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PubMed1993

Calcitonin gene-related peptide increases following axotomy of trochlear motoneurons.

Neuropeptides have long been considered to act as neurotransmitters or neuromodulators, but they may also contribute to a variety of regulatory and trophic neuronal functions. In the present study, we determined the effects of axotomy on the levels of the neuropeptide calcitonin gene-related peptide (CGRP) in trochlear motoneurons (TMNs) of adult cats. The number of neurons with detectable CGRP immunoreactivity, and the intensity of their CGRP immunoreactivity, increased dramatically 1 week postaxotomy, gradually returned toward normal levels, but remained significantly higher than normal 12 weeks postaxotomy--a time when axonal regeneration and functional reinnervation of the superior oblique muscle should be complete. Our observation that CGRP levels in TMNs increase after axotomy suggests a role for this peptide in the response of motoneurons to injury and in regeneration. In addition, since many axotomized TMNs die, we suggest that the maintenance of high CGRP levels even after regeneration is complete may reflect an increased load on those TMNs that survive.

Animals↗
PubMed1996

Axotomy-induced apoptotic cell death of neonatal rat facial motoneurons: time course analysis and relation to NADPH-diaphorase activity.

Rapid and massive death of motoneurons occurs following axotomy in neonatal mammals. This likely results from the neurons being deprived of access to target-derived trophic factors, as their death can be prevented by application of a variety of neurotrophic factors to the proximal end of the cut nerve. Since trophic factor-deprived embryonic chick motoneurons undergo apoptosis in vitro, we have investigated whether axotomized neonatal rat facial motoneurons undergo apoptotic cell death in vivo. Following facial nerve transection during the first postnatal day, the dying motoneurons show characteristic morphological changes of apoptosis and undergo DNA fragmentation, as detected by an in situ end labeling technique. An initial sharp burst of DNA fragmentation, between 12 and 24 h postaxotomy, accompanies a steep decline in neuronal numbers, indicating that neuronal cell death rapidly follows endonuclease cleavage of DNA. However, the interval between axotomy and onset of DNA fragmentation varies widely. By 4 days postnatum only 38% of the lesioned motoneurons have survived an initial rapid phase of neuronal loss, whereas 11% survive to 10 days postnatum at least. NADPH-diaphorase/nitric oxide synthase activity has been implicated as having a causal role in the death of lesioned motoneurons. We have found that there is a sustained increase in the intensity of NADPH-diaphorase histochemical staining in axotomized neonatal facial motoneurons, but that this is first detectable well after the onset of DNA fragmentation and cell death. This suggests that nitric oxide, or its metabolites, does not initiate cell death in this model.

Animals↗
PubMed1996

Axotomy affects the retrograde labeling of cervical and lumbar-cord-projecting rubrospinal neurons differently.

The effect of axotomy at cervical and lumbar spinal levels upon the ability of rubrospinal neurons to retrogradely transport tracer was compared. Unilateral rubrospinal tractotomy was performed first at C5 and, after a few days, at C2 vertebral levels. Different retrograde tracers were applied at the lesioned sites right after tractotomy. Tracer applied at C5 labeled both cervical and lumbar-cord-projecting neurons. Tracer applied at C2 also labeled both groups of neurons if performed 2 days after that at C5; however, only cervical-cord-projecting neurons were labeled when it was performed 3 or 5 days after that at C5. In another set of experiments, a T10 tractotomy without tracer application was performed 2 or 5 days prior to the C5/C2, series of tract lesions. When preceded by a T10 lesion 2 days in advance, tracer applied at C5 labeled both cervical and lumbar-cord-projecting neurons. However, a T10 lesion 5 days in advance resulted in the labeling of only cervical-cord-projecting neurons by the tracer applied at C5. In either case, tracer applied at C2 consistently labeled only cervical-cord-projecting neurons, irrespective of the intervals-2, 3, or 5 days-allowed between C5 and C2 lesions. Most neurons labeled from C2 were also double-labeled by the tracer applied at C5. Thus, unlike lumbar-cord-projecting counterparts, cervical-cord-projecting rubrospinal neurons retain the ability to uptake and/or transport retrograde tracer several days following axotomy. This implies that cervical-cord-projecting rubrospinal neurons survive in a different functional state from their lumbar-cord-projecting counterparts following axonal injury.

