Administration Of Neurotrophin-3 Research Articles

Histone deacetylase 9 plays a role in sevoflurane-induced neuronal differentiation inhibition by inactivating cAMP-response element binding protein transcription and inhibiting the expression of neurotrophin-3.

Postoperative cognitive decline (POCD) is a common and serious complication following anesthesia and surgery; however, the precise mechanisms of POCD remain unclear. Our previous research showed that sevoflurane impairs adult hippocampal neurogenesis (AHN) and thus cognitive function in the aged brain by affecting neurotrophin-3 (NT-3) expression; however, the signaling mechanism involved remains unexplored. In this study, we found a dramatic decrease in the proportion of differentiated neurons with increasing concentrations of sevoflurane, and the inhibition of neural stem cell differentiation was partially reversed after the administration of exogenous NT-3. Understanding the molecular underpinnings by which sevoflurane affects NT-3 is key to counteracting cognitive dysfunction. Here, we report that sevoflurane administration for 2 days resulted in upregulation of histone deacetylase 9 (HDAC9) expression, which led to transcriptional inactivation of cAMP-response element binding protein (CREB). Due to the colocalization of HDAC9 and CREB within cells, this may be related to the interaction between HDAC9 and CREB. Anyway, this ultimately led to reduced NT-3 expression and inhibition of neural stem cell differentiation. Furthermore, knockdown of HDAC9 rescued the transcriptional activation of CREB after sevoflurane exposure, while reversing the downregulation of NT-3 expression and inhibition of neural stem cell differentiation. In summary, this study identifies a unique mechanism by which sevoflurane can inhibit CREB transcription through HDAC9, and this process reduces NT-3 levels and ultimately inhibits neuronal differentiation. This finding may reveal a new strategy to prevent sevoflurane-induced neuronal dysfunction.

NT-3 Promotes Oligodendrocyte Proliferation and Nerve Function Recovery After Spinal Cord Injury by Inhibiting Autophagy Pathway

BackgroundSpinal cord injury (SCI) is a serious medical problem, leading to lifelong disability and increasing the health burden worldwide. Traditional treatments have limited effects on neuronal function recovery. Previous studies showed that neurotrophin-3 (NT-3) promoted oligodendrocyte survival and improved neuronal functional recovery after SCI. However, the mechanism by which NT-3 promotes oligodendrocyte survival after SCI remains unclear, which limits its application. Materials and methodsA total of 75 female Sprague–Dawley rats were randomly divided into three groups: the NS group, NT-3 group, and NT-3 + rapamycin group. After successful modeling, the spinal cord specimens were taken at the corresponding time points. Western blot was used to detect autophagy-related proteins and Olig1 protein expression and combined with pathology, immunohistochemistry, flow cytometry, and other methods to detect the proliferation of oligodendrocytes after NT-3 application. ResultsNT-3 was found to significantly promote the recovery of motor function by Basso–Beattie–Bresnahan scores analysis in the rat SCI model. Furthermore, intraspinal administration of NT-3 could downregulate the expression of Beclin-1 in oligodendrocytes, indicating that NT-3 could inhibit excessive autophagy of oligodendrocytes after SCI. The effects of NT-3 on oligodendrocyte survival could be blocked by an autophagy activator rapamycin. ConclusionsThis study found that NT-3 could promote the recovery of motor function after SCI in rats. The underlying reason may be that NT-3 inhibits the expression of autophagy proteins in oligodendrocytes and promotes oligodendrocyte proliferation. This study provided evidence for the future clinical application of NT-3 in SCI patients.

Neurotrophin-3 provides neuroprotection via TrkC receptor dependent pErk5 activation in a rat surgical brain injury model

BackgroundSurgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. MethodsSBI was induced in male Sprague Dawley rats by partial right frontal lobe resection. Temporal expression of endogenous NT-3 and TrkC was evaluated at 6, 12, 24 and 72 h after SBI. SBI rats received recombinant NT-3 which was directly applied to the brain surgical injury site using gelfoam. Brain edema and neurological function was evaluated at 24 and 72 h after SBI. Small interfering RNA (siRNA) for TrkC and Rap1 was administered via intracerebroventricular injection 24 h before SBI. BBB permeability assay and western blot was performed at 24 h after SBI. ResultsEndogenous NT-3 was decreased and TrkC expression increased after SBI. Topical administration of recombinant NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. Recombinant NT-3 administration increased the expression of phosphorylated Rap1 and Erk5. The protective effect of NT-3 was reversed with TrkC siRNA but not Rap1 siRNA. ConclusionsTopical application of NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. The protective effect of NT-3 was possibly mediated via TrkC dependent activation of Erk5.

