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PubMed1997

Effect of transforming growth factor beta 1 on spinal motor neurons after axotomy.

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor beta (TGF-beta) family, has potent effects on developing motor neurons. TGF are pluripotent cytokines that exert biological effects on a variety of neurons. TGF beta 1, on the other hand, promotes motor neuron survival in vitro and saves motor neurons from naturally occurring cell death. Here we investigate the neurotrophic effects of TGF beta 1 for axotomized motor neuron death. The sciatic nerve was cut in newborn rats and TGF beta 1 was injected, either by intraperitoneally or by lesion site, for 14 days after transection. Two or six weeks postlesion, the number and the diameter of motor neurons was assessed. TGF beta 1 significantly attenuated axotomy induced motor neuron death by intraperitoneal administration or by lesion site administration at 2 weeks after neonatal axotomy in a similar way. However, no effect was observed at 6 weeks after nerve lesion, despite continuous application of TGF beta 1 daily for 14 days. These results indicate that TGF beta 1 can prevent the death of motor neurons in vivo, but it cannot permanently rescue lesioned motor neurons.

Animals↗
PubMed1995

Effects of axotomy, deafferentation, and reinnervation on sympathetic ganglionic synapses: a comparative study.

The main physiological and morphological features of the synapses in the superior cervical ganglia of mammals and the last two abdominal ganglia of the frog sympathetic chain are summarized. The effects of axotomy on structure and function of ganglionic synapses are then reviewed, as well as various changes in neuronal metabolism in mammals and in the frog, in which the parallel between electrophysiological and morphological data leads to the conclusion that a certain amount of synaptic transmission occurs at "simple contacts." The effects of deafferentation on synaptic transmission and ultrastructure in the mammalian ganglia are reviewed: most synapses disappear, but a number of postsynaptic thickenings remain unchanged. Moreover, intrinsic synapses persist after total deafferentation and their number is strongly increased if axotomy is added to deafferentation. In the frog ganglia, the physiological and morphological evolution of synaptic areas is comparable to that of mammals, but no intrinsic synapses are observed. The reinnervation of deafferented sympathetic ganglia by foreign nerves, motor or sensory, is reported in mammals, with different degrees of efficiency. In the frog, the reinnervation of sympathetic ganglia with somatic motor nerve fibers is obtained in only 20% of the operated animals. The possible reasons for the high specificity of ganglionic connections in the frog are discussed.

Afferent Pathways↗
PubMed1996

Acceleration of membrane recycling by axotomy of cultured aplysia neurons.

The rapid transition of a stationary axon into a motile growth cone requires the recruitment of membrane and its strategic insertion into the neurolemma. The source of membrane to support the initial rapid growth postaxotomy is not known. Using membrane capacitance measurements, we examined quantitative aspects of membrane dynamics following axotomy of cultured Aplysia neurons. Axotomy activates two processes in parallel: membrane retrieval and exocytosis. Unexpectedly, membrane retrieval is the dominant process in the majority of the experiments. Thus, while a growth cone is vigorously extending, the total neuronal surface area decreases. We suggest that the initial rapid extension phase of the newly formed growth cone postaxotomy is supported by a pool of intracellular membrane that is rapidly retrieved from the neurolemma.

Animals↗
PubMed1999

Bax antisense oligonucleotides reduce axotomy-induced retinal ganglion cell death in vivo by reduction of Bax protein expression.

Following transection of the optic nerve (ON), retinal ganglion cells (RGCs) upregulate Bax protein expression and undergo apoptosis. The present study aimed at reducing Bax expression in order to test whether Bax plays a causative role in the induction of secondary RGC apoptosis. Following injection into the vitreous, fluoresceinated oligonucleotides transfected RGCs in vivo at the injection site in the temporal superior retina. Following ON lesion, and repeated injections of a partially phosphorothioated Bax antisense oligonucleotide, but not following injection of control oligonucleotides, expression of Bax protein was locally inhibited, and the number of surviving RGCs was increased in Bax antisense treated rats 8 days after axotomy. Our results indicate that Bax induction is a prerequisite for the execution of RGC apoptosis following ON axotomy. While the Bax antisense strategy offers an exciting perspective to inhibit secondary neuronal degeneration in vivo, both limited transfection efficacy, and the temporal restriction of this effect currently limit the use of this approach with respect to clinical applications for the treatment of neurodegeneration.

Animals↗
PubMed1997

Differential regulation of fast axonally transported proteins during the early response of rat retinal ganglion cells to axotomy.

