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PubMed1991

Strain-specific enhancement of splenic T cell mitogenesis and macrophage phagocytosis following peripheral axotomy.

The inbred mouse strains C57BL/6 and DBA/2 were subjected to the selective depletion of peripheral nervous system norepinephrine (NE) by the administration of the neurotoxin 6-hydroxydopamine (6-OH-DA). Measurement of mitogen-induced lymphocyte proliferation following peripheral axotomy with 6-OH-DA revealed that significant enhancement (up to 200% of control values) of T, but not B, cell proliferative responses occurred in DBA/2, while no effect was observed in C57BL/6. Enhancement (up to 196% of control values) of luminol-enhanced chemiluminescence resulting from the phagocytosis of opsonized zymosan was also observed following 6-OH-DA treatment in DBA/2, but not C57BL/6. This strain-specific enhancement of immune responses occurred even though the administration of 6-OH-DA resulted in a similar depletion of splenic NE content (greater than 97% reduction of control values) in both strains as determined by high-pressure liquid chromatography-electrochemical detection. Blockage of the neurotoxic effects of 6-OH-DA was achieved by the use of the catecholamine uptake blocker desipramine-HCl. Administration of desipramine prior to 6-OH-DA blocked the reduction of splenic NE content and abrogated the enhancement of mitogen-induced T cell proliferation. The enhancement of phagocytosis by 6-OH-DA was not, however, altered by the prior administration of desipramine.

Animals↗
PubMed1991

Expression of immunomolecules on microglial cells following neonatal sciatic nerve axotomy.

We have examined the microglial reaction accompanying motor neuron death following sciatic nerve crush in the newborn rat using lectin staining with the Griffonia simplicifolia B4-isolectin, as well as immunocytochemistry with a panel of monoclonal antibodies directed against brain macrophage antigen (ED2), and various immunologically important surface molecules (immunomolecules), such as major histocompatibility complex (MHC) class II (Ia) antigen (OX-6), CR3 complement receptor (OX-42), CD4 antigen (W3/25), and leukocyte common antigen (OX-1). The lectin histochemical method provided the earliest indication of a microglial response by demonstrating increased microglial density and clustering around dying motoneurons as early as 2 days after lesioning. Most immunomolecules were largely undetectable in the normal and early post-lesion spinal cord; however, at post-lesion day 5 localized expression of Ia antigen was visualized in the area of degenerating motor neurons. Ia expression preceded the appearance of other immunomolecules at day 8. No increase in staining with the ED2 antibody for macrophage antigen could be detected at any post-lesion interval. When compared to the microglial activation that occurs after axotomy in adult animals, our results show a similar onset in microglial activation in neonatal animals; however, the duration of immunomolecule expression is much briefer.

Animals↗
PubMed1994

Messenger plasticity in primary sensory neurons following axotomy and its functional implications.

Following peripheral axotomy, long-lasting changes in the expression of neuropeptides and their receptors in primary sensory neurons are observed. These changes involve the downregulation of the excitatory peptides substance P and calcitonin gene-related peptide and the upregulation of the inhibitory peptides neuropeptide tyrosine and galanin, resulting in a reduction of transmission in the dorsal horn. The changes observed are thought to represent adaptive responses to limit the consequences of peripheral nerve damage to the organism as a whole and to promote survival and recovery of the individual neuron.

Adaptation, Physiological↗
PubMed1993

Expression of mRNAs for neurotrophin receptors in the dorsal root ganglion and spinal cord during development and following peripheral or central axotomy.

