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PubMed2002

Effects of axotomy on the expression of NADPH-diaphorase in the visual pathway of the tench.

The distribution of NADPH-diaphorase (ND) positive elements was analyzed throughout the visual pathway of the tench in normal conditions and after optic nerve transection. In the control retina, ND-labeled elements were observed in the photoreceptor, inner nuclear, outer nuclear and ganglion cell layers. In the optic nerve of control animals, small and numerous ND-positive glial cells that were identified as presumably astrocyte-like cells were observed. In the optic tracts and optic tectum, a different type of ND-positive glial cell was detected. Axotomy induced severe changes in the ND staining pattern in the visual pathway. A decrease in the number of ND-stained cells was detected in the retina. In the optic nerve of lesioned animals, the number of small cells gradually decreased, whereas the number of large cells did not change. Two new ND-positive cell populations were observed after the lesion: microglial-like cells appeared close to the lesioned area from 24 h to 7 days after transection, and astrocyte-like cells were found throughout the optic nerve from 14 days up to at least 120 days. The total number of ND-stained glial cells increased at 30 and 60 days and returned to control parameters at 120 days. In addition, the number of ND-positive cells increased at the same survival times in the optic tracts and in the retinorecipient strata of the optic tectum with respect to control animals. Thus, degenerative/regenerative processes in the fish visual pathway are accompanied by an increase in the number of ND-positive cells. Synthesis of nitric oxide is elicited in microglial-like cells as a response to axon injury, whereas the expression in astrocyte-like cells seems to be associated with both normal processes under physiological conditions and with the regenerative phase after the lesion.

Animals↗
PubMed2002

Amyloid precursor protein gene disruption attenuates degeneration of substantia nigra compacta neurons following axotomy.

Our past work has shown that the C-terminal fragment of amyloid precursor protein (APP) translocated to the nucleus in neurons destined for delayed excitotoxic degeneration. To test whether nuclear APP fragments also play a role in the progressive loss of dopaminergic (DA) substantia nigra compacta (SNc) neurons, we performed unilateral medial forebrain bundle (MFB) transection on APP wild type (WT) and on mice with disruption of the APP gene (KO). In WT mice immunoreactivity for APP C-terminal, beta-amyloid and Alz90 epitopes appeared in the nuclei of axotomized DA neurons at 3 days post-lesion (dpl), persisted at 7 dpl and was absent in 14 dpl mice. APP N-terminal immunoreactivity was restricted to the cytosol at all time points, precluding the possibility of full length APP in the nucleus. Nuclear localization of APP epitopes was absent in neurons of the contralateral SNc or in neurons of the ipsilateral ventral tegmental area and SN reticulata. The presence of APP C-terminal and Alz90 domains was confirmed by Western blotting performed on the nuclear fraction of the SN ipsilateral to the axotomy. Quantitative morphometric analysis revealed that WT mice demonstrated earlier and more profound loss of tyrosine hydroxylase+SNc neurons than did KO mice. These data showed that a novel nuclear C-terminal fragment appeared coincident with SNc neuron degeneration, and that APP deficiency correlated with significant neuroprotection in vivo.

Amyloid beta-Protein Precursor↗
PubMed2002

Nerve growth factor alters p75 neurotrophin receptor-induced effects in mouse facial motoneurons following axotomy.

The p75 neurotrophin receptor (p75(NTR)) has been implicated as being detrimental for cell survival in facial motoneurons following injury. Although facial motoneurons do not respond to nerve growth factor (NGF) under normal circumstances, this study shows that NGF can interfere with p75(NTR)-mediated cell survival effects on motoneurons following injury. Twenty-five days following injury, the proportion of surviving axotomized neurons in NGF/p75(+/+) mice, which overexpress NGF, was significantly higher compared to wild-type mice, while NGF/p75(-/-) mice, which overexpress NGF but carry two mutated alleles for p75(NTR), had fewer neurons compared to wild-type and p75(-/-) mice, which carry two mutated alleles for p75(NTR), resulting in a lack of functional expression of this receptor. Sympathetic axons sprouted into the axotomized facial nucleus of both NGF/p75(+/+) and NGF/p75(-/-) following injury, due to transgene expression of NGF in reactive astrocytes. Removal of these sympathetic axons enhanced the number of surviving axotomized neurons in NGF/p75(-/-) mice but not in NGF/p75(+/+) mice. Although motoneurons do not express trkA and should therefore be unresponsive to NGF, our results reveal that NGF can influence p75-mediated motoneuron survival following axotomy.

