Concise Review: Bridging the Gap: Novel Neuroregenerative and Neuroprotective Strategies in Spinal Cord Injury

Abstract

Spinal cord injuries (SCIs) result in devastating lifelong disability for patients and their families. The initial mechanical trauma is followed by a damaging secondary injury cascade involving proapoptotic signaling, ischemia, and inflammatory cell infiltration. Ongoing cellular necrosis releases ATP, DNA, glutamate, and free radicals to create a cytotoxic postinjury milieu. Long-term regeneration of lost or injured networks is further impeded by cystic cavitation and the formation of an inhibitory glial-chondroitin sulfate proteoglycan scar. In this article, we discuss important neuroprotective interventions currently applied in clinical practice, including surgical decompression, blood pressure augmentation, and i.v. methylprednisolone. We then explore exciting translational therapies on the horizon, such as riluzole, minocycline, fibroblast growth factor, magnesium, and hypothermia. Finally, we summarize the key neuroregenerative strategies of the next decade, including glial scar degradation, Rho-ROCK inhibition, cell-based therapies, and novel bioengineered adjuncts. Throughout, we emphasize the need for combinatorial approaches to this multifactorial problem and discuss relevant studies at the forefront of translation. We conclude by providing our perspectives on the future direction of SCI research.

Significance: Spinal cord injuries (SCIs) result in devastating, lifelong disability for patients and their families. This article discusses important neuroprotective interventions currently applied in clinical practice, including surgical decompression, blood pressure augmentation, and i.v. methylprednisolone. Translational therapies on the horizon are discussed, such as riluzole, minocycline, fibroblast growth factor, magnesium, and hypothermia. The key neuroregenerative strategies of the next decade are summarized, including glial scar degradation, Rho-ROCK inhibition, cell-based therapies, and novel bioengineered adjuncts. The need for combinatorial approaches to this multifactorial problem is emphasized, relevant studies at the forefront of translation are discussed, and perspectives on the future direction of SCI research are presented.

Trial registration: ClinicalTrials.gov NCT02163876.

Keywords: Biomaterial; Neuroprotection; Neuroregeneration; Spinal cord injury; Stem cell; Trauma.

Figure 1.

Pathophysiology of spinal cord injury in the acute, subacute, and chronic setting. Acute traumatic injury causes cell death through ischemia, release of cytotoxic molecules, initiation of apoptotic cascades, hemorrhage, edema, and infiltration of inflammatory cells. In the subacute phase, cystic cavities begin to coalesce and become surrounded by reactive astrocytes, fibroblasts, and inflammatory cells. Inhibitory proteoglycans are secreted into the extracellular matrix. Degeneration/dieback of damaged and denuded axons occurs. In the intermediate/chronic phase, encompassing most patients, mechanical and chemotactic barriers restrict axon regeneration. Limited remyelination by oligodendrocytes and Schwann cells may portend small functional gains during this period.

Figure 2.

Schematic highlighting promising primary and adjunctive neuroregenerative strategies in spinal cord injury. Transplanted auto/allogenic cells can be differentiated to (1) oligodendrocytes to remyelinate denuded axons or (2) neurons for restoration of functional neural circuits. (3) Promoting this is likely to require molecular signaling techniques for axon guidance. (4) Enhancement of synaptic plasticity with formation of new connections may be a key mechanism of recovery. (5) Another important approach is induction of endogenous neural stem cells, particularly from the central canal. (6) The disruption of the structural architecture of the cord can be overcome by cotransplants of biomaterials that can form a framework for growth. (7) The glial scar barrier can be degraded by enzymes such as chondroitinase ABC. (8) Finally, transplanted cells can be genetically modified to secrete prosurvival, promigration, or other important factors.