Expression of mRNAs for the protein tyrosine kinases trk, trkB and trkC, encoding essential components of high-affinity neurotrophin receptors, was studied in the spinal cord and dorsal root ganglion during normal development and in the adult rat following peripheral and central axon injury. Northern blots revealed multiple trkB transcripts in the embryonic, early postnatal and adult spinal cord with different patterns of expression during development. The levels of 9.0 kb and 4.8 kb trkB transcripts, encoding a full-length trkB receptor, increased progressively during embryonic development with maximal levels around birth, followed by a decline at adulthood. In contrast, the level of 7.5/7.0 kb trkB transcripts, encoding a truncated trkB receptor, reached maximal levels shortly after birth and similar levels remained in the adult animal. In the spinal cord a 4.7kb trkC transcript was detected with maximal levels shortly after birth. In situ hybridization revealed a uniform labeling throughout the spinal cord for both trkB and trkC mRNAs with maximal intensities of labeling shortly after birth. The level of the 2.4 kb trkB transcript in the spinal cord increased 5-fold 8 days after a crush lesion of the sciatic nerve or the dorsal root, while no change was seen in the levels of the other trkB transcripts. No change in the 4.7 kb trkC mRNA was seen following these two injuries, although increased levels of several smaller size trkC transcripts were observed. For both trkB and trkC, similar size transcripts as seen in the spinal cord were also detected in adult rat dorsal root ganglia. Consistent with previous observations of decreased levels of cytoskeletal proteins after peripheral and central axotomy, the level of neurofilment light chain mRNA decreased markedly in the dorsal root ganglia following a crush lesion of the sciatic nerve or of the dorsal root. A small decrease was also seen in the level of preprotachykinin-A mRNA encoding the protein precursor of substance P. In the same animals, the levels of all five trkB transcripts increased 3-fold in the dorsal root ganglia in response to these two injuries. A small increase was also seen in the level of trkC mRNA. The level of brain-derived neurotrophic factor (BDNF) mRNA increased two-fold in the dorsal root ganglia following either of the two lesions, while no change was detected in trk mRNA following these two injuries.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Differential expression of alpha-CGRP and beta-CGRP genes within hypoglossal motoneurons in response to axotomy.

In this study we have analysed, by in situ hybridization, the expression of the genes for both alpha-CGRP and beta-CGRP in hypoglossal motor nuclei following transection of the left hypoglossal nerve. Our results show that the gene for alpha-CGRP displays a peculiar sequence of regulation (a successive up-down-up-recovery sequence) within ipsilateral hypoglossal motoneurons in response to axotomy. It is initially up-regulated, then down-regulated (displaying mRNA levels below basal), and later again up-regulated before recovery. By contrast, the gene for beta-CGRP displays a successive and distinct up-down-recovery sequence of regulation (it does not display a second increase in mRNA production). The first up-regulation of the alpha-CGRP gene occurs just during the early period of perineuronal glial reaction and the second up-regulation just during the period of delayed astrocyte reaction and muscle reinnervation. Because alpha-CGRP is a neuron-derived factor for many types of cells, including astrocytes and skeletal myocytes, our results suggest that the pleiotropic alpha-CGRP may be a motoneuron-derived trophic signal for both glial and skeletal muscle cells in order to maintain the motoneuron itself and, in consequence, might be of therapeutic interest in treating degenerative disease of motoneurons. beta-CGRP might be redundant within the hypoglossal motoneurons.

Animals↗
PubMed1996

Effect of hypothalamic lesion or chemical axotomy on restitution of immunoreactivity in mice after cyclophosphamide administration.

Splenocytes harvested from mice that underwent chemical axotomy (by 6-hydroxydopamine) or that had electric lesions in their anterior hypothalami demonstrated a significant decrease in their proliferative ability after concanavalin-A stimulation in vitro. In axotomized mice pre-treated with cyclophosphamide, faster restitution of the proliferative activity was observed on days 6-8 after the drug's administration. Splenocytes isolated from mice treated with 6-hydroxydopamine did not exhibit any suppressive activity, which is characteristic of the restitution period following administration of cyclophosphamide. These results indicate that the autonomic nervous system exert a direct effect on immunoreactivity and on processes which are responsible for restitution after cyclophosphamide-induced immunodisorders.

Animals↗
PubMed1984

Retrograde effects of axotomy on the intramedullary axon collateral systems and recurrent inhibitory reflexes of cat spinal motoneurones.

The intramedullary axon collateral systems of adult cat spinal alpha-motoneurones were studied with morphological and physiological techniques 12 weeks after peripheral transection of the motor axons. Morphologically, intracellular horseradish peroxidase (HRP) staining showed that the axotomy induced an elimination of whole collateral trees from the proximal parts of the lesioned axons. The axon collateral systems that still remained in the axotomized neurones appeared quite normal. Physiologically, intracellular recordings failed to reveal a corresponding reduction in the amount of recurrent inhibition produced by the axotomized cells. Possible explanations for the discrepancy between the morphological and physiological results are discussed.

