilateral vs. contralateral inspiratory phrenic burst at 2-12-week post-injury. Finally, the ipsilateral phrenic response to respiratory challenge (hypoxia) was greater, though not normalized, at 4-12-vs. 2-week post-injury. We conclude that recovery of ventilation deficits occurs over 2-12-week post-C2HS; however, intrinsic neuroplasticity remains insufficient to concurrently restore a normal level of ipsilateral phrenic output.

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Therapeutic Perspectives of Adenosine Receptor Compounds in Functional Restitution After Spinal Cord Injury

Nantwi

2012

Adenosine

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Respiratory Abnormalities Resulting from Midcervical Spinal Cord Injury and their Reversal by Serotonin 1A Agonists in Conscious Rats

Cited by 70 publications

References 62 publications

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats

Therapeutic Perspectives of Adenosine Receptor Compounds in Functional Restitution After Spinal Cord Injury

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