Animals↗
PubMed2003

The role of cytokines and adhesion molecules in axon degeneration after peripheral nerve axotomy: a study in different knockout mice.

The loss of axons and axonal dysfunction has become of outstanding interest with respect to degenerative and inflammatory diseases of the central and peripheral nervous system. In particular in terms of demyelinating diseases such as multiple sclerosis it is important to know the mechanisms which are responsible for the degeneration and destruction of axons. Here we focused on the loss or preservation of axons after induction of Wallerian degeneration in transected mouse sciatic nerves. We examined the distal transected nerve segments of different knockout mice (ICAM-1; TNF-alpha; iNOS; IL-6) 6 days after axotomy. Despite a distinct number of invading macrophages which phagocytosed most of the myelin and axonal debris, we were able to demonstrate, that animals which are deficient for the cell adhesion molecule ICAM-1 and the cytokine TNF-alpha showed a significantly higher number of preserved axons within the degenerating distal nerve stump. Since macrophage invasion is known to be impaired in the absence of ICAM-1, these data indicate an essential role of these cells and their secreted factors, namely TNF-alpha, but not nitric oxide or IL-6 in the destruction of the axonal cytoskeleton in the peripheral nervous system.

Animals↗
PubMed1998

MAP kinase phosphatase 1 is expressed and enhanced by FK506 in surviving mamillary, but not degenerating nigral neurons following axotomy.

The MAP kinase phosphatase 1 (MKP-1), a dual serine-threonine phosphatase, inactivates the MAP kinases ERK and JNK/SAPK which are involved in neuronal survival and neuronal cell death following injury and degenerative stimuli. We have studied by immunocytochemistry whether regulation of MKP-1 is part of the cell-body response following nerve fiber transection. The expression of MKP-1 was investigated in axotomized neurons of the corpus mamillaris (CMm) and substantia nigra pars compacta (SNC) following transection of the mamillo-thalamic tract (MT) and the medial forebrain bundle (MFB), respectively. In contrast to the surviving CMm neurons, the vast majority of SNC neurons undergoes cell death following axotomy. MKP-1 immunoreactivity which is absent in untreated adult rats, appeared in CMm neurons 24 h following MT transection, reached a maximum after 2 days and persisted in a substantial proportion of CMm neurons until 20 days, the end of observation period. In contradistinction, MKP-1 could not be detected in the SNC neurons. MKP-1 immunoreactivity was virtually restricted to the nuclei of neurons. Subcutaneous injection of the immunosuppressant FK506 that protects axotomized SNC neurons against neuronal cell death, enhanced the expression of MKP-1 in CMm, but failed to do so in SNC neurons. The selective expression of MKP-1 in CMm is the first finding on a different regulation of components in the stress kinase signal pathway in surviving vs. degenerating axotomized neurons.

Animals↗
PubMed1998

Effects of GDNF on retinal ganglion cell survival following axotomy.

Recent evidence suggests that approximately 90% of retinal ganglion cells (RGCs) die by the process of apoptosis within 14 days of optic nerve transection. RGCs begin to disappear from the retina between 5 and 7 days postaxotomy when the highest percentage of RGCs show characteristics typical of apoptosis. A single intraocular injection of glial cell-line derived neurotrophic factor (GDNF) given at the time of axotomy resulted in a delay in the initiation of RGC death and increased the densities of surviving RGCs at 7, 10 and 14 days postaxotomy. The mean RGC densities in GDNF treated retinas at 7 (2381 +/- 144), 10 (1561 +/- 117) and 14 (1123 +/- 116) days postaxotomy were significantly higher than that of controls (1835 +/- 82, 835 +/- 272 and 485 +/- 39, respectively). The loss of RGCs was paralleled by increases in TUNEL positive staining in control retinas and a lower percentage of TUNEL positive cells in GDNF treated retinas at 5, 7 and 10 days postaxotomy. These results suggest that GDNF is capable of promoting RGC survival following injury, possibly by interfering with an essential step in apoptosis.