Animals↗
PubMed1987

Increase of galanin-like immunoreactivity in rat dorsal root ganglion cells after peripheral axotomy.

The L4 and L5 dorsal root ganglia were studied in untreated rats and rats subjected to unilateral transection of the sciatic nerve, using the indirect immunofluorescence technique and antibodies to the peptide galanin (GAL). In control rats only low numbers of small ganglion cells contained GAL-like immunoreactivity (LI). After axotomy a marked increase in the number and intensity of GAL-immunoreactive ganglion cell bodies was seen on the lesion side. Thus, some primary sensory neurons react to transection of their peripheral branches by expressing increased GAL levels. A similar reaction has been described by other groups for vasoactive intestinal polypeptide.

Animals↗
PubMed1988

Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy.

Transection of the facial nerve leads to a glial response within its central nucleus of origin. Concomitant with a proliferation of satellite microglial cells an astrocytic reaction is also seen. In the present study light and electron microscopic autoradiography were performed in order to clarify whether only microglial cells undergo mitosis following facial nerve axotomy or if astrocytes also divide. Our results provide the first electron microscopical autoradiographic evidence for the labelling of endogenous microglial cells. We suggest that microglial cells are the only proliferating element during this process in the rat facial nucleus.

Animals↗
PubMed1992

Axotomy induces fusimotor-free muscle spindles in neonatal rats.

Crushing the nerve to the medial gastrocnemius (MG) muscle at birth and administering nerve growth factor to rats afterwards results in a reinnervated muscle with supernumerary muscle spindles, some of which must have formed de novo. Structure and innervation of spindles in the reinnervated MG muscles were studied in serial 1 micron transverse sections. Two types of spindle-like encapsulations were observed. The prevalent type consisted of one to three small diameter intrafusal fibers with features of nuclear chain fibers or infrequently a nuclear bag fiber. The second type of encapsulation consisted of the small-diameter fibers located in a compartment which abutted a compartment containing a large diameter extrafusal fiber. All intrafusal fibers in spindles of the experimental muscles were innervated by afferents, but most of them (85%) were devoid of efferent innervation. Thus, immature fusimotor neurons may be more susceptible than spindle afferents to cell death after axotomy at birth.

Animals↗
PubMed1992

Identified septohippocampal neurons survive axotomy: a fine-structural analysis in the rat.

Previous studies have indicated that interruption of the connections between the medial septum and hippocampus by cutting the axons results in degeneration and death of the projecting septal neurons. However, in these studies cell death has been inferred primarily from the loss of immunoreactivity for transmitter-specific enzymes. In the present study, we labeled septohippocampal projection neurons by retrograde tracing and then cut their axons. Subsequent intracellular injection of prelabeled cells revealed the morphology of the soma and dendrites and allowed us to examine the ultrastructure of these neurons. A large number of septohippocampal neurons survived even 10 weeks after axotomy, suggesting that axotomized septohippocampal neurons survive for considerable periods beyond the time at which they stop expressing transmitter-specific immunoreactivity. Survival of axotomized neurons is a prerequisite for pharmacological interference aimed at reactivating transmitter expression, axonal re-growth, and the eventual reintegration into functionally relevant circuitries.

Animals↗
PubMed1994

Sciatic axotomy compromises axonal transport of transganglionic tracer BSI-B4 from the soma to the central terminals of C fibre afferents.

The C afferent specific lectin BSI-B4 was used to examine the effects of sciatic axotomy on axonal transport by the C afferent subpopulation. From about 4 days after sciatic nerve lesion, BSI-B4 injected into the peripheral nerve is transported only as far as the neuronal cell bodies in the dorsal root ganglion. The previous demonstrations of A beta afferent terminal sprouting into lamina II, and the atrophy of lamina II terminals, in response to sciatic lesions may be related to the inability of C afferents to maintain transganglionic transport.

Animals↗
PubMed1984

Effects of electrical and mechanical stimulation on two foci of spontaneous activity which develop in primary afferent neurons after peripheral axotomy.