Animals↗
PubMed1995

PDGF and its receptors following facial nerve axotomy in rats: expression in neurons and surrounding glia.

We investigated the expression of platelet-derived growth factor (PDGF) and its receptors in rat facial nuclei following axotomy by in situ hybridization and immunohistochemistry. Facial nuclei were examined on days 3, 6, 12, 19 and 26 postoperatively (p.o.). Strong immunoreactivity for PDGF was found in facial neurons and surrounding astrocytes on the ipsilateral side of the brainstem already after 3 days p.o. and persisted at a high level until day 26 p.o. in rats with a facial nerve cut injury. After crushing of the facial nerve, a similar increase was seen in PDGF immunoreactivity which, however, decreased after day 19 p.o., when reinnervation had occurred. Reactive gliosis appeared on the operated side and was confirmed by an increase in intensity of GFAP staining. The kinetics of PDGF A-chain mRNA expression corresponded to the PDGF immunoreactivity, whereas the B-chain mRNA was present only in the neurons. The PDGF alpha-receptor immunoreactivity as well as the mRNA were detected in scattered glial cells. The density of the PDGF alpha-receptor mRNA expressing glial cells was higher on the injured side, but the intensity of the expression per cell did not change after axotomy. An increase in PDGF beta-receptor immunoreactivity was seen in the ipsilateral facial nuclei after 3-6 days p.o., however, the increase in the mRNA could not be detected. The staining persisted until day 26 p.o., when transected facial neurons showed heavier staining than those that had been crushed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Quantitative ultrastructural observations on the inhibited recovery of the hypoglossal nucleus from the axotomy response when regeneration of the hypoglossal nerve is prevented.

Electron micrographs of the left hypoglossal nucleus were quantitatively analyzed in adult rats 52 to 98 days after transection of the left hypoglossal nerve and implantation of the proximal stump into the already innervated ipsilateral sternomastoid muscle, a procedure which prevented the transected nerve from regenerating. Many presynaptic boutons with clear spherical synaptic vesicles and symmetrical synapses were lost from the injured perikarya and dendrites. Some perikarya and dendrites (and, rarely, boutons) became electron dense, and astrocyte or microglial sheaths partly surrounded them. Numbers of dendrite profiles in the neuropil decreased. These statistically significant effects persisted throughout the postoperative period, whereas after axotomy with unimpeded nerve regeneration, these features would have returned to normal by 84 days postoperatively. It was therefore suggested that their recovery depended upon successful regeneration and reconnection of the hypoglossal nerve with the tongue. Subsurface cisterns, and profiles containing unusual inclusions, were numerically normal 52 to 98 days postoperatively, so it was suggested that their early response and recovery after simple axotomy might be entirely dependent on nerve disconnection and not on nerve reconnection.

Animals↗
PubMed1987

Changes in neurofilament gene expression occur after axotomy of dorsal root ganglion neurons: an in situ hybridization study.

Neurofilaments (NFs) are predominant elements in large myelinated axons, where they are thought to serve the important function of maintaining axonal caliber. Previous studies have shown that changes in NF synthesis and axonal transport occur after axonal injury in rat dorsal root ganglion (DRG) cells. The resulting reduction in the NF supply to DRG axons is thought to be largely responsible for the observed decrease in axonal diameter in the proximal axonal stump after an injury. In the present study, we test the hypothesis that a change in NF gene expression precedes the changes in synthesis and transport of NF proteins. To address this hypothesis, the levels of mRNA encoding the 68-kilodalton (kd) neurofilament protein (NF68) in adult rat DRG neurons were assessed at different times after peripheral axotomy using in situ hybridization. For these studies we used a 35S-labeled cDNA probe to NF68. The levels of NF68 mRNA in sensory neurons located in ipsilateral fourth and fifth lumbar DRG at 1, 7, and 14 days after sciatic nerve crush were compared to those in normal DRG neurons using quantitative autoradiography. In large DRG neurons (greater than 1000 micron 2), the levels of NF68 mRNA were significantly reduced relative to normal at 1, 7, and 14 days after axotomy. Medium-sized cells (601-1000 micron 2) exhibited a reduction only at 14 days postinjury, and small-sized cells were not significantly affected. These findings indicate that larger DRG neurons which give rise to large myelinated sensory axons exhibit a change in NF gene expression after axonal injury. The observed changes in NF68 mRNA levels temporally precede changes in NF synthesis and transport in injured DRG cells. Thus, a change in NF gene expression may be an important component of an effective regenerative response and a critical step at which axonal caliber is regulated in injured neurons.