Animals↗
PubMed1997

Inhibition of glutathione synthesis can enhance cycloheximide-induced protection of developing neurons against axotomy.

Developing neurons depend for survival on target-derived trophic substances. These are thought to block the expression of a genetic program of cell death. Nevertheless, it is known that less orderly events such as oxidative stress are involved in neuron death. In vivo, retinal ganglion cell death induced by axotomy can be reduced by antioxidants. In this study, we investigated the effects of inhibiting glutathione synthesis by means of buthionine sulfoximine to characterize the influence of endogenous glutathione-dependent antioxidant systems on ganglion cell death. Moreover, since protein synthesis inhibition by cycloheximide has been shown to enhance glutathione synthesis in vitro, we studied the effects on cell death of intraocular injections of buthionine sulfoximine, cycloheximide and combinations of the two inhibitors. Cycloheximide's protective action did not seem to involve an increase in glutathione synthesis. Surprisingly, buthionine sulfoximine injected before cycloheximide enhanced its protective effects, whereas it inhibited them when injected later. We interpret our results as an interaction between death-promoting effects of glutathione depletion through an elevation of free radical concentrations and cycloheximide-sensitive effects of oxidative stress through the synthesis of both death-inhibiting and death-promoting proteins.

Animals↗
PubMed1997

Increased expression of peripheral benzodiazepine receptors in the facial nucleus following motor neuron axotomy.

Peripheral benzodiazepine receptors (PBRs) are expressed in a variety of tissues but are normally found at low levels in the brain. Following various types of nerve injury, a reactive gliosis results that exhibits a high expression of this receptor. To further characterize the expression of PBRs following neuronal injury, we evaluated PBR expression in the facial nucleus following facial nerve axotomy (FNA). Injury to a peripheral nerve results in a complex series of metabolic and morphological changes around the injured neuron. Transections of the facial nerve results in a rapid activation of both astrocytes and microglia around axotomized motor neurons. FNA resulted in an increase in the staining for both astrocytes (glial fibrillary acidic protein) and activated microglia (OX42). There was also a reduction in synaptic contacts with the motor nucleus as evidenced by reduced staining for the synaptic marker, synaptophysin. In sections labeled with [3H]-PK11195, the subsequent autoradiograms displayed marked increases in the labeling for PBRs. This increase was observed at 5, 7 and 10 days after nerve transection. The increase was primarily in the level of expression (Bmax), with no change in the affinity of the ligand (Kd). The increase in PBR expression after FNA supports the hypothesis that PBRs can be used as a sensitive marker for CNS injury.

Animals↗
PubMed2000

Activation and response to axotomy of microglia in the facial motor nuclei of G93A superoxide dismutase transgenic mice.

Mice over-expressing a human mutation of Cu(2+)/Zn(2+) superoxide dismutase (SOD1) provide a model of amyotrophic lateral sclerosis. Using tomato lectin histochemistry, we analyzed microglia in the facial nuclei of SOD1(G93A) transgenic mice in the late stage of disease. In these animals, microglia was markedly activated, and ensheathed facial motoneurons as observed in wild-type mice 1 week after nerve transection. In the axotomized facial nucleus of transgenic mice at the same time point, microglia activation was enhanced and exhibited phagocytic features. The findings show that in the facial nucleus microglial cells react to motoneuron disease caused by the SOD1 mutation and to axotomy-induced damage of facial motoneurons.

