Status of Acute Spinal Cord Injury Pathophysiology and Emerging Therapies
Status of Acute Spinal Cord Injury Pathophysiology and Emerging Therapies
This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho-associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.
The reversal of paralysis following SCI is among the most daunting challenges in all of neuroscience research. Despite significant improvements in the early medical and surgical management of SCI, coupled with a vastly improved understanding of SCI pathophysiology, there remain no effective treatments to improve neurological outcomes following SCI. Although a number of pharmacological agents (such as methylprednisolone sodium succinate and the related compound tirilazad mesylate, GM-1 ganglioside, thyrotropin-releasing hormone, gacyclidine, naloxone, and nimodipine) have been investigated in large, prospective, randomized, controlled clinical trials, all have failed to demonstrate convincing neurological benefit, despite the promise that these agents demonstrated in preclinical animal studies of SCI. The aim of this review is to provide an overview of the current state-of-the-art of SCI pathophysiology while highlighting the important aspects for which therapeutic interventions are being developed. The latter half of the review will discuss recent preclinical advances in SCI therapies, focusing mainly on cell-based approaches, and comment on the potential for clinical translation that exists.
Abstract and Introduction
Abstract
This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho-associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.
Introduction
The reversal of paralysis following SCI is among the most daunting challenges in all of neuroscience research. Despite significant improvements in the early medical and surgical management of SCI, coupled with a vastly improved understanding of SCI pathophysiology, there remain no effective treatments to improve neurological outcomes following SCI. Although a number of pharmacological agents (such as methylprednisolone sodium succinate and the related compound tirilazad mesylate, GM-1 ganglioside, thyrotropin-releasing hormone, gacyclidine, naloxone, and nimodipine) have been investigated in large, prospective, randomized, controlled clinical trials, all have failed to demonstrate convincing neurological benefit, despite the promise that these agents demonstrated in preclinical animal studies of SCI. The aim of this review is to provide an overview of the current state-of-the-art of SCI pathophysiology while highlighting the important aspects for which therapeutic interventions are being developed. The latter half of the review will discuss recent preclinical advances in SCI therapies, focusing mainly on cell-based approaches, and comment on the potential for clinical translation that exists.
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