Abstract
Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might contribute to the restorative effects of these implants.
Highlights
Axotomy of adult CNS neurons leads to severe morphofunctional alterations which include synaptic stripping and reduced firing rate [1,2]
In order to test whether the effects of central axotomy and neural progenitor cells (NPCs) implants on vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) expression were restricted to the injured neuronal population within the abducens nucleus we examined VEGF and BDNF immunoreactivity in the motoneurons of the same nucleus, whose axons were left intact
We have demonstrated that VEGF and BDNF expression in axotomized neurons can be modulated differentially by NPCs implanted in the site of injury
Summary
Axotomy of adult CNS neurons leads to severe morphofunctional alterations which include synaptic stripping and reduced firing rate [1,2]. The abducens nucleus is composed of motoneurons that innervate the ipsilateral lateral rectus muscle, and a group of premotor cells, the abducens internuclear neurons, whose axons course through the MLF to establish synaptic contacts with medial rectus motoneurons in the contralateral oculomotor nucleus [12]. After their axotomy, abducens internuclear neurons show a marked reduction in firing rate, a significant decrease in eye position and velocity sensitivities and a noticeable stripping of synaptic afferences [2,11]. It was suggested that neurotrophic factors released by the implanted tissue probably mediate the re-establishment of these axotomy-induced alterations, a hypothesis supported by the fact that abducens internuclear neurons express the different types of trk receptors for neurotrophins [15]
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