Neurotrophin-3 restores synaptic plasticity in the striatum of a mouse model of Huntington's disease.

Neurotrophin-3 (NT-3) is expressed in the mouse striatum; however, it is not clear the NT-3 role in striatal physiology. The expression levels of mRNAs and immune localization of the NT-3 protein and its receptor TrkC are altered in the striatum following damage induced by an in vivo treatment with 3-nitropropionic acid (3-NP), a mitochondrial toxin used to mimic the histopathological hallmarks of Huntington's disease (HD). The aim of this study was to evaluate the role of NT-3 on corticostriatal synaptic transmission and its plasticity in both the control and damaged striatum. Corticostriatal population spikes were electrophysiologically recorded and striatal synaptic plasticity was induced by high-frequency stimulation. Further, the phosphorylation status of Trk receptors was tested under conditions that imitated electrophysiological experiments. NT-3 modulates both synaptic transmission and plasticity in the striatum; nonetheless, synaptic plasticity was modified by the 3-NP treatment, where instead of producing striatal long-term depression (LTD), long-term potentiation (LTP) was obtained. Moreover, the administration of NT-3 in the recording bath restored the plasticity observed under control conditions (LTD) in this model of striatal degeneration. NT-3 modulates corticostriatal transmission through TrkB stimulation and restores striatal LTD by signaling through its TrkC receptor.

Functional Diversity of Neurotrophin Actions on the Oculomotor System.

Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but with peculiarities depending on each neurotrophin. For instance, the administration of NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor) or NT-3 (neurotrophin-3) protects neonatal extraocular motoneurons from cell death after axotomy, but only NGF and BDNF prevent the downregulation in ChAT (choline acetyltransferase). In the adult, in vivo recordings of axotomized extraocular motoneurons have demonstrated that the delivery of NGF, BDNF or NT-3 recovers different components of the firing discharge activity of these cells, with some particularities in the case of NGF. All neurotrophins have also synaptotrophic activity, although to different degrees. Accordingly, neurotrophins can restore the axotomy-induced alterations acting selectively on different properties of the motoneuron. In this review, we summarize these evidences and discuss them in the context of other motor systems.

Expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 in cocultures of dissociated DRG neurons and skeletal muscle cells in administration of NGF or NT-3

Both neurotrophins (NTs) and target skeletal muscle (SKM) cells are essential for the maintenance of the function of neurons and nerve-muscle communication. However, much less is known about the association of target SKM cells with distinct NTs on the expression of mRNAs for preprotachykinin (PPT), calcitonin-gene related peptide (CGRP), neurofilament 200 (NF-200), and microtubule associated protein 2 (MAP-2) in dorsal root ganglion (DRG) sensory neurons. In the present study, a neuromuscular coculture model of dissociated dorsal root ganglion (DRG) neurons and SKM cells was established. The morphology of DRG neurons and SKM cells in coculture was observed with an inverted phase contrast microscope. The effects of nerve growth factor (NGF) or neurotrophin-3 (NT-3) on the expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 was analyzed by real time-PCR assay. The morphology of DRG neuronal cell bodies and SKM cells in neuromuscular coculture at different conditions was similar. The neurons presented evidence of dense neurite outgrowth in the presence of distinct NTs in neuromuscular cocultures. NGF and NT-3 increased mRNA levels of PPT, CGRP, and NF-200, but not MAP-2, in neuromuscular cocultures. These results offer new clues towards a better understanding of the association of target SKM cells with distinct NTs on the expression of mRNAs for PPT, CGRP, NF-200 and MAP-2, and implicate the association of target SKM cells and NTs with DRG sensory neuronal phenotypes.

A new in vitro injury model of mouse neurons induced by mechanical scratching

The mixed culture of neurons and glial cells has been widely used as a mechanical insult model for the study of neuron injury in vitro. However, a better model is desirable to eliminate the interference of glial cells during the study. Here we report a new model with exclusive cerebellar granule neurons (CGNs), which can be used for the study of in vitro neuron injury without involvement of glial cells. We found that after scratching insult, there was a decrease in both the survival rate and vitality of injured CGNs. Meanwhile, pathological changes were observed by electron microscopy. With this new model, we also tested the effects of neurotrophin-3 (NT-3) on neuroprotection. The result showed that the vitality of injured CGNs was enhanced by the administration of NT-3. These findings demonstrate that this new model is useful for investigation of the precise effect of mechanical damage on neurons excluding other factors, and to detect the neuroprotective effect of certain factors on mechanically injured neurons.

