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1.
Eur J Neurosci ; 30(7): 1280-96, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19788572

ABSTRACT

Preconditioning sciatic nerve injury enhances axonal regeneration of ascending sensory neurons after spinal cord injury. A key question is whether direct injury of sensory nerves is necessary for the enhanced regeneration. The lumbar 5 ventral root transection (L5 VRT) model, a model of selective motor nerve injury, provides a useful tool to address this question. Here we examined the effects of a preconditioning L5 VRT on the regeneration after a subsequent dorsal column transection (DCT) in adult Sprague-Dawley rats. We found that L5 VRT 1 week before DCT increased the number of Fast Blue (FB)-labeled neurons in the L5 dorsal root ganglia (DRG) and promoted sprouting/regenerating axons to grow into the glial scar. L5 VRT also induced a dramatic upregulation of expression of brain-derived neurotrophic factor (BDNF) in the preconditioned DRG and in the injured spinal cord. Moreover, almost all of the FB-labeled sprouting/regenerating neurons expressed BDNF, and approximately 55% of these neurons were surrounded by p75 neurotrophin receptor-positive glial cells. This combined injury led to an increase in the number of BDNF- and TrkB-immunoreactive nerve fibers in the dorsal column caudal to the lesion site. Taken together, these findings demonstrate that L5 VRT promotes sprouting/regeneration of ascending sensory neurons, indicating that sensory axotomy may not be essential for the plasticity of injured dorsal column axons. Thus, the sensory neurons could be preprimed in the regenerative milieu of Wallerian degeneration and neuroinflammation, which might alter the expression of neurotrophic factors and their receptors, facilitating sprouting/regeneration of ascending sensory neurons.


Subject(s)
Nerve Regeneration/physiology , Neuronal Plasticity/physiology , Sensory Receptor Cells/physiology , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/therapy , Spinal Nerve Roots/injuries , Aging , Animals , Axons/physiology , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Female , Ganglia, Spinal/physiopathology , Nerve Tissue Proteins , Neuroglia/physiology , Rats , Rats, Sprague-Dawley , Receptor, trkB/metabolism , Receptors, Growth Factor , Receptors, Nerve Growth Factor/metabolism , Spinal Nerve Roots/physiopathology , Time Factors
2.
Life Sci ; 84(3-4): 61-8, 2009 Jan 16.
Article in English | MEDLINE | ID: mdl-19026664

ABSTRACT

AIMS: After peripheral nerve injury, p75NTR was upregulated in Schwann cells of the Wallerian degenerative nerves and in motor neurons but down-regulated in the injured sensory neurons. As p75NTR in neurons mediates signals of both neurotrophins and inhibitory factors, it is regarded as a therapeutic target for the treatment of neurodegeneration. However, its physiological function in the nerve regeneration is not fully understood. In the present study, we aimed to examine the role of p75NTR in the regeneration of peripheral nerves. MAIN METHODS: In p75NTR knockout mice (exon III deletion), the sciatic nerves and facial nerves on one side were crushed and regenerating neurons in the facial nuclei and in the dorsal root ganglia were labelled by Fast Blue. The regenerating fibres in the sciatic nerve were also labelled by an anterograde tracer and by immunohistochemistry. KEY FINDINGS: The results showed that the axonal growth of injured axons in the sciatic nerve of p75NTR mutant mice was significantly retarded. The number of regenerated neurons in the dorsal root ganglia and in the facial nuclei in p75NTR mutant mice was significantly reduced. Immunohistochemical staining of regenerating axons also showed the reduction in nerve regeneration in p75NTR mutant mice. SIGNIFICANCE: Our data suggest that p75NTR plays an important role in the regeneration of injured peripheral nerves.


Subject(s)
Nerve Regeneration , Peripheral Nerves/physiology , Receptors, Nerve Growth Factor/physiology , Animals , Axons/physiology , Calcitonin Gene-Related Peptide/analysis , GAP-43 Protein/analysis , Ganglia, Spinal/physiology , Mice , Motor Neurons/physiology , Ubiquitin Thiolesterase/analysis
3.
PLoS One ; 3(3): e1707, 2008 Mar 05.
Article in English | MEDLINE | ID: mdl-18320028