Animals↗
PubMed1989

Induction of heat shock protein 70 mRNA in adult hamster facial nuclear groups following axotomy of the facial nerve.

In this study, the effects of axotomy on heat shock protein 70 (hsp70) mRNA levels were analyzed by northern blot hybridization with a mouse-inducible hsp70 cDNA probe. The right facial nerve of adult golden hamsters was axotomized external to the skull, with the left nerve serving as sham-operated and internal control. Postoperative survival times were 0.5, 2, 6, 12, and 24 hr, with three to six animals per time point. Total RNA in the axotomized and control facial nuclear groups, dissected from the brain stem, was isolated by guanidinium-thiocyanate extraction and analyzed by northern hybridization and scanning densitometry. For normalization, the blots were rehybridized with a genomic cDNA probe complementary to the 28 S rRNA. At 0.5 hr postoperative, there was a 68% induction of hsp70 mRNA levels as compared to control. This increase peaked at 2 hr postoperative with a 280% induction and declined subsequently to 160% at 6 hr, 33% at 12 hr, and -56% at 24 hr, relative to control levels. As a positive control, hyperthermia-induced hsp70 expression was established in hamster whole brain using northern blot hybridization and the mouse-inducible hsp70 cDNA probe. There was a 126% increase in hsp70 mRNA levels relative to control at 1.5 hr following hyperthermia. By 6.5 hr after the 1.5-hr hyperthermic period, there was a 40% decrease in hsp70 mRNA levels below control. The results provide the first evidence that peripheral axotomy acts as a cell stressor to induce the expression of hsp70 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Motor axon sprouting in frog sartorius muscles is not altered by contralateral axotomy.

Sartorius muscles of the frog Rana pipiens were used to study the incidence of motor nerve sprouting in normal unoperated muscles, in experimental muscles contralateral to axotomy of the sartorius nerve, and in sham-operated control muscles. Muscles were stained with either a combination of nitroblue tetrazolium nerve terminal stain and cholinesterase stain or with a combination of silver nerve terminal stain and cholinesterase stain. Each endplate that could be clearly seen was classified into one or more of the following categories: normal endplates without sprouts, three types of terminal sprouts, preterminal sprouts, nodal sprouts, sprouts of unknown origin and destination, and doubly innervated gutters. A quantitative study of 318 endplates from nine unoperated muscles, 779 endplates from 45 experimental muscles, and 694 endplates from 41 control muscles showed that all muscles had a high incidence of motor nerve sprouting and other forms of remodelling (20-28% of all endplates). There were, however, no significant differences between experimental, control, and unoperated muscles when results obtained with the same stains were compared. Results obtained with the two different stains were only slightly different. We conclude that sprouting is a very common but highly variable feature of normal frog neuromuscular junctions, and in the sartorius, contralateral axotomy does not alter this ongoing remodelling.

Animals↗
PubMed1994

Co-induction of neuronal interferon-gamma and nitric oxide synthase in rat motor neurons after axotomy: a role in nerve repair or death?