We have found that the early response of axotomized rat retinal ganglion cells is characterized by the differential regulation of a number of fast axonally transported proteins. The abundance of 23 radiolabeled fast transported proteins was analyzed at 2 and 5 days after axotomy using two-dimensional gel electrophoresis. Corresponding changes in retinal GAP-43 mRNA were measured using northern analysis. Within 2 days of injury, > 40% of the transported proteins analyzed, including GAP-43, showed increased labeling above control levels. Approximately 13% of transported proteins decreased below control levels, whereas the remainder did not change. Five days after axotomy, only GAP-43 and another fast transported protein, C3, continued to sustain measurable increased labeling above control levels; all previously elevated proteins appeared to have been down-regulated by this time, which corresponds to the onset of cell death. These differential changes were accompanied by parallel increases in GAP-43 mRNA. These results suggest that the molecular changes within rat retinal ganglion cells are differentially regulated within two stages subsequent to damage, initial regenerative growth followed by cell death.

Animals↗
PubMed1994

Galanin antisense oligonucleotides reduce galanin levels in dorsal root ganglia and induce autotomy in rats after axotomy.

Antisense (AS) oligonucleotides (ONs) to galanin (GAL) were applied to the proximal end of a transected sciatic nerve, allowing their cellular uptake and transport into injured axons. GAL expression in dorsal root ganglia and self-mutilation behavior (autotomy) were then studied. AS-ONs with phosphorothioate or allyl modifications significantly suppressed the axotomy-induced increase in GAL levels, as demonstrated by immunohistochemistry and exaggerated autotomy behavior, whereas no significant effect on GAL mRNA levels could be demonstrated with in situ hybridization. Allyl-ONs were more effective than phosphorothioate-ONs. An AS-ON with three base mismatches did not induce any of the above effects. These results support the view that the inhibition of axotomy-induced GAL up-regulation is related to autotomy.

Animals↗
PubMed1995

A serine protease inhibitor, protease nexin I, rescues motoneurons from naturally occurring and axotomy-induced cell death.

Protease nexin I (PNI) is a member of the family of serine protease inhibitors (serpins) that have been shown to promote neurite outgrowth in vitro from different neuronal cell types. These include neuroblastoma cells, hippocampal neurons, and sympathetic neurons. Free PNI protein is markedly decreased in various anatomical brain regions, including hippocampus, of patients with Alzheimer disease. Here, we report that PNI rescued spinal motoneurons during the period of naturally occurring (programmed) cell death in the chicken in a dose-dependent fashion. Furthermore, PNI prevented axotomy-induced spinal motoneuron death in the neonatal mouse. The survival effect of PNI on motoneurons during the period of programmed cell death was not associated with increased intramuscular nerve branching. PNI also significantly increased the nuclear size of motoneurons during the period of programmed cell death and prevented axotomy-induced atrophy of surviving motoneurons. These results are consistent with the possible role of PNI as a neurotrophic agent. They also support the idea that serine proteases or, more precisely, the balance of proteases and serpins may be involved in regulating the fate of neuronal cells during development.

Amyloid beta-Protein Precursor↗
PubMed1992

The response of rubrospinal neurons to axotomy at different stages of development in the North American opossum.

Rubral axons can grow around a lesion of their pathway in the thoracic spinal cord of developing opossums and a critical period exists for that plasticity. The critical period probably begins when rubral axons first grow into the thoracic cord, and it extends until approximately postnatal day 30. We previously noted that most rubrospinal neurons die after transection of their axon during the critical period, suggesting that plasticity results primarily from growth of axons not damaged by the lesion (Xu and Martin, J. Comp. Neurol. 279, 368-381, 1989). That observation led us to study the response of rubrospinal neurons to axotomy in more detail and at additional stages of development, using a prelabeling paradigm. We first injected fast blue (FB) into the caudal thoracic or rostral lumbar spinal cord in animals ranging from estimated postnatal day 9 to 50 and, about 4 days later, lesioned the rubrospinal tract several segments rostral to the injection. Approximately 30 days later, the animals were killed so that the red nucleus could be searched for labeled neurons. During the critical period for plasticity, rubrospinal neurons showed signs of degeneration 1 week after their axon was cut. When animals were killed 2-3 weeks after lesioning, there was an obvious decrease in axotomized neurons within the red nucleus, and by 4 weeks, more than 75% of them had degenerated. The marked susceptibility of rubrospinal neurons to axotomy during the critical period for plasticity is consistent with the hypothesis that developmental plasticity of the rubrospinal tract results primarily from growth of axons that were not damaged by the lesion. Our results also suggest that survival of axotomized rubrospinal neurons increases with age.