ABSTRACT

BACKGROUND: The blood brain barrier (BBB) and truncated trkB receptor on astrocytes prevent the penetration of brain derived neurotrophic factor (BDNF) applied into the peripheral (PNS) and central nervous system (CNS) thus restrict its application in the treatment of nervous diseases. As BDNF is anterogradely transported by axons, we propose that peripherally derived and/or applied BDNF may act on the regeneration of central axons of ascending sensory neurons. METHODOLOGY/PRINCIPAL FINDINGS: The present study aimed to test the hypothesis by using conditioning lesion of the sciatic nerve as a model to increase the expression of endogenous BDNF in sensory neurons and by injecting exogenous BDNF into the peripheral nerve or tissues. Here we showed that most of regenerating sensory neurons expressed BDNF and p-CREB but not p75NTR. Conditioning-lesion induced regeneration of ascending sensory neuron and the increase in the number of p-Erk positive and GAP-43 positive neurons was blocked by the injection of the BDNF antiserum in the periphery. Enhanced neurite outgrowth of dorsal root ganglia (DRG) neurons in vitro by conditioning lesion was also inhibited by the neutralization with the BDNF antiserum. The delivery of exogenous BDNF into the sciatic nerve or the footpad significantly increased the number of regenerating DRG neurons and regenerating sensory axons in the injured spinal cord. In a contusion injury model, an injection of BDNF into the footpad promoted recovery of motor functions. CONCLUSIONS/SIGNIFICANCE: Our data suggest that endogenous BDNF in DRG and spinal cord is required for the enhanced regeneration of ascending sensory neurons after conditioning lesion of sciatic nerve and peripherally applied BDNF may have therapeutic effects on the spinal cord injury.


Subject(s)
Brain-Derived Neurotrophic Factor/physiology , Ganglia, Spinal/physiology , Nerve Regeneration/physiology , Neurons, Afferent/physiology , Spinal Cord Injuries/physiopathology , Animals , Axons/pathology , Behavior, Animal , Brain-Derived Neurotrophic Factor/pharmacology , Female , GAP-43 Protein/metabolism , Immunoenzyme Techniques , Male , Nerve Tissue Proteins , Rats , Rats, Sprague-Dawley , Receptors, Growth Factor , Receptors, Nerve Growth Factor/metabolism
4.
Eur J Neurosci ; 24(9): 2444-52, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17100833

ABSTRACT

Recent studies have shown that the precursor of brain-derived neurotrophic factor (pro-BDNF) activates p75NTR with high affinity to induce apoptosis. Here we show that pro-BDNF is transported anterogradely and retrogradely in sensory neurons of adult rats. After a crush injury of sciatic nerves, dorsal roots or dorsal column in adult Sprague-Dawley rats, the immunoreactivity for pro-BDNF accumulated at both the proximal and distal segments. The accumulation reached a maximum at 24 h after injury. Western blot analysis also revealed pro-BDNF in sciatic nerve segments proximal and distal to the ligature and in the spinal cord. Biotinylated or Alexa-488-labelled pro-BDNF injected into sciatic nerve was internalized and transported both retrogradely and anterogradely within sensory neurons. These results demonstrate that pro-BDNF is anterogradely and retrogradely transported in sensory neurons, suggesting that endogenous pro-BDNF may be released and play important functions.


Subject(s)
Axonal Transport/physiology , Brain-Derived Neurotrophic Factor/metabolism , Neurons, Afferent/metabolism , Animals , Blotting, Western , Mice , Nerve Crush , Neurons, Afferent/pathology , Rats , Rats, Sprague-Dawley , Sciatic Nerve/injuries , Sciatic Nerve/pathology , Spinal Cord/metabolism , Spinal Cord/pathology , Spinal Nerve Roots/metabolism , Spinal Nerve Roots/pathology
5.
J Neurochem ; 96(3): 833-42, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16336221

ABSTRACT

Remyelination is an important aspect of nerve regeneration after nerve injury but the underlying mechanisms are not fully understood. The neurotrophin receptor, p75(NTR), in activated Schwann cells in the Wallerian degenerated nerve is up-regulated and may play a role in the remyelination of regenerating peripheral nerves. In the present study, the role of p75(NTR) in remyelination of the sciatic nerve was investigated in p75(NTR) mutant mice. Histological results showed that the number of myelinated axons and thickness of myelin sheath in the injured sciatic nerves were reduced in mutant mice compared with wild-type mice. The myelin sheath of axons in the intact sciatic nerve of adult mutant mice is also thinner than that of wild-type mice. Real-time RT-PCR showed that mRNA levels for myelin basic protein and P0 in the injured sciatic nerves were significantly reduced in p75(NTR) mutant animals. Western blots also showed a significant reduction of P0 protein in the injured sciatic nerves of mutant animals. These results suggest that p75(NTR) is important for the myelinogenesis during the regeneration of peripheral nerves after injury.