Effects of neurotrophin 3 on gastric and colonic motility in awake rats

Neurotrophin 3 (NT3) and its receptors are expressed throughout the gastrointestinal tract, especially in the enteric nervous system. However, little is known about the effects of NT3 on gastrointestinal motility. To investigate the effects of NT3 on gastric or colonic motility under baseline conditions, after subdiaphragmatic vagotomy and in a model of postoperative ileus. Sprague-Dawley rats were equipped with strain gauge transducers on the gastric or colonic wall. Motility was recorded for 30 min, followed by i.v. administration of NT3 and motility-recording for another 60 min. Experiments were performed on three consecutive days and separately in a postoperative ileus model. To evaluate a vagal pathway, experiments were also performed on vagotomized rats. NT3 inhibited gastric motility. This inhibitory effect was reduced by subdiaphragmatic vagotomy. Preoperative treatment with NT3 prolonged the postoperative gastric ileus compared to vehicle treatment. Colonic motility in the intact animal was unchanged by NT3, but was increased postoperatively. NT3 treatment inhibited gastric but not colonic motility. This inhibition of gastric motility seems to be partly mediated by the vagus nerve. NT3 aggravates gastric postoperative ileus but attenuates colonic postoperative ileus, which corresponds to the observed positive effects of NT3 on constipated patients.

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are primarily unknown. In this study, we report that embryonic overexpression of neurotrophin-3 (NT3) in muscles disrupts the development of these specific Ia-MN connections, using transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic EPSPs evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.

SPINAL CORD REGENERATION: THE ACTION OF NEUROTROPHIN-3 IN SPINAL CORD INJURY IN RATS

For many years, it was believed that medullary regeneration could not occur, although currently there are many trials using neurotrophic factors, stem cells, fetal medulla grafts, peripheral nerve grafts, and antibodies against myelin-associated proteins that demonstrate the existence of the possibility of spinal cord regeneration. The purpose of this study was to investigate the action of neurotrophin-3, a novel neurotrophic factor. The New York University impactor, a standardized device for delivery of spinal cord injuries was used on 33 rats, which were divided into 2 groups: a control group receiving distilled water intraperitoneally and a treatment group receiving neurotrophin-3 intraperitoneally. Using the Basso, Beattie, and Bresnahan scale, the locomotor recovery curve for the neurotrophin-3 treated group was superior to that of the control group (P < 0.05); the administration of neurotrophin-3 was associated with the absence of deaths, while the control group showed a 28.5% (P = 0.026) mortality rate. Other parameters (hematuria rate and histological analysis) showed no significant differences. Based on these results, it appears that a strong relationship exists between the use of neurotrophin-3 in rats with spinal cord injury and better functional recovery.

Combined delivery of neurotrophin-3 and NMDA receptors 2D subunit strengthens synaptic transmission in contused and staggered double hemisected spinal cord of neonatal rat

We investigated whether administration of neurotrophin-3 (NT-3) and NMDA-2D-expressing units, found previously to enhance transmission in neonatal rat spinal cord, strengthens synaptic connections in the injured neonatal cord. We employed electrophysiological methods to evaluate the strength of synaptic transmission to individual motoneurons in the contusion and staggered double hemisection spinal cord injury (SCI) models. SCI at caudal thoracic levels (T11–T12) was carried out at postnatal day 2 (P2). Plugs containing NT-3- secreting fibroblasts and NR2D-expressing HSV-1 amplicons (HSVnr2d) were implanted above the lesion. Control animals were treated with an amplicon-expressing β-galactosidase (HSVlac). After 8–10 days of treatment, the rats were sacrificed and spinal cords were removed for intracellular recording. Untreated contused cords preserved a fraction of white matter and weak monosynaptic responses were observed through the injury region. However, no synaptic connections were observed in control cords receiving double hemisection injury. Combined treatment with NT-3 and HSVnr2d strengthened monosynaptic connections in contused cords and induced the appearance of weak but functional multisynaptic connections in double hemisected cords. In contrast, treatment with either NT-3 or HSVnr2d alone failed to induce appearance of synaptic responses through the hemisected region. These results suggest that chronic treatment with NT-3 secreting fibroblasts combined with facilitated function of NMDA receptors by HSVnr2d treatment strengthens connections that survive incomplete SCI and therefore that such combined treatment might facilitate recovery of function following SCI.

Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

Injection of acid into the gastrocnemius muscle results in a persistent, mechanical hyperalgesia of the hindpaw (Sluka et al., 2001). Here, the ability of neurotrophins to alter the development of this secondary hyperalgesia was assessed using transgenic mice and exogenous neurotrophin administration. Acid-induced hyperalgesia was measured in wild-type and transgenic mice that overexpress neurotrophin-3 (NT-3) in muscle (myo/NT-3 mice). Mechanical and thermal sensitivity of the hindpaws were assessed after injections of acidic saline, pH 4, into the right medial gastrocnemius. Wild-type mice exhibited mechanical but not thermal hyperalgesia in both paws 1 d after acid injection. In contrast, myo/NT-3 mice developed a transient mechanical hyperalgesia in both paws that disappeared by 2-3 d. The reversal of hyperalgesia in myo/NT-3 mice could be mimicked by intramuscular administration of exogenous NT-3 to acid-injected mice but not by other neurotrophins. The route of NT-3 administration appears critical, because intrathecal or intraperitoneal delivery were ineffective. The hyperalgesia could only be reversed by NT-3 treatment concurrent with acid injection and not after the emergence of hyperalgesia. The acid-induced hyperalgesia did not redevelop after the termination of NT-3 treatment, suggesting that NT-3 permanently reversed the hyperalgesia. Consistent with the behavioral data, paw palpation of acid-injected mice significantly increased Fos expression in the spinal cord of wild-type but not myo/NT-3 or NT-3-injected mice. The attenuation of hyperalgesia suggests that NT-3 may be a modulator of muscle-derived pain, and NT-3 may suppress events that lead to secondary hyperalgesia triggered by insult to muscle afferents.

Effect of IGF-I and neurotrophin-3 on gracile neuroaxonal dystrophy in diabetic and aging rats

Neuroaxonal dystrophy (NAD), a distinctive axonopathy characterized by dramatic swelling of preterminal axons and nerve terminals by the accumulation of a variety of subcellular organelles, develops in the central projections of sensory neurons to medullary gracile nuclei in aged animals and man, and in a number of diseases and experimental conditions. Although its pathogenesis is unknown, proposed mechanisms include abnormalities of axonal regeneration, collateral sprouting and synaptic plasticity which may reflect alteration in neurotrophic support. In the current study, we have demonstrated quantitatively that aging causes the expected marked increase in the frequency of gracile NAD; however, substantial numbers of dystrophic axons develop between 6 and 10 months of age, earlier than expected. Although diabetes has been reported to increase the frequency of NAD in the central processes of sensory neurons in the gracile fasciculus of genetically diabetic BB rats, we have found that 8–10 months of streptozotocin-induced diabetes results in fewer dystrophic axons in the gracile nucleus than in age-matched controls. Administration of neurotrophin-3 (NT-3) and insulin-like growth factor-I (IGF-I), which have been shown to affect synaptic plasticity (implicated in the pathogenesis of NAD), for the last two months before sacrifice did not affect the frequency of gracile NAD in controls or diabetics. The sensory terminals in the gracile nuclei provide a simple, well-characterized experimental system in which questions of pathogenesis and prevention of neuroaxonal dystrophy can be addressed.

NT-3 modulates NPY expression in primary sensory neurons following peripheral nerve injury.

Peripheral nerve transection induces significant changes in neuropeptide expression and content in injured primary sensory neurons, possibly due to loss of target derived neurotrophic support. This study shows that neurotrophin-3 (NT-3) delivery to the injured nerve influences neuropeptide Y (NPY) expression within dorsal root ganglia (DRG) neurons. NT-3 was delivered by grafting impregnated fibronectin (500 ng/ml; NT group) in the axotomised sciatic nerve. Animals grafted with plain fibronectin mats (FN) or nerve grafts (NG) were used as controls. L4 and L5 DRG from operated and contralateral sides were harvested between 5 and 240 d. Using immunohistochemistry and computerised image analysis the percentage, diameter and optical density of neurons expressing calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and NPY were quantified. Sciatic nerve axotomy resulted in significant reduction in expression of CGRP and SP, and significant upregulation of VIP and NPY (P < 0.05 for ipsilateral vs contralateral DRG). By d 30, exogenous NT-3 and nerve graft attenuated the upregulation of NPY (P < 0.05 for NT and NG vs FN). However, NT-3 administration did not influence the expression of CGRP, SP or VIP. The mean cell diameter of NPY immunoreactive neurons was significantly smaller in the NT-3 group (P < 0.05 for NT vs FN and NG) suggesting a differential influence of NT-3 on larger neurons. The optical densities of NPY immunoreactive neurons of equal size were the same in each group at any time point, indicating that the neurons responding to NT-3 downregulate NPY expression to levels not detectable by immunohistochemistry. These results demonstrate that targeted administration of NT-3 regulates the phenotype of a NPY-immunoreactive neuronal subpopulation in the dorsal root ganglia, a further evidence of the trophic role of neurotrophins on primary sensory neurons.

