Identification of the axon pathways which mediate functional recovery of a paralyzed hemidiaphragm following spinal cord hemisection in the adult rat

Moreno, Dale E.; Yu, Xiao Jun; Goshgarian, Harry G.

doi:10.1016/0014-4886(92)90001-7

Cited by 118 publications

(120 citation statements)

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“…Recovery of respiratory-related activity after a left C2 hemisection by a hypoxia-induced activation of a latent respiratory motor pathway has been shown in previous studies (10). Restoration of function after C2 hemisection can also be pharmacologically induced with methylxanthine, theophylline (adenosine A 1 and A 2A receptor antagonist), and serotonin (11)(12)(13)23,24).…”

Section: Discussionsupporting

confidence: 59%

“…However, respiratory function can be restored to the paralyzed hemidia-phragm by activation of a previously quiescent respiratory motor pathway (8)(9)(10). The axons of the latent pathway are not transected, because they descend into the cord contralateral to the hemisection, cross the midline, and innervate phrenic motoneurons ipsilateral and caudal to the hemisection.…”

Section: Introductionmentioning

confidence: 99%

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Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Petrov

Kreipke

Alilain

et al. 2007

The Journal of Spinal Cord Medicine

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Background: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated via adenosine receptors to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although spinal phrenic motoneurons immunopositive for adenosine receptors have been demonstrated (C3-C5), it is unclear if adenosine receptor protein levels are altered after C2 hemisection and theophylline administration.Objective: To assess the effects of C2 spinal cord hemisection and theophylline administration on the expression of adenosine receptor proteins.Methods: Adenosine A 1 and A 2A receptor protein levels were assessed in adult rats classified as (a) noninjured and theophylline treated, (b) C2 hemisected, (c) C2 hemisected and administered theophylline orally (33 daily) for 3 days only, and (d) C2 hemisected and administered theophylline (33 daily for 3 days) and assessed 12 days after drug administration. Assessment of A 1 protein levels was carried out via immunohistochemistry and A 2A protein levels by densitometry.Results: Adenosine A 1 protein levels decreased significantly (both ipsilateral and contralateral to injury) after C2 hemisection; however, the decrease was attenuated in hemisected and theophylline-treated animals. Attenuation in adenosine A 1 receptor protein levels persisted when theophylline administration was stopped for 12 days prior to assessment. Adenosine A 2A protein levels were unchanged by C2 hemisection; however, theophylline reduced the levels within the phrenic motoneurons. Furthermore, the decrease in A 2A levels persisted 12 days after theophylline was withdrawn.Conclusion: Our findings suggest that theophylline mitigates the effects of C2 hemisection by attenuating the C2 hemisection-induced decrease in A 1 protein levels. Furthermore, A 2A protein levels are unaltered by C2 hemisection but decrease after continuous or interrupted theophylline administration. The effects on protein levels may underlie the stimulant actions of theophylline.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Petrov

Kreipke

Alilain

et al. 2007

The Journal of Spinal Cord Medicine

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“…1). The latent pathway is known as the "crossed phrenic pathway" (Moreno et al 1992). The exact mechanisms involved in the induction or the maintenance of activity in the phrenic nerve ipsilateral to the hemisection have not been clearly demonstrated (Vinit et al 2007;Fuller et al 2003;2005).…”

