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

Abstract

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.

Systemic Administration of Rolipram Increases Medullary and Spinal cAMP and Activates a Latent Respiratory Motor Pathway After High Cervical Spinal Cord Injury

“…The results of this study have extended a previous study from our laboratory in which we reported that long-term (3-day) administration of phosphodiesterase inhibitors such as pentoxifylline and rolipram can bring about long-lasting phrenic nerve recovery in animals subjected to a left C2 spinal cord lesion (21). These studies provide support for the exploration of cAMPelevating agents as an effective approach in alleviating some of the respiratory insufficiency that is associated with high cervical spinal cord injury.…”

“…Recently, we have shown that, after a left C2 spinal cord lesion, chronic inhibition of phosphodiesterase activity (over a 3-day period) can induce long-lasting phrenic nerve recovery in the previously quiescent left phrenic nerve (21). Furthermore, other studies have implicated the cAMP signaling cascade as a possible stimulator of respiratory neurons (22,23).…”

Immune-Based Therapies for Spinal Cord Injury

“…Additionally, intravenous rolipram restored respiratory-related activity to the phrenic nerve ipsilateral to the injury and significantly enhanced phrenic nerve inspiratory burst activity in both normal and C2 hemisected animals. These results provided evidence that PDE inhibitors can Science Publications AJN strengthen spared ineffective synaptic connections at the level of the phrenic nucleus and may enhance phrenic nerve output and restore respiratory related phrenic nerve function after high cervical SCI (Kajana and Goshgarian, 2008).…”

“…Kajana and Goshgarian (2008) shown that rolipram can increase phrenic nerve output ipsilateral to an experimental C2 hemisection lesion. Additionally, intravenous rolipram restored respiratory-related activity to the phrenic nerve ipsilateral to the injury and significantly enhanced phrenic nerve inspiratory burst activity in both normal and C2 hemisected animals.…”

Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors

“…The synthesis steps of the nanoconjugate are described in Figure 2a. MSA-capped AuNP was prepared according to the literature (Jana et al, 2001). The proform of DPCPX ( pro-DPCPX) was synthesized based on the Mannich reaction (Sloan and Bodor, 1982).…”