Advancements in neuroregenerative and neuroprotective therapies for traumatic spinal cord injury

Abstract

Traumatic spinal cord injuries (SCIs) continue to be a major healthcare concern, with a rising prevalence worldwide. In response to this growing medical challenge, considerable scientific attention has been devoted to developing neuroprotective and neuroregenerative strategies aimed at improving the prognosis and quality of life for individuals with SCIs. This comprehensive review aims to provide an up-to-date and thorough overview of the latest neuroregenerative and neuroprotective therapies currently under investigation. These strategies encompass a multifaceted approach that include neuropharmacological interventions, cell-based therapies, and other promising strategies such as biomaterial scaffolds and neuro-modulation therapies. In addition, the review discusses the importance of acute clinical management, including the role of hemodynamic management as well as timing and technical aspects of surgery as key factors mitigating the secondary injury following SCI. In conclusion, this review underscores the ongoing scientific efforts to enhance patient outcomes and quality of life, focusing on upcoming strategies for the management of traumatic SCI. Each section provides a working knowledge of the fundamental preclinical and patient trials relevant to clinicians while underscoring the pathophysiologic rationale for the therapies.

Keywords: biomaterials; cell based therapies; neuromodulation; neuroprotection; neuroregeneraion; spinal cord injury.

Figure 1

Secondary Injury and site of action for neuroprotective and neuroregenerative therapies. Demyelination leads to invasion of phagocytic inflammatory cells (Macrophage and Microglia), that clear myelin debris and release cytotoxic byproducts, including free radicals (O2−, hydrogen peroxide and peroxynitrite), causing additional necrotic, and apoptotic cell death due to DNA-, protein-, and lipid oxidation. Activated microglia and macrophages additionally propagate the inflammatory response and contribute to ongoing apoptosis of oligodendrocytes. Degenerated oligodendrocytes release neurite outgrowth inhibitor A (Nogo-A), oligodendrocyte-myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG). These molecules can all bind the Nogo receptor and p75 neurotrophin receptor (p75NTR) to activate RHOA and Rho-associate protein kinase (ROCK), which further causes neurite retraction and apoptosis. Oligodendrocyte precursor cells (OPC) can differentiate into mature oligodendrocytes and remyelinate these injured axons. However, remyelination is inhibited by the presence of EphrinB3 in myelin debris. This leads to deprived remyelination post-injury. EPO, Erythropoietin; MPSS, Methylprednisolone Sodium Succinate; PNT, peroxinytrite.

Figure 2

Phases of tSCI and timeline of neuroprotective and neuroregenerative therapies. Overview of clinical and preclinical therapies and their respective therapeutic windows. MPSS, Methylprednisolone Sodium Succinate; BP, Blood Pressure; HGF, Hepatocyte growth factor; bFGF, Basic fibroblast growth factor; IVIG, Intravenous Immunoglobulin G; EPO, Erythropoietin; Nogo, Oligodendrocytes release neurite outgrowth inhibitor A; RGMa, Repulsive Guidance Molecule A; Rho/ROCK, Rho-associated coiled-coil protein kinase; Mg, Magnesium.