Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy

Abstract

Neurons projecting into the peripheral nervous system (PNS) regenerate their axons after injury, in contrast to those confined to the central nervous system (CNS). Both neuronal and nonneuronal factors contribute to the lack of CNS regeneration. In this review we concentrate on the differential gene expression response to axotomy in PNS vs. CNS neurons. In general CNS neurons fail to up-regulate or sustain the expression of regenerationassociated proteins (RAGs), including trophic factors and their receptors. The presumed lack of trophic support of axotomized CNS neurons provided the rationale for the exogenous application of trophic factors, either to the lesion site or to the cell bodies. Here, we review our data on the application of trophic factors to rubrospinal and corticospinal neurons. Cell body treatment of axotomized rubrospinal neurons with brain-derived neurotrophic factor (BDNF) reversed atrophy, increased GAP-43 and T␣-1 tubulin mRNA expression, and promoted axonal regeneration into peripheral nerve grafts. Importantly, BDNF cell body treatment was still effective in the chronic setting, i.e., when initiated 1 year after injury, but BDNF had no effect when applied to the chronic spinal cord injury site. The ability to promote regeneration in chronically injured neurons will hopefully contribute to the development of treatment strategies for chronic spinal injuries. © 2002 Wiley-Liss, Inc.It is becoming increasingly evident that several factors are implicated in the failure of central nervous system (CNS) neurons to regenerate their axons after injury. These factors are often conceptualized as being either intrinsic (i.e., related to the native gene expression response of the axotomized CNS neuron) or extrinsic in nature (i.e., related to molecules and/or physical barriers in the CNS environment that inhibit axonal growth). This conceptual differentiation is somewhat an oversimplification, because extrinsic factors such as molecules that influence growth cone motility/guidance may also induce intrinsic factors such as neuronal gene expression. With regard to the extrinsic factors, numerous molecules that are inhibitory to axonal growth have been found in association with CNS myelin and the CNS injury site and have been extensively reviewed elsewhere (Davies et al

Tissue engineering applied to the retinal prosthesis: Neurotrophin-eluting polymeric hydrogel coatings

“…Several researchers have proposed the use of neurotrophin as a therapeutic treatment for peripheral nerve and spinal cord injuries [32,33]. However, our results suggest that any extension obtained would be short-lived in the absence of other cues.…”

Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

“…Injured ascending sensory axons are responsive to NGF, BDNF, and neurotrophin 3 (NT-3) (Bradbury et al, 1999;Oudega and Hagg, 1999). Lesioned rubrospinal and corticospinal axons are also responsive to BDNF, which promotes regeneration of rubrospinal axons Plunet et al, 2002) and survival but not regrowth of lesioned corticospinal axons . NT-4/5 prevents atrophy of rat rubrospinal neurons after axotomy and promotes rubrospinal regeneration (Kobayashi et al, 1997).…”

Spinal Interneuron Axons Spontaneously Regenerate after Spinal Cord Injury in the Adult Feline

“…However, it is widely accepted that axons of the adult mammalian CNS are not capable of spontaneous functional regeneration after injury (Ramon y Cajal, 1959;Yiu and He, 2006). Regeneration fails partly because cut CNS axons do not typically acquire the appropriate proteins for growth cone formation and extension (Plunet et al, 2002). In addition, the few axons that do form growth cones are faced with the formidable barrier of navigating through the glial scar at the injury site.…”