Induction of an interferon-gamma-like molecule, previously isolated from neurons (N-IFN-gamma), and of the neuronal isoform I of the synthetic enzyme of the free radical nitric oxide, nitric oxide synthase I, as well as of NADPH-diaphorase, were examined in axotomized dorsal motor vagal and hypoglossal neurons. Unilateral transection of the vagal and hypoglossal nerves was performed in the same rat and an induction of N-IFN-gamma and nitric oxide synthase I immunostaining as well as NADPH-diaphorase histochemical positivity was observed in the ipsilateral motoneurons after 2-4 days. The immuno- and enzyme-histochemical positivities were much stronger in the dorsal motor vagal neurons than in hypoglossal neurons. Two and 4 weeks after axotomy N-IFN-gamma immunoreactivity and NADPH-diaphorase positivity persisted in the former, but started to decrease in the latter neurons. Previous data have shown that 23 weeks after nerve transection the majority of the dorsal motor vagal neurons are lost, while the majority of the hypoglossal neurons survive. The high and persistent expression of N-IFN-gamma and nitric oxide synthase I after axotomy in the dorsal motor vagal neurons, that are largely destined to die, indicates that the co-induction of these two molecules may be implicated in the pathogenesis of neuronal degeneration.

Amino Acid Oxidoreductases↗
PubMed1992

Characterization of the sprouting response of axon-like processes from retinal ganglion cells after axotomy in adult hamsters: a model using intravitreal implantation of a peripheral nerve.

Peripheral nerves provide a favourable environment for damaged CNS axons to sprout and regenerate. It has also been demonstrated that retinal ganglion cells respond to a peripheral nerve segment grafted to the retina by emitting axon-like processes from the somatodendritic compartment into the graft. The factors influencing the pattern of sprouting of axotomized retinal ganglion cells were explored in this study by implanting a short segment of peripheral nerve, which did not come into contact with the retina, into the vitreous body of an eye whose optic nerve was concurrently crushed. Silver staining was used to assess the morphology of the retinal ganglion cells which underwent sprouting. Some retinal ganglion cells were induced to sprout axon-like processes; these emerged primarily from dendrites and less frequently from the soma or intraretinal axon. Implantation of a nonviable graft (freeze-thawed) elicited only minimal sprouting. These results suggest that diffusible factors secreted by cells in the graft are a possible stimulus to sprouting in axotomized retinal ganglion cells. Examination of the pattern of dendritic sprouting indicates that sprouting was most intense (in terms of number of sprouts per cell) at early times post-axotomy. Moreover, a differential pattern of development of sprouts arising from individual primary dendrites of the same cell was observed; sprouts tend to arise from all primary dendrites initially but as the post-axotomy time increased, retraction of sprouts from some primary dendrites occurred. Concomitant with this retraction, however, there was an increase in the number of sprouts on those primary dendrites which were still in the active phase of sprouting. Selective stabilization of sprouts by extrinsic factors may account for this phenomenon. Changes in the area and outline (irregularity) of the somata of retinal ganglion cells with sprouts from two weeks to two months after optic nerve crush could be correlated temporally with the intensity of sprouting from the dendritic tree, suggesting that during sprouting, intrinsic mechanisms coordinate the responses of different cellular compartments. In contrast to extensive ectopic sprouting of axotomized retinal ganglion cells in the presence of an intravitreal graft, when a long peripheral nerve segment is grafted to the cut optic nerve, there is extensive axonal regeneration into the graft from retinal ganglion cells, most of which did not exhibit ectopic sprouting. Thus, a hierarchy of sprouting sites within a neuron seems to exist, with the damaged axonal tip being the most favoured site, followed by the dendrites, and then the intraretinal axon.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Scanning electron microscopic study of degeneration and regeneration in the olfactory epithelium after axotomy.