Vocalization-related subregions in the midbrain periaqueductal gray in the guinea pigs

We investigated whether administration of neurotrophin-3 (NT-3) and NMDA-2D-expressing units, found previously to enhance transmission in neonatal rat spinal cord, strengthens synaptic connections in the injured neonatal cord. We employed electrophysiological methods to evaluate the strength of synaptic transmission to individual motoneurons in the contusion and staggered double hemisection spinal cord injury (SCI) models. SCI at caudal thoracic levels (T11–T12) was carried out at postnatal day 2 (P2). Plugs containing NT-3- secreting fibroblasts and NR2D-expressing HSV-1 amplicons (HSVnr2d) were implanted above the lesion. Control animals were treated with an amplicon-expressing β-galactosidase (HSVlac). After 8–10 days of treatment, the rats were sacrificed and spinal cords were removed for intracellular recording. Untreated contused cords preserved a fraction of white matter and weak monosynaptic responses were observed through the injury region. However, no synaptic connections were observed in control cords receiving double hemisection injury. Combined treatment with NT-3 and HSVnr2d strengthened monosynaptic connections in contused cords and induced the appearance of weak but functional multisynaptic connections in double hemisected cords. In contrast, treatment with either NT-3 or HSVnr2d alone failed to induce appearance of synaptic responses through the hemisected region. These results suggest that chronic treatment with NT-3 secreting fibroblasts combined with facilitated function of NMDA receptors by HSVnr2d treatment strengthens connections that survive incomplete SCI and therefore that such combined treatment might facilitate recovery of function following SCI.

Endogenous nerve growth factor and neurotrophin-3 act simultaneously to ensure the survival of postnatal sympathetic neurons in vivo

For many years nerve growth factor was the only factor known to influence embryonic and postnatal development of sympathetic neurons. Its deprivation by antibody neutralization or gene mutation results in extensive neuron death. Recently it has been shown that these neurons also require neurotrophin-3 for survival in the late developmental period. Using neurotrophin-3 antiserum to neutralize endogenous factor in newborn rats, our laboratory has shown that extensive numbers of neurons are lost from both pre- and paravertebral ganglia, indicating a continuing requirement for neurotrophin-3. In the present study we sought to determine whether neurons could survive in vivo in the presence of excess amounts of either nerve growth factor or neurotrophin-3 alone. Consistent with previous findings, administration of antiserum to nerve growth factor or neurotrophin-3 to newborn rats for eight days, resulted in an extensive loss of sympathetic neurons. Interestingly, administration of neurotrophin-3 together with nerve growth factor antiserum or nerve growth factor with neurotrophin-3 antiserum, reversed this neuronal loss. However the latter combination was less effective than the former. Furthermore, the ability of exogenous nerve growth factor to increase both the number and size of sympathetic neurons was prevented by the simultaneous deprivation of endogenous neurotrophin-3. Unlike nerve growth factor, exogenous neurotrophin-3 failed to rescue the naturally occurring neuronal death in these newborn rats. Further evidence for a physiological role for both nerve growth factor and neurotrophin-3 was found by the detection of both trkA and trkC immunoreactivity in neurons of the superior cervical ganglion.Taken together, these results suggest that sympathetic neurons do not have an absolute requirement for either nerve growth factor or neurotrophin-3 and that the endogenous supply of either factor alone is insufficient to support neuronal survival postnatally. However, while each factor may play similar roles in the regulation of postmitotic neuronal function, some evidence for distinct functions has been identified.

