Novel regenerative drug, SPG302 promotes functional recovery of diaphragm muscle activity after cervical spinal cord injury

Spinal cord hemisection at C-2 (C2SH), sparing the dorsal column is widely used to investigate the effects of reduced phrenic motor neuron (PhMN) activation on diaphragm muscle (DIAm) function, with reduced DIAm activity on the injured side during eupnoea. Following C2SH, recovery of DIAm EMG activity may occur spontaneously over subsequent days/weeks. Various strategies have been effective at improving the incidence and magnitude of DIAm recovery during eupnoea, but little is known about the effects of C2SH on transdiaphragmatic pressure (P-di) during other ventilatory and non-ventilatory behaviours. We employ SPG302, a novel type of pegylated benzothiazole derivative, to assess whether enhancing synaptogenesis (i.e., enhancing spared local connections) will improve the incidence and the magnitude of recovery of DIAm EMG activity and P-di function 14 days post-C2SH. In anaesthetised Sprague-Dawley rats, DIAm EMG and P-di were assessed during eupnoea, hypoxia/hypercapnia and airway occlusion prior to surgery (C2SH or sham), immediately post-surgery and at 14 days post-surgery. In C2SH rats, 14 days of DMSO (vehicle) or SPG302 treatments (i.p. injection) occurred. At the terminal experiment, maximum P-di was evoked by bilateral phrenic nerve stimulation. We show that significant EMG and P-di deficits are apparent in C2SH compared with sham rats immediately after surgery. In C2SH rats treated with SPG302, recovery of eupneic, hypoxia/hypercapnia and occlusion DIAm EMG was enhanced compared with vehicle rats after 14 days. Treatment with SPG302 also ameliorated P-di deficits following C2SH. In summary, SPG302 is an exciting new therapy to explore for use in spinal cord injuries.

Automated summary

This study investigates the effects of C2SH on diaphragm muscle and transdiaphragmatic pressure, as well as the potential therapeutic effect of SPG302. The results show that immediate deficits in diaphragm EMG activity and transdiaphragmatic pressure occur after C2SH surgery, while treatment with SPG302 can enhance the recovery of diaphragm EMG and transdiaphragmatic pressure within 14 days post-surgery.