The olfactory epithelium of the adult hamster (Mesocricetus auratus) was examined with the scanning electron microscope following olfactory nerve axotomy. Axotomy results in retrograde degeneration of mature olfactory neurons. Maximum degeneration was observed around day 4. During the degeneration period the epithelium consists primarily of supporting and basal cells. Microvillar columnar supporting cells were observed to have fine cellular processes extending from their lateral border to neighbouring cells. Supporting cells extended to the basal lamina where they terminated in foot-like processes of variable shapes (club, splay and hook). Basal cells which gave rise to new replacement olfactory neurons were observed near the basal lamina. They had a rough cellular surface covered with small granules and fine cellular extensions. Bowman's gland duct cells extended unbranched through the epithelium where they formed funnel duct openings covered with microvilli. During early recovery periods (5-30 days) the number of olfactory neurons in the lower epithelium region increased. We observed olfactory neurons with developing axon and dendritic processes. Specialized growth cone structures were seen at the tips. Olfactory neuron growth cones were elongated or club-shaped and had a ruffled membrane surface. Several thin filopodia extended from the growth cone and made contact with adjacent cells. At late recovery periods (35-120 days) there was a marked increase in the number of olfactory neurons within the middle and lower epithelium regions. Numerous dendritic processes extended to the epithelial surface and terminated in knob-like ciliated structures. Olfactory axons passed basally, forming small intra-epithelial bundles that penetrated the basal lamina then fasciculated into larger bundles within the lamina propria. This study provides detailed three-dimensional observations of the olfactory epithelium following neuron injury, and describes neural degenerative changes, replacement of olfactory neurons, development and maturation. In addition, we describe the structure and basal attachment of supporting cells and their glial-like relation with olfactory neurons.

Animals↗
PubMed1987

Expression of growth factor receptors in injured nervous tissue. I. Axotomy leads to a shift in the cellular distribution of specific beta-nerve growth factor binding in the injured and regenerating PNS.

We have studied beta-nerve growth factor (beta-NGF) receptor expression in the injured and regenerating chick PNS using [125I]-iodinated beta-NGF as a radioactive probe to map and quantitate autoradiographically the in situ distribution of specific [125I] beta-NGF binding. Two different mechanisms are involved in the reappearance of specific [125I] beta-NGF binding on the normally unlabelled adult peripheral nerves. The anterograde and retrograde axonal transport of beta-NGF binding sites leads to a rapid but transient accumulation of [125I] beta-NGF binding on both sides of crushed or transected sciatic and brachial nerves. There is a dramatic decrease in the axonal transport of beta-NGF binding sites, starting 1 day after nerve injury (1 DPO) and reaching basal levels of 10-20% of the control values at 3 to 10 DPO. Gradual but complete recovery of this axonal transport was noted in the sciatic neurites allowed to regain contact with their peripheral targets. A very different regulation pattern was observed for the local reappearance of specific [125I] beta-NGF binding on the endoneurial Schwann cells throughout the distal part of the axotomized nerve. It was first observed at 4 DPO, becoming maximal at 6 DPO. Reinnervation of the nerve after crush led to a rapid decrease of this specific [125I] beta-NGF binding, which followed a proximo-distal temporal gradient. These results show that axotomy leads to a drastic decrease in the axonal expression of [125I] beta-NGF binding, while causing its appearance on the Schwann cells of the denervated endoneurium. They suggest that these endoneurial cells may become the primary target for beta-NGF following axotomy and during regeneration.

Animals↗
PubMed1997

Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve.

By in situ hybridization histochemistry, expression of mRNAs for the two species of serine/ threonine protein kinase Akt, Akt1 and Akt2, were examined in the mouse brain during normal development and in the hypoglossal nucleus following axotomy. On the embryonic days, the gene expression for Akt1 and Akt2 was detected at high levels throughout the entire neuroaxis, then decreased gradually to adult levels during postnatal development. In the adult brain, the gene expression for Akt1 and Akt2 was weak in almost all neurons with no difference of expression levels. The expression level of Akt1 mRNA in the affected hypoglossal nucleus increased dramatically after 48 h to 7 d following axotomy of the hypoglossal nerve, whereas no change was seen in the level of Akt2 mRNA. The present findings suggest that Akt may contribute some important roles not only in neurogenesis, but also in regeneration of injured neuron.

Animals↗
PubMed1996

Characterization and molecular reaction scheme of a chloride channel expressed after axotomy in crayfish.

