Rapid and robust restoration of breathing long after spinal cord injury

Abstract

There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (5HT) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via 5HT2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust patterned respiratory recovery after a near lifetime of paralysis.

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

“…Chondroitinase ABC can attenuate the inhibitory activity of CSPGs and promote axonal regeneration (Bradbury et al, 2002;Pakulska et al, 2017). It can significantly propel functional recovery in many kinds of SCI models and can also be combined with other treatments (e.g., stem cell transplantation, peripheral nerve autografts, and conditioning treatment) to achieve better results (Alilain et al, 2011;DePaul et al, 2015;Suzuki et al, 2017;Warren et al, 2018). Other studies on chondroitinase ABC aim to innovate the delivery route to promote clinical applications (Burnside et al, 2018;Hu et al, 2018).…”

“…As a relatively mature strategy targeting the glial scar, chondroitinase ABC has been used in many studies to investigate combination therapies (Griffin and Bradke, 2020). By removing the inhibitory microenvironment, chondroitinase ABC treatments amplify the effects of other treatments, leading to better recovery (Alilain et al, 2011;DePaul et al, 2015;Suzuki et al, 2017;Warren et al, 2018). Other strategies targeting the glial scar may also apply to combination therapy, and in general, combinations of glial scar manipulations may help to overcome some of the key challenges in enhancing SCI recovery.…”

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury

“…In turn, it will be important to determine when medication may be gradually discontinued without compromising any beneficial functional outcome. Whether our treatment strategy may synergize in experimental models of chronic SCI with other promising interventions, such as administration of the membrane-permeable intracellular sigma peptide that binds and inactivates protein tyrosine phosphatase sigma (56,57), or exercise and cardiovascular training (58,59) remains to be tested. Whereas rehabilitative training allows refining and stabilizing newly formed neuronal networks, intensive training early after injury negatively affects network reorganization, leading to recovery failure (60).…”

Neuroimmune System as a Driving Force for Plasticity Following CNS Injury

“…Injury-induced reorganization also affects subcortical and spinal autonomic circuits, eliciting adaptive and/or deleterious outcomes. Rewiring of medullary respiratory networks, sprouting of serotonergic fibers and spinal interneurons, and formation of new neural connections are key forms of anatomical plasticity that positively influence respiratory recovery after CNS injury (Bezdudnaya et al, 2017 ; Warren et al, 2018 ; Zholudeva et al, 2018 ). Additionally, rewiring local intraspinal networks can contribute to the recovery of micturition reflexes in rodent models of SCI (De Groat and Yoshimura, 2012 ; Hou and Rabchevsky, 2014 ).…”