Spinal cord injury: time to move?

Abstract

This symposium aims at summarizing some of the scientific bases for current or planned clinical trials in patients with spinal cord injury (SCI). It stems from the interactions of four researchers involved in basic and clinical research who presented their work at a dedicated Symposium of the Society for Neuroscience in San Diego. After SCI, primary and secondary damage occurs and several endogenous processes are triggered that may foster or hinder axonal reconnection from supralesional structures. Studies in animals show that some of these processes can be enhanced or decreased by exogenous interventions using drugs to diminish repulsive barriers (anti-Nogo, anti-Rho) that prevent regeneration and/or sprouting of axons. Cell grafts are also envisaged to enhance beneficial immunological mechanisms (autologous macrophages, vaccines) or remyelinate axons (oligodendrocytes derived from stem cells). Some of these treatments could be planned concurrently with neurosurgical approaches that are themselves beneficial to decrease secondary damage (e.g., decompression/reconstructive spinal surgery). Finally, rehabilitative approaches based on the presence of functional networks (i.e., central pattern generator) below the lesion combined with the above neurobiological approaches may produce significant functional recovery of some sensorimotor functions, such as locomotion, by ensuring an optimal function of endogenous spinal networks and establishing new dynamic interactions with supralesional structures. More work is needed on all fronts, but already the results offer great hope for functional recovery after SCI based on sound basic and clinical neuroscience research.

Figures

Figure 1.

Left, Schematic representation of a spinal lesion together with some descending pathways originating from the telencephalon or the brainstem. Some axons are lesioned, and others are intact although they could be demyelinated. Below the lesion, a CGP for locomotion interacts with descending inputs and peripheral afferents originating from a lower limb. Middle, Endogenous processes lead to sprouting of descending fibers but little axonal growth through the glial scar. Autonomous spinal functions return to a certain degree. Right, Various exogenous interventions enhance or diminish some mechanisms that may help regeneration or sprouting. Cellular replacement may also favor beneficial immunological processes or foster remyelination. Rehabilitation such as treadmill training can accelerate and stabilize locomotor performance.

Figure 2.

Molecular mechanisms involved in neurite growth inhibition in CNS myelin include Nogo-A, MAG, and OMgp and their signaling partners. Methods and reagents that were successfully used to induce regenerative fiber growth and functional recovery in rats, mice, or monkeys after spinal cord injury are shown in red. Nogo-66, 66 aa extracellular domain of Nogo; NgR, Nogo-66 receptor; Cai, intracellular calcium; Y27632, selective ROCK inhibitor; Nogo-KO, Nogo-A knock-out mouse; NgR-Fc, soluble fusion protein blocking Nogo-A; NEP1–40, first 40 aa of the Nogo-66 region of Nogo-A, which act as an Nogo-66 receptor antagonist; Ab α-Nogo-A, anti-Nogo-A antibody; Ab α-Lingo-1, anti-Lingo-1 antibody; NgR KD, NgR knockdown (small interference RNA experiments).

Figure 3.

Early recruitment of blood-borne monocytes at the margins of the lesion site is needed for CNS repair. The blood-borne monocytes acquire a beneficial phenotype only when they encounter the extracellular matrix proteins that delineate the lesion site. Spontaneous recruitment of blood-borne monocytes is restricted. Therefore, timely injection to the margins of the lesion site of specifically activated autologous macrophages can promote recovery. TNFα, Tumor necrosis factor α; MHCII, class II major histocompatibility complex proteins; IGF-I, insulin-like growth factor I.