Aging↗
PubMed1993

Axotomy induces NADPH diaphorase activity in neonatal but not adult motoneurones.

Rat sciatic motoneurones do not normally express NADPH diaphorase activity. However, after cutting the sciatic nerve in the mid-thigh of neonates and applying the retrograde tracer fast blue, such reactivity was found colocalized with fast blue in about one-fifth of sciatic motoneurones 4 days following the lesion. This proportion of sciatic motoneurones expressing NADPH diaphorase activity remained approximately constant for 14 days after axotomy during which time extensive motoneurone death occurred. Many NADPH diaphorase-positive motoneurones appeared shrunken with degenerative changes to the nucleus. In contrast, the same lesion in adult animals failed to induce any reactivity or cause motoneurone death 4-28 days after axotomy. Induction of nitric oxide synthesising capability may play a role in the death of target-deprived immature motoneurones.

Aging↗
PubMed1994

Expression of neuropeptides in the rat mesencephalic trigeminal nucleus after peripheral axotomy.

Certain populations of dorsal root ganglion cells upregulate galanin (GAL) and neuropeptide Y (NPY) after peripheral axotomy. Less is known of the functional properties of the neurones reacting in this way. The primary sensory mesencephalic trigeminal (Me5) neurones are considered to have purely proprioceptive functions. In this study immunohistochemistry and in situ hybridization have been used to investigate the expression of NPY and GAL in Me5 neurones after peripheral axotomy. Both methods revealed a transient upregulation of GAL and NPY in Me5 neurones which was first observed 3 days postoperatively, peaking at 1 and 2 weeks and then being reduced. The results show that proprioceptive neurones may upregulate these peptides as a consequence of injury.

Animals↗
PubMed1996

Acute application of an interleukin-1 beta-converting enzyme-specific inhibitor delays axotomy-induced motoneurone death.

When performed during the postnatal period, lesioning of the facial nerve induces apoptotic death of facial motoneurones. Several lines of evidence indicate that the ICE proteases family, the mammalian homologues of Ced-3, are positive effectors of this process. In order to determine whether these proteases are involved in axotomy-induced cell death in vivo, we applied a peptide inhibitor of ICE, YVAD-CHO, to the lesioned facial nerve of 2-day-old mice. The effect of YVAD-CHO on motoneurone death was tested using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling (TUNEL) method, which labels apoptotic DNA breaks in situ. Our results show that acute application of YVAD-CHO can partially delay motoneurone death since 32% fewer TUNEL-labelled motoneurones were observed in treated mice. These results indicate that ICE or ICE-like proteases may be involved in the cell death processes induced by an axotomy in vivo.

Animals↗
PubMed1998

Persistence of somatic and dendritic growth associated processes and induction of dendritic sprouting in motoneurones after neonatal axotomy in the rat.

The effect of neonatal axotomy on the maturation of motoneurone somadendritic morphology was studied in identified motoneurones innervating the ankle dorsiflexor muscles tibialis anterior (TA) and extensor digitorum longus (EDL) of the rat by intracellular injection of Lucifer Yellow and confocal microscopy. At birth, the entire somatodendritic surface is covered with fine filopodial growth-associated processes. These are eliminated from the soma and proximal dendrites during the first postnatal week as part of a somatofugal process of dendritic maturation. Following neonatal axotomy, the postnatal elimination of growth associated processes was halted and new, axonal-like processes were seen to sprout from the soma and proximal dendrites in some of the axotomized motoneurones. These results indicate that synaptic interaction with the target muscle during the early postnatal period is essential for the maturation of the somatodendritic receptive surface of the motoneurone.

Aging↗
PubMed1979

Axonal underdevelopment from axotomy in kittens.

Permanent axotomy, by hind limb amputation in kittens, is found by morphometric evaluation at 9 months after amputation to result in failure of ventral and dorsal root myelinated fibers (MFs) to attain adult calibers. The positions of the median diameter and of diameter peaks were unequivocally displaced to smaller diameters, but more so for dorsal than for ventral roots. When fiber spectra of amputated roots were compared with those of kittens at the time of amputation, the median diameter, the position of peaks of diameter histograms, and the diameters of largest MFs were clearly at larger diameters, an indication that axonal development had continued (especially for motor fibers) for some time after amputation. These studies have shown that whereas in adult cats, permanent axotomy results in axonal atrophy, in kittens axonal development continues, but stops short of reaching adult values. As axonal caliber presumably ultimately relates to perikaryal synthesis of protein, one must infer either that the signal to decrease protein synthesis is slow in arriving at the perikarya or that the decreased axonal flow of materials resulting from such a signal is slow and thus allows continued axonal growth for a period after amputation.

