Diaphragmatic recovery in rats with cervical spinal cord injury induced by a theophylline nanoconjugate: Challenges for clinical use

Abstract

Context: Following a spinal cord hemisection at the second cervical segment the ipsilateral hemidiaphragm is paralyzed due to the disruption of the rostral ventral respiratory group (rVRG) axons descending to the ipsilateral phrenic motoneurons (PN). Systemically administered theophylline activates a functionally latent crossed phrenic pathway (CPP) which decussates caudal to the hemisection and activates phrenic motoneurons ipsilateral to the hemisection. The result is return of function to the paralyzed hemidiaphragm. Unfortunately, in humans, systemically administered theophylline at a therapeutic dose produces many unwanted side effects.

Design and setting: A tripartite nanoconjugate was synthesized in which theophylline was coupled to a neuronal tracer, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), using gold nanoparticles as the coupler. Following intradiaphragmatic injection of the nanoconjugate, WGA-HRP selectively targets the theophylline-bound nanoconjugate to phrenic motoneurons initially, followed by neurons in the rVRG by retrograde transsynaptic transport.

Participants: (N/A)

Interventions: (N/A)

Outcome Measures: Immunostaining, Electromyography (EMG).

Results: Delivery of the theophylline-coupled nanoconjugate to the nuclei involved in respiration induces a return of respiratory activity as detected by EMG of the diaphragm and a modest return of phrenic nerve activity.

Conclusion: In addition to the modest return of phrenic nerve activity, there were many difficulties using the theophylline nanoconjugate because of its chemical instability, which suggests that the theophylline nanoconjugate should not be developed for clinical use as explained herein.

Keywords:

• Nanoconjugate
• Spinal cord injury
• Gold nanoparticle
• Crossed phrenic pathway
• Targeted drug delivery

Acknowledgements

The work presented herein is patented: Goshgarian, H. G., Mao, G., Zhang, Y.; Transporter Protein-Coupled Nanodevices for Targeted Drug Delivery. US Patent Publication number: US9649381 B2, May 16, 2017; US20150125926 A1. May 7, 2015. Application number: 14/534,994, Date Filed: November 6, 2014.

Disclaimer statements

Contributors None.

Funding This study was supported by a grant from the Craig H. Neilsen Foundation and National Institutes of Health grant HD-31550 (to HGG). This study was conducted in partial fulfillment of the requirements for the PhD degree at Wayne State University awarded to JLBW.

Conflicts of interest Wayne State University owns the patent therefore; the authors declare no competing financial interests.

Ethics approval None.

ORCID

Janelle Schafer http://orcid.org/0000-0003-1576-6298