Section: Introductionmentioning

confidence: 99%

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Satkunendrarajah

Goshgarian

2008

Experimental Neurology

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High cervical spinal cord hemisection interrupts the descending respiratory drive from the medulla to the ipsilateral phrenic motoneurons, consequently leading to the paralysis of the ipsilateral hemidiaphragm. Previous studies have shown that chronic oral administration of theophylline, a phosphodiesterase inhibitor and an adenosine receptor antagonist, can restore function to the quiescent phrenic nerve and hemidiaphragm ipsilateral to hemisection. Both of these actions of theophylline result in an increase in 3′-5′-cyclic adenosine monophosphate (cAMP). Furthermore, the chronic theophylline-mediated respiratory recovery persists long after the animals have been weaned from the drug. To date, the precise cellular mechanisms underlying the recovery induced by theophylline are still not known. Since theophylline has two modes of action, in the present study we tested whether chronic administration of pentoxifylline, a non-selective phosphodiesterase inhibitor, rolipram, a phosphodiesterase-4 specific inhibitor, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, would induce recovery similar to that induced by theophylline in male Sprague Dawley rats following a left C2 spinal cord lesion. Recovery of left phrenic nerve activity was assessed at 5 or 10 days after the last drug administrations to assess the persistent nature of the recovery. Pentoxifylline, rolipram and DPCPX, all capable of modulating 3′, 5′-cyclic monophosphate (cAMP) levels, brought about long-term respiratory recovery in the phrenic nerve ipsilateral to the left C2 lesion at 5 and 10 days after the last drug administration. Therefore, these results suggest that compounds capable of regulating cAMP levels may be therapeutically useful in promoting functional recovery following spinal cord injury.

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Section: Introductionmentioning

confidence: 99%

“…1) (Moreno et al, 1992;Dobbins and Feldman 1994;Lipski et al, 1994). Although most crossed pathways decussate in the brainstem, an apparently ineffective synaptic pathway crosses the spinal midline caudal to C2 (i.e., the "crossed phrenic pathway") (Goshgarian, 1981;Moreno et al, 1992). This pathway can be revealed after C2 spinal hemisection either by increasing respiratory drive chemically or pharmacologically (Nantwi and Goshgarian, 2001) or by activating spinal serotonin receptors (Ling et al, 1994) of the 5-HT 2 receptor subtype Zhou et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Synaptic Pathways to Phrenic Motoneurons Are Enhanced by Chronic Intermittent Hypoxia after Cervical Spinal Cord Injury

Fuller¹,

Johnson²,

et al. 2003

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Spinal hemisection at C2 reveals caudal synaptic pathways that cross the spinal midline (crossed phrenic pathways) and can restore inspiratory activity in ipsilateral phrenic motoneurons. Intermittent hypoxia induces plasticity in the cervical spinal cord, resulting in enhanced inspiratory phrenic motor output. We hypothesized that chronic intermittent hypoxia (CIH) (alternating 11% O 2 and air; 5 min periods; 12 hr per night; 7 nights) would strengthen crossed phrenic pathways. Experiments were performed on anesthetized, vagotomized, paralyzed, ventilated, and spinally injured (C2 hemisection) rats that were exposed to either normoxia or CIH before acute injury (preconditioning) or after chronic injury (postconditioning). Spontaneous inspiratory bursts or compound action potentials evoked via stimulation of the ventrolateral funiculus (contralateral to injury) were recorded in both phrenic nerves. Spontaneous or evoked activity in crossed phrenic pathways were minimal or absent in all acutely injured rats regardless of preconditioning. In rats postconditioned with normoxia, crossed phrenic inspiratory bursts were observed occasionally during baseline conditions and always during chemoreceptor stimulation (hypoxia and hypercapnia). However, CIH postconditioned rats had substantially larger crossed phrenic inspiratory bursts during baseline, hypoxia, and hypercapnia (all p Ͻ 0.05 vs normoxic group). Short-latency (0.7 msec) evoked crossed phrenic potentials were also enhanced by CIH conditioning in chronically injured rats ( p Ͻ 0.05). We conclude that CIH induced spinal cord plasticityenhanced phrenic motor output. This plasticity required preconditions established by chronic spinal injury.

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Identification of the axon pathways which mediate functional recovery of a paralyzed hemidiaphragm following spinal cord hemisection in the adult rat

Cited by 118 publications

References 39 publications

Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Synaptic Pathways to Phrenic Motoneurons Are Enhanced by Chronic Intermittent Hypoxia after Cervical Spinal Cord Injury

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Identification of the axon pathways which mediate functional recovery of a paralyzed hemidiaphragm following spinal cord hemisection in the adult rat

Cited by 118 publications

References 39 publications

Differential Expression of Adenosine A1and A2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Differential Expression of Adenosine A1and A2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Synaptic Pathways to Phrenic Motoneurons Are Enhanced by Chronic Intermittent Hypoxia after Cervical Spinal Cord Injury

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Product

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Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

Differential Expression of Adenosine A₁and A_2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats