Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Abstract

Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

Neurotrophin treatment to promote regeneration after traumatic CNS injury

“…For example, NGF supports the sprouting and regeneration of cholinergic local motor axons, primary nociceptive axons, and cerulospinal axons (Tuszynski et al, 1996; Grill et al, 1997; Romero et al, 2001; Tang et al, 2004a). Similarly, BDNF secreting bone marrow stromal cell transplants enhance regeneration of multiple neuronal populations including raphaespinal, cerulospinal, rubrospinal, local motor and propriospinal axons, while NT3 expression promotes regeneration of ascending sensory neurons across the DREZ and within the dorsal columns (Hollis and Tuszynski, 2011). Several studies show that the location of neurotrophin expression can also determine the extent of regeneration (Lu et al, 2001; Taylor et al, 2006).…”

Low-level laser therapy for spinal cord injury in rats: effects of polarization

“…Thus, SCI patients are left with serious residual disabilities, such as paralysis, respiratory difficulty, chronic pain, urinary problems, and neurologic decline, leading to considerable decrease in quality of life. Various strategies have been examined for repair of SCI in animal models, including blockage of the endogenous growth inhibitory factors, 1,2 infusion of neurotrophic factors, 3,4 and transplantation of growth promoting cells. [5][6][7] However, no effective treatment for SCI has yet been established.…”

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

“…The initial result of SCI is the interruption of ascending and descending circuits, the death of proximal neurons and glia, and an immediate loss of function [15]. Following SCI, the lesion is rapidly invaded by neutrophils, macrophages, and microglia [16,17], leading to inflammatory cascades that cause secondary degeneration of glia and axons, cystic cavitation, and the eventual establishment of a glial scar [16,17].…”