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PubMed1996

Deprenyl and pergolide rescue spinal motor neurons from axotomy-induced neuronal death in the neonatal rat.

It has been reported that both the monoamine oxidase inhibitor, deprenyl and the dopamine receptor agonist, pergolide have neuroprotective actions. To investigate the effect of deprenyl and pergolide on axotomized motor neuron death, we examined the survival of spinal motor neurons after sciatic nerve transection in the neonatal rats. Newborn rats were anesthetized with hypothermia. Sciatic nerve was cut near the obturator tendon in the left thigh. Animals were then treated daily with deprenyl (10 mg kg(-1)), pergolide (5 mg kg(-1)), or PBS for 14 days with intraperitoneal injections in a blind fashion. After the treatment, the number of spinal motor neurons in the L 4-6 was counted. There was approximately a 50% loss of spinal motor neurons in PBS-treated group. By contrast, both deprenyl and pergolide prevents spinal motor neuron death after axotomy Co-administration of deprenyl and pergolide is more effective than either agent alone but not significant. These findings are consistent with the idea that deprenyl and pergolide are survival factors for developing spinal motor neurons.

Animals↗

PubMed1992

Testosterone fails to rescue motoneurons from axotomy-induced death in young rats.

This study was undertaken to determine whether testosterone acting on muscle alone could enhance motoneuron survival after axotomy. Facial nerves were transected unilaterally in 10-day old rats in which androgen receptors were already present in skeletal muscle but not yet developed in motoneurons. Testosterone treatment lessened chromatolysis but failed to reduce neuronal loss which reached more than 50% 2 weeks postaxotomy. The inefficacy of testosterone was attributed to the death of motoneurons before they could re-establish synaptic contact with targets, thereby rendering target-derived trophic substances stimulated by testosterone unable to rescue motoneurons in a timely manner. The present finding is consistent with our hypothesis that functional neuromuscular connectivity is a prerequisite for testosterone to promote neuronal survival.

Animals↗

PubMed1993

BDNF protection of basal forebrain cholinergic neurons after axotomy: complete protection of p75NGFR-positive cells.

To elucidate the role of brain derived neurotrophic factor (BDNF) in the protection of cholinergic neurons in the basal forebrain, recombinant human BDNF and as a positive control, human recombinant nerve growth factor (NGF), were infused for 20 days into the lateral ventricle of adult rats with fimbrial transections. BDNF and NGF administration protected cholinergic basal forebrain cells from degenerative changes after axotomy, as assessed with immunohistochemical analysis of the two cholinergic marker proteins ChAT and p75NGFR. Both BDNF and NGF treatment completely prevent the lesion induced loss of p75NGFR-positive cells in the septal area of animals with fimbrial transections. This finding contrasts with the result obtained with ChAT immunohistochemistry, where BDNF treatment protects only part of the population of neurons which disappear following the transections. These findings are compatible with the view that there is a cascade of events induced in cholinergic neurons by the transections, so that ChAT expression is lost before p75NGFR expression, and that BDNF reduces degenerative events in the entire population of cholinergic neurons, maintaining some of them as p75NGFR-positive but ChAT-negative cells.

Acetylcholine↗

PubMed1994

Astrocytes as rapid sensors of peripheral axotomy in the facial nucleus of rats.

Facial nerve transection leads to functional and structural reactions in lesioned motor neurones and surrounding glial cells. Data from this study provide evidence that the most rapid reaction described so far consists of an increase in immunoreactivity of connexin-43 (cx-43), the predominant gap junction protein in astrocytes. The ipsilateral facial nucleus is selectively marked as early as 0.75 to 1.5 hours after axotomy, while the unlesioned side as well as the unoperated controls remain faintly stained. Thus, enhanced coupling capacity of astrocytes by gap junctions appears to be a sensitive indicator of modified neuronal-glial interaction in the CNS.

Animals↗

PubMed1994

Leukaemia inhibitory factor rescues motoneurones from axotomy-induced cell death.

The death of spinal motoneurones after axotomy provides a useful model for studying novel factors which prevent motoneurone loss in vivo. Peripheral nerves of newborn rats were unilaterally transected and treated with either a vehicle solution or leukaemia inhibitory factor (LIF). Compared with the vehicle controls, treatment with a gelfoam containing LIF significantly reduced motoneurone loss: from 38% to 22% after 3 days and from 55% to 38% after 7 days. The loss of motoneurones was further reduced by placing the LIF-containing gelfoam inside a silicone chamber: from 39% to 15% after 7 days, which represented a 62% rescue. Thus, LIF is a potential therapeutic agent for preventing the loss of injured or diseased motoneurones.

