Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin-diabetic rats

Fernyhough, Paul; Diemel, Lara T.; Tomlinson, David R.

doi:10.1007/s001250050907

Cited by 95 publications

(67 citation statements)

References 39 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other factors including neurotrophic factors such as NGF and NT-3 could be involved in the improvement of NCV. In the present study, NGF and NT-3 protein contents were reduced in hind limb muscles of STZ-induced diabetic rats, consistent with previous works that demonstrated the role of these neurotrophines in DPN (43,44). However, MSC transplantation improved NCV without affecting the protein levels of NGF and NT-3 in hind limb muscles of STZ-induced diabetic rats.…”

Section: Discussionsupporting

confidence: 92%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS-MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number-to-muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS-VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number-to-muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. D iabetic polyneuropathy (DPN) is the most common complication of diabetes. It is estimated that ϳ20 -30% of diabetic patients are affected by symptomatic DPN (1). Generally, DPN develops symmetrically in a length-dependent fashion, with dying back or dropout of the longest nerve fibers; both myelinated and unmyelinated, large and small are affected. Diabetic patients suffer from various symptoms of DPN, such as spontaneous pain, hyperalgesia, and diminished sensation (2). It has been shown that tight glycemic control is effective in slowing the progression of DPN but cannot completely prevent it (3). Therefore, additional therapeutic strategies are required. CONCLUSIONS-TheseNeural cell degeneration and decreased nerve blood flow (NBF) have been recognized as pathophysiologically characteristic features of DPN (4). Therefore, therapeutic agents that could act as both neurotrophic and angiogenic factors would be useful for the treatment of DPN even at an advanced stage. We previously demonstrated that local administration of basic fibroblast growth factor (bFGF) by intramusclar injection with crosslinked gelatin hydrogel improved the impaired nerve functions of streptozotocin (STZ)-induced diabetic rats, including amelioration of decreased NBF, hypoalgesia, and the delayed motor nerve conduction velocity (MNCV) on the treated side of sciatictibial nerves and that these effects were maintained for at least 30 days (5). Schratzberger et al. (6) showed that vascular endothelial growth factor (VEGF) gene transfer significantly increased the NCV and NBF as well as the vascular densities in muscle and peripheral nerv...

show abstract

Section: Discussionsupporting

confidence: 92%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Early on in experimental diabetes, reduced production of NGF and neurotrophin-3 in the target tissues leads to the reduced retrograde axonal transport of these proteins to the DRGs [7,9,11]. This, in turn, leads to impairment of p75 neurotrophin receptor and trkA and trkC mRNA synthesis in DRGs [8,11,12], reducing neurotrophin receptor occupancy [29].…”

Section: Discussionmentioning

confidence: 99%

“…Neurotrophins are involved in the regulation of cell survival [3] and cell death [4], and also play a role in the regulation of neuronal size [5,6]. In experimental diabetes, target-tissue expression of nerve growth factor (NGF) and neurotrophin-3 is reduced, as is their retrograde transport to the DRG [7,8,9,10,11]. This reduces the expression of the low-affinity p75 neurotrophin receptor and the highaffinity tyrosine kinase receptor (trk) A and C mRNA in the DRG and the bi-directional axonal transport of the p75 neurotrophin receptor [8,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

The role of the p75 neurotrophin receptor in the morphology of dorsal root ganglion cells in streptozotocin diabetic mice: effects of sciatic nerve crush

Jiang

Jakobsen

2004

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis. Neuronal dorsal root ganglion (DRG) cells seem to be vulnerable in diabetes. The aim of this study was to determine whether the p75 neurotrophin receptor stimulates perikaryal shrinkage and neuronal death, and further accelerates neuronal DRG cell loss after axotomy in a mouse model of diabetes. Methods. Nine non-diabetic BALB/c p75 +/+ mice, seven diabetic BALB/c p75 +/+ mice, nine non-diabetic p75 −/− mice and nine diabetic p75 −/− mice received a unilateral sciatic nerve crush 1 to 2 days after streptozotocin treatment. Tissues were fixed 28 days later by vascular perfusion, and the volume and number of the fifth lumbar DRG neurons were obtained using assumption-free stereological techniques. Results. In diabetic p75 +/+ mice there was a 9% reduction in the perikaryal volume of the DRG A cells (p<0.05) and a 10% reduction in the perikaryal volume of the DRG B cells (p<0.05) on the non-crushed side compared with in non-diabetic p75 +/+ mice. However, neuronal cell number was not reduced. Conversely, no perikaryal shrinkage of A cells or B cells occurred on the non-crushed side in diabetic p75 −/− mice, and no neuronal cell loss was observed. Following nerve crush, there was a loss of B cells in non-diabetic p75 +/+ mice (37±6%) and in diabetic p75 +/+ mice (36±4%). In non-diabetic p75 −/− mice, no neuronal cell loss occurred after crush, whereas in diabetic p75 −/− mice the loss of B cells (14±4%) was small but significant (p<0.02). Conclusions/interpretation. In experimental diabetes the p75 neurotrophin receptor is involved in neuronal DRG cell body shrinkage without loss of neuronal DRG cells. Following sciatic nerve crush, DRG cell loss is not accelerated in diabetic p75 +/+ mice.

show abstract

“…In diabetic neuropathy, peripheral nerves are compromised in their ability to transport neurotrophins, suggesting that reduced neurotrophin support contributes to peripheral nerve abnormalities (Jakobsen et al, 1981;Hellweg and Hartung, 1990;Schmidt et al, 1985;Fernyhough et al, 1998;Apfel, 1999;Vinik, 1999). Nociceptive sensory neurons are embryonically dependent upon NGF.…”

Section: Nih Public Accessmentioning

confidence: 99%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

View full text Add to dashboard Cite

Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to STZ administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to NF-H and MBP. Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pin prick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared to non-diabetic mice. To test whether two neurotrophins NGF and/or NT-3 known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for two weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared to diabetic mice treated with insulin for two weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared to control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophininduced increases in dermal innervation and behavior emphasize the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. KeywordsNeuropathy; diabetes; dermis; innervation; myelinated axon NGF; NT-3 *Correspondence: Douglas Wright, Ph.D., Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, Phone:913-588-2713, Fax: 913-588-2710, email: dwright@kumc.edu. Section Editor: Donna HammondPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 1984). The predominant type of diabetic neuropathy is a distal, symmetrical, sensorimotor polyneuropathy and preferentially affects sensory function in the distal regions, i...

show abstract

Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin-diabetic rats

Cited by 95 publications

References 39 publications

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

The role of the p75 neurotrophin receptor in the morphology of dorsal root ganglion cells in streptozotocin diabetic mice: effects of sciatic nerve crush

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Contact Info

Product

Resources

About