Undesired effects of a combinatorial treatment for spinal cord injury--transplantation of olfactory ensheathing cells and BDNF infusion to the red nucleus

Eur J Neurosci. 2008 Nov;28(9):1795-807. doi: 10.1111/j.1460-9568.2008.06462.x.

Abstract

Transplantations of olfactory ensheathing cells (OECs) have been reported to promote axonal regeneration and functional recovery after spinal cord injury, but have demonstrated limited growth promotion of rat rubrospinal axons after a cervical dorsolateral funiculus crush. Rubrospinal neurons undergo massive atrophy after cervical axotomy and show only transient expression of regeneration-associated genes. Cell body treatment with brain-derived neurotrophic factor (BDNF) prevents this atrophy, stimulates regeneration-associated gene expression and promotes regeneration of rubrospinal axons into peripheral nerve transplants. Here, we hypothesized that the failure of rubrospinal axons to regenerate through a bridge of OEC transplants was due to this weak intrinsic cell body response. Hence, we combined BDNF treatment of rubrospinal neurons with transplantation of highly enriched OECs derived from the nasal mucosa and assessed axonal regeneration as well as behavioral changes after a cervical dorsolateral funiculus crush. Each treatment alone as well as their combination prevented the dieback of the rubrospinal axons, but none of them promoted rubrospinal regeneration beyond the lesion/transplantation site. Motor performance in a food-pellet reaching test and forelimb usage during vertical exploration (cylinder test) were more impaired after combining transplantation of OECs with BDNF treatment. This impaired motor performance correlated with lowered sensory thresholds in animals receiving the combinatorial therapy - which were not seen with each treatment alone. Only this combinatorial treatment group showed enhanced sprouting of calcitonin gene-related peptide-positive axons rostral to the lesion site. Hence, some combinatorial treatments, such as OECs with BDNF, may have undesired effects in the injured spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axotomy / adverse effects
  • Brain Tissue Transplantation / adverse effects*
  • Brain-Derived Neurotrophic Factor / adverse effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Efferent Pathways / drug effects
  • Efferent Pathways / injuries
  • Efferent Pathways / physiopathology
  • Growth Cones / drug effects
  • Growth Cones / metabolism
  • Growth Cones / ultrastructure
  • Male
  • Mice
  • Mice, Transgenic
  • Movement Disorders / drug therapy
  • Movement Disorders / physiopathology
  • Movement Disorders / surgery
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology
  • Neuroglia / cytology
  • Neuroglia / metabolism
  • Neuroglia / transplantation*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Olfactory Bulb / cytology
  • Olfactory Bulb / metabolism
  • Olfactory Bulb / transplantation
  • Rats
  • Rats, Sprague-Dawley
  • Red Nucleus / drug effects*
  • Red Nucleus / physiopathology
  • Retrograde Degeneration / drug therapy
  • Retrograde Degeneration / physiopathology
  • Retrograde Degeneration / prevention & control
  • Sensory Thresholds / physiology
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / physiopathology
  • Spinal Cord Injuries / surgery*

Substances

  • Brain-Derived Neurotrophic Factor