Alanine↗
PubMed1997

Modification of group I field potentials in the intermediate nucleus of the cat spinal cord after chronic axotomy of an extensor nerve.

In walking decerebrate cats the influence of group I afferents from the medial gastrocnemius (MG) and the lateral gastrocnemius/soleus (LGS) muscles on stance phase duration is altered after axotomy of the LGS nerve [Whelan, P.J., Hiebert, G.W. and Pearson, K.G., J. Neurophysiol., 74 (1995) 2782-2787]. We examined whether a site for this plasticity is the connection from group I afferents onto spinal interneurons. Group I field potentials from MG, LGS and plantaris (PL) muscle afferents were recorded in the intermediate nucleus of the L6/L7 segments. Within 5 days following the transection of the LGS nerve in one hind leg, the field potential amplitudes from LGS afferents were decreased, from MG increased and those from PL were unchanged. The changes in the field potentials parallel modifications in the influence of group I afferents from the MG and LGS muscles on stance phase duration during walking.

Animals↗
PubMed2003

Temporal and sequential analysis of microglia in the substantia nigra following medial forebrain bundle axotomy in rat.

Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis after transection of the medial forebrain bundle. We have assessed the temporal and sequential activities of microglia in these events by examining the complement-3 (OX-42), major histocompatibility complex class II antigen presentation (OX-6) and phagocytic activity (ED1), and correlating these indicators with dopaminergic neuronal loss. Microglia in the ipsilateral substantia nigra pars reticulata evinced activation morphology at 12 h postaxotomy. Phagocytic microglia apposed dying dopaminergic neurons in the pars compacta starting at 3 days postlesion; their number increased through 14 days and slowly decreased. Nuclear chromatin condensation and significant loss of tyrosine hydroxylase-positive dopaminergic neurons occurred around 7 days postlesion. In contrast to microglial expression of interleukin-1beta and inducible nitric oxide synthase at the axotomy site, nigral microglia were interleukin-1beta and inducible nitric oxide synthase-negative. Consistently, RNase protection assays showed that interleukin-1beta and inducible nitric oxide synthase transcripts in nigra were equivocal. The present data support the idea that phagocytosis of axotomized neurons by activated microglia is not limited to dead neurons but includes dying neurons probably without cytotoxic effects of inflammatory substances, such as interleukin-1beta or nitric oxide.

Animals↗
PubMed1998

Motoneuron survival and expression of neuropeptides and neurotrophic factor receptors following axotomy in adult and ageing rats.

Three months after facial nerve transection, total numbers of motoneurons in the facial nucleus of six month (adult) Fischer 344 and Wistar rats were reduced to 83% and 75% of contralateral values, respectively (P < 0.05). This procedure in 22-26 month (ageing) Fischer 344 rats and Wistar rats resulted in a reduction of motoneuron numbers to 77% and 60% of the respective contralateral values (P < 0.05). Compared to adults, contralateral facial nuclei of aging Fischer 344 rats contained 10% fewer motoneurons (non-significant), while ageing Wistar rats had 22% fewer (P < 0.05). No significant changes were found in the proportion of surviving motoneurons expressing calcitonin gene-related peptide, galanin, receptor tyrosine kinase-C or the alpha subunit of the ciliary neurotrophic factor receptor. We conclude that ageing reduces facial motoneuron number and increases their vulnerability to axotomy in Wistar rats, but not in Fischer 344 rats. In neither strain, however, does the proportion of surviving motoneurons expressing the above neuropeptides or neurotrophic factor receptors change. This information may be relevant to those hypotheses of age-related neuronal degenerations which assume that decreased neurotrophic support renders ageing neurons more vulnerable to injury.

Aging↗
PubMed1998

Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets.