The nerve to the deep extensor abdominal muscle (DEAM) in crayfish species Astacus astacus, containing four excitatory and one inhibitory motor axons, was cut in the third segment on one side of the animal. The distal axon stump was not subject to phagocytosis but was present for months after the axotomy. The two lateral bundles of the DEAM were prepared 4-6 weeks after the axotomy. The gamma-aminobutyric-acid-(GABA-) activated chloride channel of these bundles was characterized by applying pulses of GABA to outside-out patches of the muscle membrane and measuring the responses. Based on the dose/response relationship of the peak current and of the rise time as well as on single-channel kinetics, a detailed molecular scheme for the reaction of the channel with GABA was derived. This scheme contains four binding steps of the agonist to the receptor and two open states. Simulations of the dose/response relationships with this model resulted in a set of rate constants which generate proper fits. In comparison to the channels present in innervated muscles, the channels of denervated muscles have a higher affinity for GABA, a lower single-channel conductance, four versus five binding steps, and non-cooperative binding. The first three of these adaptations of denervated muscles correspond to similar changes in denervated vertebrate muscles.

Abdominal Muscles↗
PubMed1996

Quantitative image analysis of the chromatolysis in rat facial and hypoglossal motoneurons following axotomy with and without reinnervation.

Image analysis was used to quantify the time course of chromatolysis in regenerating and degenerating motoneurons. Following facial-facial, hypoglossal-hypoglossal nerve suture, or resection of facial and hypoglossal nerves with postoperative survival times of 4 h to 112 days, the texture of the Nissl substance of facial and hypoglossal motoneurons was analyzed on both sides of the brainstem in paraffin serial sections with a VIDASplus image analyzer. In this quantitative study of 149 Wistar rats, alterations of the Nissl substance were measured that were statistically significant but not yet visible to the human eye. Chromatolysis started significantly as early as 8 h and was not fully reversed 112 days after any of the types of axotomy. The reaction was more intense and longer lasting following axotomy without reinnervation than with reinnervation. Thus, chromatolysis starts much faster and lasts far longer than was previously known. The quantified chromatolysis is much stronger after permanent target deprivation than during complete regeneration of motoneurons but is reversible in both cases.

Animals↗
PubMed1975

The effect of cortisone treatment and reoperation on reactive changes in the facial nucleus after axotomy.

The material, with few exceptions, consists of PAS-gallocyanin stained paraffin sections from 4- to 6-month-old male rabbits fixed by perfusion first with saline and then with Bouin's solution. (1) In animals treated with cortisone prior to and subsequent to axotomy, the neurons exhibit an accelerated dispersal and delayed reconstitution of Nissl substance (ribosomes). While mitotic activity is depressed at various sites, formation of new microglial cells is evident. Neuronal degeneration with karyorrhexis is occasionally noted in single neurons in the lateral parts of the facial nucleus. An increase in intraneuronal glycogen deposition is manifested by a greater number of glycogen-rich neurons; such neurons are depleted of their glycogen after axotomy. (2) In other animals, reoperation of the facial nerve on the 6th, 22nd, 60th and 120th day, followed by survival of 3 days, results in dispersal of restored Nissl substance and in increased extravascular mitotic activity which is of less intensity than in single-operated animals.

Animals↗
PubMed1976

Effects of axotomy on the trans-synaptic regulation of enzyme activity in adult rat superior cervical ganglia.

The effects of surgical transection of the postganglionic nerve trunk of the superior cervical ganglion on the total protein content and levels of the enzymes tyrosine hydroxylase, DOPA decarboxylase and choline acetyltransferase have been studied in the adult rat. There is a minor decrease in the total activities of these 3 enzymes accompanied by a large increase in the total protein content of the ganglion. The trans-synaptic induction of the enzyme tyrosine hydroxylase by reserpine is not affected by postganglionic axotomy. Increased activity mediated by reserpine caused no change in the total activities of either DOPA decarboxylase or choline acetyltransferase. Previously observed effects of postganglionic axotomy on preventing transmission through the ganglion are compared with these results and the possible mechanisms by which trans-synaptic induction may occur are discussed.

Animals↗
PubMed1983

Sprouting in intact sartorius muscles of the frog following contralateral axotomy.

The intact hind limb sartorius muscle of the frog was examined anatomically for sprouting following axotomy of the sciatic nerve that contains motor axons innervating the contralateral sartorius muscle. The incidence of sprouting in intact muscles of experimental animals increased more than 3-fold over normal. Thus, contralateral axotomy produces sprouting in intact sartorius muscles much the same as it does in cutaneous-pectoris and piriformis muscles of the frog.

Animals↗