Amputation, Surgical↗
PubMed1981

Permanent axotomy by amputation results in loss of motor neurons in man.

Morphometric assessment of the size distribution of cell bodies (cytons) in motor neuron columns from serial sections of lumbar spinal segments reproducibly yields three peaks. Using troughs between peaks as division points, it is possible to determine the number of large (Cl), intermediate (Ci), and small (Cs) cytons per lumbar segment. In a patient with above-knee amputation 4 1/2 years previously, the number of Cl was 42%, Ci 99%, and Cs 129% that of normal. Nine years after total amputation of a lower limb for chondrosarcoma, a second patient exhibited values of 25%, 14%, and 55%, respectively. Normal results were obtained from the non-amputated sides. These results, and our previous studies on the permanent axotomy model, show that loss of target tissue by axotomy leads to atrophy and then loss of motor neurons. Extrapolated to the interpretation of morphologic abnormalities of proximal neuronal alterations in peripheral neuropathy, these results suggest that atrophy and loss of such proximal elements cannot be explained by acute distal pathology, but could be the result of chronic disorders, particularly when severe.

Amputation, Surgical↗
PubMed1989

Ultrastructural alterations of primary afferent axons in the nucleus gracilis after peripheral nerve axotomy.

Alterations of primary afferent axons in the nucleus gracilis were studied at three weeks and four, 12, and 24 months after peripheral nerve axotomy by hindlimb amputation at the hip joint in 19 female cats. The contralateral side and two cats not subjected to amputation were controls. We observed two major types of fiber alterations. One, fibers showed changes of axonal atrophy, myelin remodelling, and degeneration. Adaxonal invagination occurred more frequently (p less than 0.005) at three weeks postamputation, in territories known to contain centrally directed axons of primary afferent neurons of the lower limb, than in controls. Perhaps adaxonal sequestration contributed to axonal attenuation. Two, there were filamentous, granular, central core, and other types of axonal swellings found in territories containing central axons of primary afferent neuron terminals of the lower limb. These changes occurred most frequently at 12 and 24 months and were significantly more frequent than in control tissue. These reactive/dystrophic axons therefore were associated with permanent axotomy, but we have not established that they occur in central axons of primary afferent neurons, or whether they are degenerative or abortive regenerative changes.

Animals↗
PubMed1994

Increased production of ubiquitin mRNA in motor neurons after axotomy.

Ubiquitin targets proteins for attack by certain proteolytic enzymes, but the ubiquitinated cytoplasmic inclusions seen in some chronic neurodegenerative diseases may indicate the occurrence of reparative rather than destructive metabolic events. We have examined the production of ubiquitin in motor neurons of the rat's left hypoglossal nucleus after transection of their axons in circumstances that favour or prevent axonal regeneration. One week after axotomy, in situ hybridization with a radiolabelled cRNA probe revealed a twofold increase in the ubiquitin mRNA content of neurons with regenerating axons (nerve crushed) but not significant change when axonal regeneration had been prevented (nerve transected and ligated). After 2 weeks, ubiquitin mRNA was elevated to about 1.5 times the contralateral control level, regardless of the type of nerve injury, and by 4 weeks there were no longer any differences between the left and right sides. Despite the increased transcription, axotomy was not followed by any change in the quantity of ubiquitin-immunoreactive material in the nuclei or perikarya of hypoglossal neurons as measured by video image analysis of immunohistochemically stained sections. We suggest that ubiquitin is synthesized in neuronal cell bodies and transported into their axons, and that ubiquitin-mediated proteolysis is a metabolic process involved in the elongation of regenerating axons.

Animals↗
PubMed1991

The Relationship of Microglial Cells to Dying Neurons During Natural Neuronal Cell Death and Axotomy-induced Degeneration of the Rat Retina.