Subject(s)
Myelin Sheath/physiology , Nerve Regeneration/physiology , Receptor, Nerve Growth Factor/deficiency , Sciatic Neuropathy/physiopathology , Animals , Axons/pathology , Axons/physiology , Blotting, Western/methods , Disease Models, Animal , Male , Mice , Mice, Knockout , Microglia/pathology , Microglia/ultrastructure , Microscopy, Electron, Transmission/methods , Myelin Sheath/pathology , Myelin Sheath/ultrastructure , Nerve Regeneration/genetics , RNA, Messenger/metabolism , Receptor, Nerve Growth Factor/physiology , Recovery of Function/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Sciatic Neuropathy/genetics , Sciatic Neuropathy/pathology , Time Factors
6.
J Neurochem ; 91(3): 704-15, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15485500

ABSTRACT

The precursors for neurotrophins are proteolytically cleaved to form biologically active mature molecules which activate their receptors p75NTR and trks. A recent study showed that the precursor for nerve growth factor (NGF) can bind to p75NTR with a high affinity and induces apoptosis of neurons in vitro. Mutation in Val66Met of brain-derived neurotrophic factor (BDNF) results in reduction in hippocampal function in learning and in the dysfunction of intracellular BDNF sorting and secretion. To examine the functions of pro-neurotrophins in vivo, it is essential to know where they are expressed in the nervous system. In the present study, we have raised and characterized rabbit polyclonal antibodies against a peptide coding for the precursor region of the BDNF gene. The antibody specifically recognizes the precursor for BDNF by western blot. With the affinity purified precursor antibody, we have mapped the distribution and localization of the precursor for BDNF. The results showed that, like mature BDNF, pro-BDNF is localized to nerve terminals in the superficial layers of dorsal horn, trigeminal nuclei, nuclei tractus solitarius, amygdaloid complex, hippocampus, hypothalamus and some peripheral tissues. These results suggest that pro-BDNF, like mature BDNF, is anterogradely transported to nerve terminals and may have important functions in synaptic transmission in the spinal cord and brain.


Subject(s)
Brain-Derived Neurotrophic Factor/biosynthesis , Central Nervous System/metabolism , Peripheral Nervous System/metabolism , Presynaptic Terminals/metabolism , Protein Precursors/biosynthesis , Animals , Antibody Specificity , Blotting, Western , Brain/cytology , Brain/metabolism , Brain-Derived Neurotrophic Factor/analysis , Cells, Cultured , Central Nervous System/cytology , Female , Ganglia, Spinal/cytology , Immunohistochemistry , Male , Neurons/metabolism , Organ Specificity , Peripheral Nervous System/cytology , Protein Precursors/analysis , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/metabolism , Transfection
7.
J Neurosci ; 24(2): 542-6, 2004 Jan 14.
Article in English | MEDLINE | ID: mdl-14724254

ABSTRACT

The neurotrophin receptor p75NTR is the coreceptor for Nogo receptor, mediating growth cone collapse in vitro by MAG, myelin oligodendrocyte glycoprotein (Omgp), and Nogo. Whether p75NTR plays any role in the failure of nerve regeneration in vivo is not known. Immunohistochemical data showed that p75NTR was expressed in only a very small subset of ascending sensory axons but not in any corticospinal axons in the dorsal column of either normal or injured spinal cord. Using p75NTR-deficient mice, we showed that the depletion of the functional p75NTR did not promote the regeneration of the descending corticospinal tract and ascending sensory neurons in the spinal cord 2 weeks after spinal cord injury. Local administration of p75NTR-Fc fusion molecule, the dominant-negative receptor to block the function of neurite outgrowth inhibitors, did not improve regeneration of ascending sensory neurons in the injured spinal cord. Our results suggest that p75NTR may not be a critical molecule mediating the function of myelin-associated inhibitory factors in vivo.


Subject(s)
Nerve Regeneration , Receptors, Nerve Growth Factor/physiology , Spinal Cord/physiology , Animals , Axons/physiology , Denervation , Mice , Mice, Inbred BALB C , Mice, Knockout , Nerve Fibers/physiology , Neurons, Afferent/cytology , Neurons, Afferent/physiology , Pyramidal Tracts/cytology , Pyramidal Tracts/physiology , Receptor, Nerve Growth Factor , Receptors, Nerve Growth Factor/genetics , Spinal Cord/cytology , Spinal Cord/surgery
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