Adult olivocerebellar axons are capable of vigorous regeneration when provided with growth-permissive environmental conditions. To elucidate the contribution of intrinsic properties to the regenerative capabilities of inferior olivary neurons, we have examined the cellular modifications occurring in these neurons following axotomy and target deprivation in the absence of exogenous growth-promoting influences. Axotomized inferior olivary neurons undergo perikaryal shrinkage, dendritic atrophy and a loss of anti-calbindin immunoreactivity. A conspicuous cell death occurs during the first few weeks after lesion, but about 35% of the affected neurons survive up to 60 days. Coincidentally, a subset of the injured nerve cells become strongly reactive for NADPH diaphorase histochemistry, and this expression is correlated with survival in the medial accessory olive and in the principal olive. In addition, the affected neurons express or maintain the expression of several markers related to regenerative processes, including transcription factors c-Jun, JunD and Krox-24, the growth-associated protein GAP-43 and the developmentally regulated calcitonin gene-related peptide (CGRP). The expression of all these markers is sustained up to two months after lesion, the longest survival time examined. These results show that although adult axotomized inferior olivary neurons undergo severe regressive modifications leading to a conspicuous cell loss, at least a subset of them is resistant to the lesion. In addition, the long-lasting expression of several axon-growth associated markers expressed in these neurons in response to injury reveals that they are endowed with a strong intrinsic regenerative potential.

Animals↗
PubMed1999

Regulation of ciliary neurotrophic factor receptor alpha in sciatic motor neurons following axotomy.

Spinal motor neurons are one of the few classes of neurons capable of regenerating axons following axotomy. Injury-induced expression of neurotrophic factors and corresponding receptors may play an important role in this rare ability. A wide variety of indirect data suggests that ciliary neurotrophic factor receptor alpha may critically contribute to the regeneration of injured spinal motor neurons. We used immunohistochemistry, in situ hybridization and retrograde tracing techniques to study the regulation of ciliary neurotrophic factor receptor alpha in axotomized sciatic motor neurons. Ciliary neurotrophic factor receptor alpha immunoreactivity, detected with two independent antisera, is increased in a subpopulation of caudal sciatic motor neuron soma one, two and six weeks after sciatic nerve transection and reattachment, while no changes are detected at one day and 15 weeks post-lesion. Ciliary neurotrophic factor receptor alpha messenger RNA levels are augmented in the same classes of neurons following an identical lesion, suggesting that increased synthesis contributes, at least in part, to the additional ciliary neurotrophic factor receptor alpha protein. Separating the proximal and distal nerve stumps with a plastic barrier does not noticeably affect the injury-induced change in ciliary neurotrophic factor receptor alpha regulation, thereby indicating that this injury response is not dependent on signals distal to the lesion traveling retrogradely through the nerve or signals generated by axonal growth through the distal nerve. The prolonged increases in ciliary neurotrophic factor receptor alpha protein and messenger RNA found in regenerating sciatic motor neurons contrast with the responses of non-regenerating central neurons, which are reported to display, at most, a short-lived increase in ciliary neurotrophic factor receptor alpha messenger RNA expression following injury. The present data are the first to demonstrate, in vivo, neuronal regulation of ciliary neurotrophic factor receptor alpha protein in response to injury. Moreover, they suggest that the ability of a subpopulation of spinal motor neurons to regulate ciliary neurotrophic factor receptor alpha levels in response to injury may play a role in their survival and axonal regeneration. Consistent with such a role, we also find relatively high, and probably elevated, levels of ciliary neurotrophic factor receptor alpha immunoreactivity in regenerating axons.

Animals↗
PubMed2001

Evaluation of muscle re-innervation employing pre- and post-axotomy injections of fluorescent retrograde tracers.

