Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons (original) (raw)
Related papers
The role of neurotrophic factors in nerve regeneration
Neurosurgical Focus, 2009
This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell–derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effe...
Molecular Neurobiology, 2003
Over a half a century of research has confirmed that neurotrophic factors promote the survival and process outgrowth of isolated neurons in vitro. The mechanisms by which neurotrophic factors mediate these survival-promoting effects have also been well characterized. In vivo, peripheral neurons are critically dependent on limited amounts of neurotrophic factors during development. After peripheral nerve injury, the adult mammalian peripheral nervous system responds by making neurotrophic factors once again available, either by autocrine or paracrine sources. Three families of neurotrophic factors were compared, the neurotrophins, the GDNF family of neurotrophic factors, and the neuropoetic cytokines. Following a general overview of the mechanisms by which these neurotrophic factors mediate their effects, we reviewed the temporal pattern of expression of the neurotrophic factors and their receptors by axotomized motoneurons as well as in the distal nerve stump after peripheral nerve injury. We discussed recent experiments from our lab and others which have examined the role of neurotrophic factors in peripheral nerve injury. Although our understanding of the mechanisms by which neurotrophic factors mediate their effects in vivo are poorly understood, evidence is beginning to emerge that similar phenomena observed in vitro also apply to nerve regeneration in vivo.
Experimental Neurology, 2001
Dorsal roots have a limited regeneration capacity after transection. To improve nerve regeneration, the growth-promoting effects of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were evaluated. The proteins were continuously released by synthetic nerve guidance channels bridging a 4-mm gap in the transected dorsal root. Four weeks after lesion, the regenerated nerve cables were analyzed for the presence of myelinated and unmyelinated axons. While BDNF showed a limited effect on axonal regeneration (863 ؎ 39 axons/regenerated nerve, n ؍ 6), NGF (1843 ؎ 482) and NT-3 (1495 ؎ 449) powerfully promoted regeneration of myelinated axons compared to channels releasing the control protein bovine serum albumin (293 ؎ 39). In addition, NGF, but not BDNF nor NT-3, had a potent effect on the regeneration of unmyelinated axons (NGF, 55 ؎ 1.4; BDNF, 4 ؎ 0.3; NT-3, 4.7 ؎ 0.3 axons/100 m 2 ; n ؍ 6). The present study suggests that synthetic nerve guidance channels slowly and continuously releasing the neurotrophins NGF and NT-3 can overcome the limited regeneration of transected dorsal root.
Journal of Neurosurgery, 2010
Object Glial cell line–derived neurotrophic factor (GDNF) has potent survival effects on central and peripheral nerve populations. The authors examined the differential effects of GDNF following either a sciatic nerve crush injury in mice that overexpressed GDNF in the central or peripheral nervous systems (glial fibrillary acidic protein [GFAP]–GDNF) or in the muscle target (Myo-GDNF). Methods Adult mice (GFAP-GDNF, Myo-GDNF, or wild-type [WT] animals) underwent sciatic nerve crush and were evaluated using histomorphometry and muscle force and power testing. Uninjured WT animals served as controls. Results In the sciatic nerve crush, the Myo-GDNF mice demonstrated a higher number of nerve fibers, fiber density, and nerve percentage (p < 0.05) at 2 weeks. The early regenerative response did not result in superlative functional recovery. At 3 weeks, GFAP-GDNF animals exhibit fewer nerve fibers, decreased fiber width, and decreased nerve percentage compared with WT and Myo-GDNF mic...
Journal of Neurotrauma, 2003
The response of supraspinal neurons to acute or delayed treatment with GDNF following a spinal cord injury was examined. A cervical level 3 hemisection lesion cavity was created by tissue aspiration in adult, female rats. In one experiment gel foam saturated with GDNF was placed into the lesion cavity immediately after injury to determine if the extent of axonal retraction was affected by neurotrophic factor treatment. One week prior to sacrifice animals received a microinjection of biotinylated dextran amine (BDA) into the red nucleus and reticular formation to label descending spinal pathways by anterograde transport mechanisms. Animals were sacrificed 1 or 4 weeks after injury and treatment with GDNF. The terminal end of injured BDA-labeled rubrospinal and reticulospinal tract axons was identified and the distance from the lesion was measured. In comparison to PBS-treated animals, GDNF-treatment resulted in a significant decrease in the extent of axonal retraction of both rubrospinal and reticulospinal tract axons at 1 week after spinal cord injury for both tracts. At 4 weeks after injury the mean distance from the lesion was less than 240 mm following GDNF-treatment for both tracts, compared to over 480 mm following PBS-treatment. In the second experiment injured supraspinal neurons were labeled by retrograde transport of True Blue that had been placed into the lesion cavity. One month later scar tissue was removed from the cavity by aspiration to enlarge the cavity by approximately 500 mm in a rostral direction. GDNF-saturated gel foam was placed into the cavity for 60 min prior to apposition of an autologous peripheral nerve (PN) graft to the rostral cavity wall. One month later Nuclear Yellow was applied to the distal end of the PN graft and animals were sacrificed after 2 days. The number of supraspinal neurons containing both True Blue and Nuclear Yellow was counted as a measure of axonal regeneration by chronically injured neurons. There was a seven-fold increase in the number of regenerating neurons after GDNF-treatment, with the majority (65%) of dual-labeled neurons located within the reticular formation. These results indicate that GDNF has neuroprotective effects when provided acutely after injury and promotes axonal regeneration when provided in a chronic injury situation.
Neuroscience Letters, 1989
Severed adult rat dorsal roots were apposed to an intraspinal transplant of fetal spinal cord (FSC) tissue co-grafted with nerve growth factor (NGF)-treated nitrocellulose strips. Axonal regrowth from the injured roots was assessed by calcitonin gene-related peptide immunoreactivity (CGRP-IR). Dense fascicles of regenerating CGRP-IR axons lined the entire length of NGF-treated nitrocellulose, with many crossing the graft host interface ventrally to extend into the host neuropil. In contrast, CGRP-IR axon regrowth was not promoted by untreated nitrocellulose implants. These results indicate that substrate bound NGF can promote and direct the intraspinal regeneration of a specific population of dorsal root axons. Centrally directed sensory axons generally fail to regenerate following implantation of the cut end of a dorsal root into the adult spinal cord [1], although a modest ingrowth of these fibers has been described following a crush lesion [2, 8]. In each case. those axons that appeared to have regenerated were essentially confined to the dorsal root entry zone. In its simplest terms this paucity of ingrowth has been attributed to either the formation of a dense glial scar at the PNS/CNS interface [10] or to evidence that the adult CNS represents a non-permissive environment for extensive axonal growth [12]. Recent studies demonstrate that many sensory neurons do have the potential to regrow their central process if an appropriate environmental milieu, such as fetal spinal cord (FSC) tissue [14] or millipore strips coated with immature glial cells [6] is provided. Nerve growth factor (NGF) is the prototypical neurotrophic factor which serves as a target derived survival factor required by developing dorsal root ganglion (DRG) neurons [15, 16]. While adult DRG neurons may no longer require NGF for survival, the expression of some neurotransmitter/neuromodulator peptides in many
International journal of molecular sciences, 2016
After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PL...