Effects of nitric oxide on ambiguous motoneurons

We investigated whether administration of neurotrophin-3 (NT-3) and NMDA-2D-expressing units, found previously to enhance transmission in neonatal rat spinal cord, strengthens synaptic connections in the injured neonatal cord. We employed electrophysiological methods to evaluate the strength of synaptic transmission to individual motoneurons in the contusion and staggered double hemisection spinal cord injury (SCI) models. SCI at caudal thoracic levels (T11–T12) was carried out at postnatal day 2 (P2). Plugs containing NT-3- secreting fibroblasts and NR2D-expressing HSV-1 amplicons (HSVnr2d) were implanted above the lesion. Control animals were treated with an amplicon-expressing β-galactosidase (HSVlac). After 8–10 days of treatment, the rats were sacrificed and spinal cords were removed for intracellular recording. Untreated contused cords preserved a fraction of white matter and weak monosynaptic responses were observed through the injury region. However, no synaptic connections were observed in control cords receiving double hemisection injury. Combined treatment with NT-3 and HSVnr2d strengthened monosynaptic connections in contused cords and induced the appearance of weak but functional multisynaptic connections in double hemisected cords. In contrast, treatment with either NT-3 or HSVnr2d alone failed to induce appearance of synaptic responses through the hemisected region. These results suggest that chronic treatment with NT-3 secreting fibroblasts combined with facilitated function of NMDA receptors by HSVnr2d treatment strengthens connections that survive incomplete SCI and therefore that such combined treatment might facilitate recovery of function following SCI.

Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors.

In rodent models of diabetes, there are expression deficits in nerve growth factor (NGF) and in mRNA for its high-affinity receptor, trkA, leading to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurons, with reduced expression of their neuropeptides, substance P and calcitonin gene-related peptide (CGRP). Treatment of diabetic rats with intensive insulin normalized these deficits, and treatment with exogenous NGF caused dose-related increases, giving levels of NGF and neuropeptides that were greater than those of controls. Neurotrophin-3 (NT-3) mRNA was also deficient in leg muscle from diabetic rats, and administration of recombinant NT-3 to diabetic rats increased the conduction velocity of sensory nerves without affecting motor conduction velocity. In regenerating nerves after experimental crush injury, expression of NGF in the nerve trunk is increased in diabetes to a greater extent than in controls, but this is offset by a greater reduction in the neuronal expression of trkA in dorsal root ganglia of diabetic rats. Nonetheless, targeted administration of exogenous NGF via impregnated conduits stimulated regeneration in both control and diabetic rats. These findings implicate deficient neurotrophic support in diabetic neuropathy and suggest that its correction should be a paramount therapeutic target.

Neurotrophic factors—regulation of neuronal phenotype

In rodent models of diabetes there are expression deficits in nerve growth factor (NGF) in some neuronal target tissues. This leads to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurones, with reduced expression of their neuropeptides, substance P and calcitonin gene-related peptide (CGRP). Treatment of diabetic rats with intensive insulin normalised these deficits and treatment with exogenous NGF caused dose-related increases, giving levels of NGF and neuropeptides which were greater than those of controls. Neurotrophin-3 (NT-3) mRNA was also deficient in leg muscle from diabetic rats and administration of recombinant NT-3 to diabetic rats increased the conduction velocity of sensory nerves without affecting motor nerve conduction velocity. In regenerating nerves after experimental crush injury, expression of NGF in the nerve trunk is increased in diabetes to a greater extent than in controls. There is, however, reduced retrograde axonal transport of NGF in crushed nerves of non-diabetic rats and in both intact and crushed nerves of diabetic rats (relative to intact control nerves). There were no alterations in axonal transport of the high-affinity NGF receptor, trkA, in sciatic nerves associated with either a crush injury or with induction of diabetes. However, the pattern of axonal transport of the low-affinity receptor, p75NTR resembled closely the pattern of retrograde transport of NGF, though cause and effect cannot yet be determined. These changes in neurotrophic support merit further investigation to elucidate the pathogenesis of diabetic neuropathy and to develop novel therapies. © 1997 John Wiley & Sons, Ltd.

Neurotrophins and peripheral neuropathy.

The most common form of peripheral neuropathy is that associated with diabetes mellitus. In rodent models of diabetes there are expression deficits in nerve growth factor (NGF) and in its high-affinity receptor, trkA, leading to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurons, with reduced expression of their neuropeptides, substance P and calcitonin gene-related peptide (CGRP). Treatment of diabetic rats with intensive insulin normalized these deficits and treatment with exogenous NGF caused dose-related increases, giving levels of NGF and neuropeptides which were greater than those of controls. Neurotrophin-3 (NT-3) mRNA was also deficient in leg muscle from diabetic rats and administration of recombinant NT-3 to diabetic rats increased the conduction velocity of sensory nerves without affecting motor conduction velocity. These findings implicate deficient neurotrophic support in diabetic neuropathy and suggest that its correction should be a paramount therapeutic target.