In 28 Sprague-Dawley rats, unilateral division of the sciatic nerve at the level of the midfemur was performed. Animals were observed for behavioral changes for 1-21 days, and electrophysiological recordings were made from microfilaments dissected from the ipsilateral L5 dorsal rootlets and sciatic nerve from 1 to 14 days postoperatively. Spontaneous discharges of two types were recorded: (1) variable frequency (0-100 Hz) discharges which typically occurred in rhythmic bursts and could be driven by mechanical stimulation of the neuroma; and (2) lower frequency (0.25-14 Hz) irregular activity which persisted after either excision or local anesthesia of the neuroma. The latter activity could also be recorded from the proximal cut end of the sciatic nerve following removal of the neuroma. The first type of activity was felt to be produced from the neuroma while the second originated in the region of the dorsal root ganglion (DRG). Analysis of the conduction velocities of fibers involved in each type of discharge indicated that both involved smaller myelinated filaments. However, the DRG activity involved significantly smaller fibers with conduction velocities in the A delta range. Spontaneous activity was recorded at 3 and 4 days for the neuroma and DRG activity, respectively. Ongoing discharges maximized at 7-10 days and were rare by 14 days. Autotomy of the ipsilateral foot was found to occur over a similar time course. Tetanic electrical stimulation (100 Hz) produced either little change in the baseline firing rate or prolonged afterdischarges in fibers manifesting neuroma activity. In fibers with ongoing activity of DRG origin, stimulation produced a stereotyped, brief low-frequency afterburst and then prolonged inhibition of firing. Mechanical stimulation of the neuroma produced both brief increases in spontaneous discharges and prolonged afterdischarges. In fibers with spontaneous DRG activity, minimal mechanical stimulation of their ganglion of origin produced high-frequency firing. This study demonstrates that peripheral axotomy of DRG neurons produces spontaneous activity distinct from ongoing neuroma activity in a proportion of fibers which are potentially nociceptive (A delta) as well as abnormal mechanosensitivity of the DRG. Furthermore, electrical stimulation of these fibers produces prolonged inhibition of the discharge. This finding may partially explain the prolonged relief of symptoms patients with chronic pain of peripheral origin may experience following peripheral tetanic electrical stimulation.

Animals↗
PubMed1991

Time-dependent differences in the increase in GAP-43 expression in dorsal root ganglion cells after peripheral axotomy.

Peripheral axotomy of primary afferent neurons results in the up-regulation of the growth-associated phosphoprotein GAP-43, by dorsal root ganglion cells. We have studied the temporal sequence of GAP-43 expression in those dorsal root ganglion neurons with unmyelinated axons (the small dark cells) and in those with myelinated axons (the large light cells) after sciatic nerve section in the adult rat. Immunoreactivity for the RT 97 neurofilament epitope, which is detectable only in large light dorsal root ganglion cells, was used to differentiate the two types of dorsal root ganglion cell. Within two days of a sciatic nerve section the number of GAP-43-immunoreactive profiles in the ipsilateral ganglion had increased five-fold and this increase persisted for 80 days post-section. While 50% of the small numbers of GAP-43-positive cells in control ganglia were RT 97 positive, only 8% of the large number of GAP-43-immunoreactive cells four days post-section, were RT 97 positive. By 14 days the number of RT 97-positive/GAP-43-positive cells had increased to 29%. This was paralleled by an increase in GAP-43 immunoreactivity in large diameter profiles at 14 days. The signals that alter GAP-43 expression in unmyelinated (small, RT 97 -ve) and myelinated (large, RT 97 +ve) afferents after peripheral nerve injury appear to operate with different time-courses.

Animals↗
PubMed1994

The effects of intrathecal neuropeptide Y on the spinal nociceptive flexor reflex in rats with intact sciatic nerves and after peripheral axotomy.