Animals↗

PubMed2003

Axotomy differentially regulates voltage-gated calcium currents in mice sensory neurones.

Medium sized dorsal root ganglion neurones are involved in tactile sensation and responsible for allodynia following nerve injury. We examined the effects of sciatic nerve injury on the expression of low and high voltage-gated calcium currents in medium sized neurones isolated from lumbar dorsal root ganglia of adult mice. Based on the relative expression of these calcium channel types, three populations of medium sized neurones were identified in controls. Type I, II and III populations were characterised respectively by small, predominant and no low voltage-gated current compared to the high voltage-gated current. Five days after nerve injury, calcium current expression was differentially affected by axotomy in these three subsets of medium neurones. Altogether, these results suggest that calcium channels are heterogeneously distributed among the medium sized neurones. This heterogeneity should provide specificity not only to sensory functions but also to sensory responses following nerve injury.

Animals↗

PubMed1990

On the Role of Galanin, Substance P and Other Neuropeptides in Primary Sensory Neurons of the Rat: Studies on Spinal Reflex Excitability and Peripheral Axotomy.

The interaction of intrathecally (i.t.) applied galanin (GAL) with substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), somatostatin (SOM) and C-fibre conditioning stimulation (CS) with regard to their effects on the spinal nociceptive flexor reflex was studied in decerebrate, spinalized, unanaesthetized rats with intact or sectioned sciatic nerves. SP, CGRP, VIP and SOM applied onto the surface of lumbar spinal cord or a brief CS train (1 Hz, 20 s) to the sural nerve facilitated the flexor reflex for several minutes in animals with intact or sectioned nerves. Pretreatment with GAL, which by itself had a biphasic effect on the flexor reflex in a dose-dependent manner, antagonized the reflex facilitation induced by sural CS before and after sciatic nerve section. SP-induced facilitation of the flexor reflex was antagonized by GAL in rats with intact sciatic nerves, but not after nerve section. In contrast, VIP-induced reflex facilitation was antagonized by GAL only after sectioning of the sciatic nerve. GAL was effective in antagonizing the facilitatory effect of CGRP under both situations, but had no effect on SOM-induced facilitation. A parallel immunohistochemical study revealed that after sciatic nerve section GAL-like immunoreactivity (LI) and VIP-LI are increased in the dorsal root ganglia and that these two peptides coexist in many cells. The present results indicate that GAL antagonizes the excitatory effect of some neuropeptides which exist in the spinal cord. This antagonism could explain the inhibitory effect of GAL on C-fibre CS-induced facilitation of the flexor reflex, which is presumably due to the release of some of these neuropeptides from the terminals of primary afferents. Furthermore, the interaction between GAL and other neuropeptides is altered by sciatic nerve section, paralleling changes in the levels of these neuropeptides in primary afferents and their pattern of coexistence after nerve section. It is proposed that SP and CGRP are important mediators of the spinal flexor reflex in intact rats. However, after axotomy VIP may replace SP in this capacity, paralleling the decrease in SP and marked increase in VIP levels. In general the study provides further support for involvement of peptides in sensory function.

Journal Article↗

PubMed1994

Axotomy-induced changes in Ca2+ homeostasis in rat sympathetic ganglion cells.

Some of the marked biochemical and electrophysiological changes provoked by section of the axon in mature neurons suggest that the intracellular calcium concentration ([Ca2+]i) may be increased. We have measured the [Ca2+]i using the fluorescent indicator Indo-1 microinjected into rat superior cervical ganglion neurons. No differences in resting [Ca2+]i levels were found between control neurons and cells which had been axotomized 7-10 days before. However, the rise in [Ca2+]i evoked by orthodromic or antidromic stimulation and the recovery after the stimulating train were considerably slower in axotomized neurons than in control cells. We also found that the number of calbindin-D28k-immunopositive cells in the ganglion increases after axotomy, which could be related to the observed differences in calcium homeostasis.

Action Potentials↗

PubMed1994

Exposure to kainic acid mimics the effects of axotomy in cerebellar Purkinje cells of the adult rat.

We have investigated the long-term structural changes which affect Purkinje cells exposed to a single dose of kainic acid. Following intraparenchymal injection of the excitotoxin in the cerebellar cortex (1 microliter of a 1 mg/ml solution), Purkinje cells which survived within the lesioned area or close to its edges showed remarkable axonal abnormalities, involving the formation of torpedoes, hypertrophy of recurrent collaterals and atrophy of the corticofugal portion of the axon. In addition, their dendritic trees were often affected by conspicuous regressive alterations. The climbing fibres contacting these Purkinje cells were characterized by thick perisomatic plexuses, whereas their peridendritic branches were atrophic. The dendrites innervated by such atrophic olivary arbours were studded with huge numbers of newly formed spines. These alterations were already present a few days after kainic acid administration and persisted for the total period of observation of 6 months after the lesion. The remarkable similarity between the abnormalities of Purkinje cells exposed to kainic acid and those observed after axotomy indicates that in these two conditions common mechanisms determine analogous long-lasting modifications in the affected neurons. It is proposed that kainic acid-induced intracellular calcium overload disrupts cytoskeletal components and impairs axonal transport, thus depriving the affected Purkinje cells of retrograde trophic influences from their target neurons. As a consequence the affected neurons undergo long-lasting regressive modifications and compensatory remodelling phenomena.

