Regenerating interest in pharmacotherapy for spinal cord injury

The respiratory control network is essential for sustaining life. Phrenic motor neurons receive phasic ipsilateral bulbospinal glutamatergic input from the rostral ventral respiratory group in the medulla oblongata and in turn provide inspiratory drive to the principal muscle of inspiration, the diaphragm, via the phrenic nerves, facilitating breathing. Cervical spinal cord injury interrupts excitatory drive to the phrenic motor nucleus, resulting in a profound reduction or complete cessation of diaphragm muscle activation. The respiratory consequences of spinal cord injury are dependent on the site and extent of the injury, but respiratory insufficiency is common in people with cervical spinal cord injury, and respiratory failure is the primary cause of death (Winslow & Rozovsky, 2003). Spared latent contralateral excitatory inputs to phrenic motor neurons may provide a substrate for neuroplasticity and recovery of inspiratory-related diaphragm muscle activity, harnessing intrinsic compensatory mechanisms and restoring diaphragm contractile function, and thus ventilatory and airway protective behaviours. Such pathways are a target for various neurorehabilitation strategies. Surprisingly, there is a relative dearth of promising neurotherapeutic drugs in the translational pipeline for spinal cord injury. In this issue of The Journal of Physiology, Fogarty et al. (2023) examine a novel therapeutic in an established rat model of cervical spinal injury to characterize diaphragm muscle performance across ventilatory and non-ventilatory behaviours. The authors explored if SPG302, a pegylated benzothiazole derivative, which purportedly increases synaptogenesis, improves the incidence and magnitude of recovery of diaphragm EMG activity and related transdiaphragmatic pressure generation following spinal injury. This novel pharmacotherapy has shown promise in animal models of traumatic brain injury and Alzheimer's disease. Studies were performed in adult male rats following sham surgery or cervical (C2) spinal hemi-section. Spinal hemi-section resulted in a complete loss of EMG activity in the ipsilateral hemi-diaphragm, whereas activity of the contralateral hemi-diaphragm was unchanged. Injured rats were injected intraperitoneally with vehicle or SPG302 daily for 14 consecutive days. A strength of the study design is that diaphragm muscle EMG activity recorded immediately before cervical spinal hemi-section or sham surgeries was used as a baseline for subsequent analysis of diaphragm muscle EMG activity following surgery. Diaphragm muscle EMG activity was normalized to the pre-injury value for each behaviour across the ventilatory and non-ventilatory range (airway occlusion), allowing quantification in each animal of the relative decline in performance following injury and the efficacy of drug intervention. SPG302 treatment resulted in an impressive increase in recovery of diaphragm muscle activity, as evidenced by robust ipsilateral diaphragm muscle EMG activity 14 days following treatment, compared to vehicle-treated control rats. Transdiaphragmatic pressure measurements, which assessed the mechanical performance of the diaphragm in situ, revealed that deficits in injured rats were ameliorated following SPG302 treatment and were notably improved compared to vehicle-treated controls. Improved function was demonstrated across the spectrum of respiratory-related behaviours, preserving ventilatory transdiaphragmatic pressures to pre-surgery levels and improving the injury-induced deficit in maximal transdiaphragmatic pressure evoked by bilateral phrenic nerve stimulation, a finding relevant to high force-dependent manoeuvres of the diaphragm such as airway clearance, which is clinically relevant. The study is an important milestone in the quest for pharmacotherapeutic options for spinal cord injury. As acknowledged by the authors, to fully capitalize on the therapeutic potential of SPG302, further investigation into its mode of action is warranted to fully elucidate the mechanism of diaphragm muscle EMG activity recovery. It will be important to determine whether pre- or postsynaptic neurotransmission onto phrenic motor neurons is enhanced by SPG302. Spontaneous axonal sprouting from contralateral descending axons may be potentiated by SPG302. Furthermore, synaptic neurotransmitters and postsynaptic membrane receptor expression may be modulated by SPG302. Thus, SPG302 and related compounds show promise for the treatment of respiratory insufficiency in spinal cord injury. Beyond spinal cord injury, SPG302 offers therapeutic potential for the treatment of respiratory insufficiency in neurodegenerative diseases such as amyotrophic lateral sclerosis, characterized by respiratory motor neuron pathology (Bradley et al., 1983). It would be interesting to further explore the potential of SPG302 in other models of spinal cord injury (e.g. contusion models), extending to large animal models, and as part of a combined approach with therapies such as intermittent hypoxia with and without task-specific training (Vose et al., 2022), and spinal and cortical stimulation strategies (Michel-Flutot et al., 2022), which aim to harness intrinsic neuroplasticity, recovering neural drive to ensure adequate electrical activation of the respiratory muscles for the crucial act of breathing. The innovative study by Fogarty et al. (2023) highlights the potential application of pegylated benzothiazole derivatives for the recovery of respiratory muscle activity following spinal cord injury, providing renewed focus on the potential of pharmacotherapy for neural regeneration and rehabilitation in spinal cord injury. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. K.O'H. Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. A.S. Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. Open access funding provided by IReL.