We examined the effects of intrathecally administered neuropeptide Y on the spinal nociceptive flexor reflex in decerebrate, spinalized, unanesthetized rats with intact sciatic nerves, or 11-39 days after unilateral transection of the sciatic nerve. In rats with intact sciatic nerve, intrathecal neuropeptide Y at low doses (10 and 100 ng) caused a brief facilitation of the flexor reflex. At a dose of 300 ng, the effect of neuropeptide Y on the flexor reflex was biphasic, i.e. a brief facilitation followed by slight depression. At higher doses (1 and 10 micrograms), the effect of neuropeptide Y was mainly inhibitory, causing substantial and usually prolonged depression of the flexor reflex magnitude. The reflex depression caused by intrathecal neuropeptide Y was not reversed by the opioid antagonist naloxone or the alpha 2 adrenoceptor antagonist atipamezole. Intrathecal neuropeptide Y at doses up to 1 and 10 micrograms had no effect on reflex facilitation caused by conditioning stimulation of C-fibers, intrathecal substance P or neurokinin A. Topical application of neuropeptide Y (1 microgram/microliter) failed to influence the monosynaptic reflex in normal rats. Eleven to 16 days after peripheral axotomy, the initial excitation of the flexor reflex to intrathecal neuropeptide Y was significantly enhanced in axotomized compared with normal rats. However, the depressive effect of neuropeptide Y on the flexor reflex was unchanged. Neuropeptide Y did not influence the monosynaptic reflex in axotomized rats at this period. In experiments performed on rats in which the sciatic nerve had been transected 31-39 days previously, the facilitatory effect of neuropeptide Y on the flexor reflex remained enhanced compared with normal rats. Furthermore, the inhibitory effect of neuropeptide Y also increased as 100 ng intrathecal neuropeptide Y was able to produce reflex depression in a similar fashion as 300 ng neuropeptide Y normally and the reflex depression caused by 1 microgram neuropeptide Y was stronger and longer lasting than in normal rats. Intrathecal neuropeptide Y (100 ng-10 micrograms) in rats with intact sciatic nerves caused a moderate decrease in spinal cord dorsal surface blood flow as measured with a laser Doppler flowmeter. This effect of neuropeptide Y was unchanged in axotomized rats. The present results support previous observations that spinal application of neuropeptide Y in normal rats caused antinociception. As the depressive effect of neuropeptide Y is independent of spinal opioid and alpha 2-adrenergic systems, it may be mediated by its own receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Axonal outgrowth and neuronal apoptosis in cultured adult mouse dorsal root ganglion preparations: effects of neurotrophins, of inhibition of neurotrophin actions and of prior axotomy.

Dorsal root ganglia (L4 and L5) with attached spinal roots and nerve stumps were isolated from young adult mice and cultured in a layer of extracellular matrix material (matrigel). Within one day, a large number of axons grew out from the cut ends of the nerve and the dorsal root. The average outgrowth length was more than doubled by nerve growth factor, which also strongly increased the number of fibres, showing extensive branching. There was also a significant outgrowth stimulation by neurotrophin-3, but no observable effect by brain-derived neurotrophic factor. In preparations isolated and cultured six days after peripheral nerve transection in vivo, there was an increase in both the outgrowth length (about 1.5- to 2-fold) and in the number of axons. Stimulation of axonal outgrowth, which concerned outgrowth from both the peripheral nerve and the dorsal root, could be further enhanced by the addition of nerve growth factor to the culture. K-252a, a selective inhibitor of neurotrophin receptor-associated tyrosine kinase activity, did not affect either the normal outgrowth or the increased outgrowth in pre-axotomized preparations, at a concentration which abolished the stimulating effects by exogenous nerve growth factor and neurotrophin-3. Under the culturing conditions used, spontaneous apoptosis occurred, but none of the neurotrophins tested, nor K-252a, affected the number of apoptotic neuronal cells analysed by nick-labelling DNA breaks at the end of a 48-h culturing period. Altogether, the present data suggest that for most dorsal root ganglia neurons, signalling through the trk receptors does not influence the apoptosis in vitro and is not required for either the spontaneous axonal outgrowth in matrigel or the increased outgrowth which occurs after prior axotomy in vivo.

Animals↗
PubMed1987

Axotomy increases NADPH-diaphorase staining in rat vagal motor neurons.

Left cervical vagotomy increased NADPH-diaphorase (NADPH-d) histochemical staining in neuronal perikarya of the ipsilateral dorsal motor nucleus of the vagus (dmnX) and the rostral part of the nucleus ambiguus (nAmb). This effect appeared by 2 days, was maximal around 10 days, and declined by 30 days after vagotomy. Light and dark stained perikarya occurred in dmn X ipsilateral to the vagotomy which could not be explained on the basis of the biochemical or transmitter content of these neurons. It is unlikely that the increases of NADPH-d activity resulted from changes in cholinergic transmission since vagotomy is known to decrease cholinergic enzyme function. Since vagotomy increased both the glucose metabolic rate and NADPH-d staining of dmnX and nAmb in these experiments, it is more likely that these effects represent regenerative metabolic responses to axotomy.

Animals↗