The interactions between dying neurons and phagocytotic cells within the developing and injured retina remain controversial. The present work explored the role of microglia and investigated whether so-called resident microglial cells are permanently responsible for removing cell debris whenever it is produced. As a first goal, I characterized some quantitative and morphometric features of the small ipsilateral retinocollicular projections and analysed the permanent function of phagocytosing microglia with these projections as a paradigm. To achieve this, I combined the fluorescent dyes Dil and 4Di-10ASP, both of which persist in the labelled ganglion cells after injection into the superior colliculus (SC), and retrograde labelling. After neuronal degradation, the dyes accompany the degradation products, become interiorized and then persist within the phagocytosing microglia. Consequently, early labelling of microglial cells can be assessed by injecting one dye into the SC during the first postnatal day of life, that is, prior to advanced natural neuronal cell death. Labelling of the remaining ipsilaterally projecting neurons with the second dye following intraorbital axotomy in adulthood and during subsequent neuronal death would therefore result in double labelling of some microglial cells, if these were involved in phagocytosis during both the natural and the induced phases of neuronal degradation. The ganglion cells which survived natural neuronal cell death remained fluorescent for 3 months after labelling with either dye on the day of the animal's birth, indicating that both fluorescent probes persisted within neurons. Quantitatively, 1770+/-220 ganglion cells/mm2 were labelled within the contralateral retina and a total population of 1442+/-120 cells/retina were observed within the periphery of the inferior/temporal quadrant of the ipsilateral retina. A smaller, ipsilateral projection of 150+/-24 cells/retina was uniformly scattered throughout the rest of the retinal surface. Transient projections of ganglion cells to either the contralateral or the ipsilateral colliculi and death of labelled ganglion cells during the first postnatal days resulted in labelling of 210+/-36 microglial cells/mm2 within the contralateral retina and a total number of 800+/-120 cells/retina within the inferior/temporal and 200+/-22 cells/retina within the rest of the retina. These labelled microglial cells were observed in adulthood and indicated that after taking away the neuronal cell debris they persisted within the retinal tissue. The small number of prelabelled ganglion cells which formed persistent ipsilateral projections until adulthood were axotomized by transecting the optic nerve, and resulted in additional labelling of microglial cells with the second fluorescent dye as well. Double-labelled microglia were observed within the inferior/temporal quadrant (3500+/-240 cells/retina) and to a lesser extent (340+/-40 cells/retina) scattered over the entire retinal surface. The chronotopological sequence of microglial labelling paralleled that of ganglion cell degeneration. Injection of protease inhibitors into the vitreous body during optic nerve transection retarded retrograde glial cell degeneration, probably by blocking microglial proteases. The results directly proved that the same microglial cells which remove neuronal cell debris in the postnatal retina were reactivated later in life to proteolytically degrade and then phagocytose neurons which had altered because of the axotomy.

Journal Article↗
PubMed1995

Quasi-reversible photo-axotomy used to investigate the role of extensor muscle tension in controlling the kick motor programme of grasshoppers.

The jump and kick of the grasshopper are behaviours which are potentially critical for the survival of the animal, and whose maximal performance depends upon optimizing the rate and level of tension development in the extensor tibiae muscle of the hind legs. In experimental conditions extensor tension control can be reduced to a single motoneuron, the fast extensor tibiae (FETi). The axon of FETi can be cut using dye-mediated laser photoaxotomy without damaging the central or peripheral portions of that neuron or any other neuron innervating the leg. The axotomy can be functionally reversed (i.e. the cut axon repaired) by an electronic axonal bypass which detects FETi spikes on the proximal side of the cut and stimulates the axon on the distal side of the cut. In this way motor spikes can either be allowed to reach the muscle or prevented from doing so (by switching the bypass on or off), and the motor programmes produced with and without extensor tension can be compared. The jump and kick are normally produced by a three-stage motor programme: (i) initial flexion brings the tibia into the fully flexed position; (ii) coactivation of extensor and flexor muscles allows the extensor muscle to develop maximal tension almost isometrically, while the simultaneous contraction of the flexor muscle holds the tibia flexed; (iii) sudden trigger inhibition of the flexor system (motoneurons and muscle) releases the tibia and allows the behaviour to be expressed. The grasshopper can produce fictive kicks with motor programmes which show each of these three major structural features of a normal kick, but without any extensor tension whatsoever. There is no significant difference in the frequency of FETi spikes, the duration of coactivation or the maximum depolarization of the flexor motoneurons between fictive and quasi-normal (i.e. reversed axotomy) kicks. The trigger inhibition of flexor motoneurons is shallower in fictive than in quasi-normal kicks. The significance of this is discussed in relation to the activity of the interneuron M, which is known to mediate trigger inhibition onto FITi motoneurons. There are two main conclusions from this study. First, the CNS does not need feedback from ETi muscle tension in order to produce the three-stage motor programme of the kick (and, by implication, the jump). Second, the CNS does not adjust the frequency or duration of FETi activity in response to unexpected changes in ETi tension. ETi tension appears to be under open-loop control in the kick motor programme.

Animals↗