In experimental studies on peripheral nerve repair, the possibility to objectively compare original and post-operative innervation is of decisive importance for the selection of the proper nerve-reconstruction strategy. Herewith we report serious drawbacks encountered with the standard method of pre- and post-operative intramuscular injections of widely used retrograde neuronal tracers. Labeling of rat facial motoneurons by injection of Fast-Blue (FB; Group 1), Dil (Group 2), or Fluoro-Gold (FG; Group 3) into the whisker pad muscles was followed by transection and suture of the facial nerve. Two months later, the same rats received Dil (Group 1), FG (Group 2), and FB (Group 3) injections with the same parameters as the pre-operative injections. By quantitative evaluation of single- and double-retrogradely labeled perikarya of facial motoneurons, we tried to estimate the accuracy of re-innervation. Observations through a "UV-filter" (for FB-labeled perikarya) and a "rhodamine-filter" (for Dil-labeled perikarya) in Group 1 revealed an unexpected axotomy-triggered leakage of FB which compromised the counts. After pre-operative Dil labeling, nerve suture, and post-operative FG labeling (Group 2), Dil created an extracellular deposit in the whisker pad. Thus, the uptake of pre-operative tracer by sprouts of re-growing axons compromised counts of retrogradely labeled motoneurons. Employing the "UV-filter" in Group 3 (FG-, FB-, FG+FB-labeled perikarya), the emission of FB obscured that of FG and also compromised cell counts. The use of filter sets constructed ad hoc for detection of FG and FB rendered possible an objective comparison.

Amidines↗
PubMedDate not supplied

Role of NGF in axotomy-induced c-Jun expression in medial septal cholinergic neurons.

The extent of neuronal regeneration after axotomy largely depends on the survival capacity of the injured cell. It has been shown for a long time that nerve fiber transection results in retrograde changes in the parent neuronal cell body, and that these changes may eventually lead to neuronal degeneration. At present, little is known about the sequence of events initiated in a nerve cell body by the transection of its axonal process. In this report, we will focus on an interaction of nerve growth factor (NGF) with the transcription factor c-Jun in intact and axotomized septohippocampal projection neurons.

Animals↗
PubMed1998

Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation.

The emergence of a neuronal growth cone from a transected axon is a necessary step in the sequence of events that leads to successful regeneration. Yet, the molecular mechanisms underlying its formation after axotomy are unknown. In this study, we show by real time imaging of the free intracellular Ca2+ concentration, of proteolytic activity, and of growth cone formation that the activation of localized and transient Ca2+-dependent proteolysis is a necessary step in the cascade of events that leads to growth cone formation. Inhibition of this proteolytic activity by calpeptin, a calpain inhibitor, abolishes growth cone formation. We suggest that calpain plays a central role in the reorganization of the axon's cytoskeleton during its transition from a stable differentiated structure into a dynamically extending growth cone.

Animals↗
PubMed1997

Alterations in glial fibrillary acidic protein (GFAP) mRNA levels in the hamster facial motor nucleus: effects of axotomy and testosterone.

Testosterone propionate (TP) administered at the time of facial nerve injury in the hamster accelerates the rate of regeneration. In this study, we tested the hypothesis that the mechanism by which TP augments peripheral nerve regeneration involves regulation of glial fibrillary acidic protein (GFAP) mRNA in the facial motor nucleus. Castrated male hamsters were subjected to right facial nerve transection, with half the animals implanted subcutaneously with Silastic capsules containing exogenous TP and the remainder sham implanted. Postoperative survival times were 0.25, 1, 2, 4, 7, and 14 d. Qualitative/quantitative analyses of both film and emulsion autoradiograms were accomplished. Axotomy, with or without TP, resulted in a dramatic increase in GFAP mRNA levels by 1 d post-operative on the axotomized side, relative to controls. GFAP mRNA levels remained elevated throughout all postoperative times in both the nonhormone- and TP-treated animals. Qualitative examination of the film autoradiograms indicated a generalized decrease in the amount of GFAP mRNA in the control and axotomized nuclei of TP-treated animals when compared to the control and axotomized nuclei, respectively, of nonhormone-treated animals. Statistical comparison of the values obtained for both the film and emulsion autoradiograms confirmed this impression. Thus, while the injury-induced increases in GFAP mRNA expression were not blocked by TP, the overall extent of the increase was significantly tempered by steroid treatment. These data suggest that hormonal modulation of the astrocytic response to peripheral nerve injury may be a contributing factor in the ability of steroids to enhance the regenerative capacities of injured motor neurons.

Animals↗