Animals↗

PubMed1995

Expression of NMDA receptor mRNAs in rat motoneurons is down-regulated after axotomy.

The cytotoxic effects of glutamate via the N-methyl-D-aspartate (NMDA) receptor have been suggested to take part in the events leading to death of motoneurons after neonatal axotomy. By the use of in situ hybridization and immunohistochemistry we have investigated motoneuron mRNA expression of the NMDA receptor subunits NR1, NR2B and NR2D and of the NR1 subunit protein in two lesion models leading to partial motoneuron death: sciatic nerve transection early postnatally in the rat and ventral root avulsion in the adult rat. The results were compared with a lesion model with no subsequent death of motoneurons, i.e. sciatic nerve transection in the adult rat. All lesions were followed by down-regulation of the mRNAs for all studied subunits in severed motoneuron populations; down-regulation was detectable already at early stages postoperatively before any significant death had taken place. The strongest down-regulation was in fact seen in the lesion with the largest loss of motoneurons (ventral root avulsion). The reduction in the expression of NR1 mRNA was paralleled by a decrease in NR1 subunit protein. We conclude that down-regulation of NMDA receptor subunit expression is part of the acute response to axonal injury in motoneurons, whether or not neuronal death follows, and that the susceptibility of lesioned motoneurons to excitotoxic effects should be highest early after axonal injury.

Animals↗

PubMed1996

Localization and axotomy-induced regulation of the peptide secretoneurin in the rat superior cervical ganglion.

This study demonstrates the localization and regulation of a novel neuropeptide of 33 amino acids, secretoneurin (SN), in the rat superior cervical ganglion. Gel filtration chromatography of ganglion proteins followed by a specific radioimmunoassay revealed that SN is the predominant cleavage product of secretogranin II, a member of the chromogranin/secretogranin protein family, in adult ganglia. SN was detected within the majority of nerve endings surrounding postganglionic neurons that were identified by the presence of synaptophysin and, in part, colocalized leu-encephalin. Applying immuno-electronmicroscopy, SN was localized to large dense core vesicles of neuronal and small intensely fluorescent (SIF) cells. In situ hybridization revealed the presence of secretogranin II mRNA in postganglionic neurons and, to a lesser extent, in SIF cells. One week after transection of the postganglionic branches SN levels were not significantly altered; however, a decrease of secretogranin II mRNA was observed in postganglionic neurons but not in SIF cells. After decentralization of the ganglion, SN-immunoreactive nerve terminals disappeared and intraganglionic SN levels were reduced by 70%, indicating the preganglionic origin of SN-positive nerve fibres and varicosities. Secretogranin II mRNA was slightly reduced under this condition. Combined axotomy and decentralization further diminished intraganglionic secretogranin II mRNA, although peptide levels increased significantly above control values under these conditions. Double-labelling immunofluorescence with antibodies against the somatodendritic marker microtubule-associated protein 2 (MAP2) revealed that the increase in SN immunoreactivity was due to an accumulation of SN in axonal processes of postganglionic neurons. SN immunoreactivity was also detected in dissociated neonatal superior cervical ganglion cultures and increased significantly upon treatment with nerve growth factor, the survival and differentiation factor of sympathetic neurons during perinatal development. Co-culture with non-neuronal cells or addition of leukaemia inhibitory factor, a cytokine known to stimulate synthesis of various peptides after nerve transection, did not influence SN immunoreactivity. Therefore, since no fixed relationship between SN and any of the known neuropeptides or neurotransmitters expressed in sympathetic neurons was observed, the expression of this novel peptide appears to be independently regulated.

Animals↗

PubMed1989

Decrease of atrial natriuretic peptide content in rat superior cervical sympathetic ganglion after denervation and axotomy.

We found atrial natriuretic peptide (ANP), known as a humoral factor in regulating body fluid volume and blood pressure, in considerable quantities in rat superior cervical sympathetic ganglion (SCG) by radioimmunoassay after separation with reverse-phase HPLC. Although the ANP content of the immature rat 1 week after birth was low, it doubled at 2 weeks and then increased gradually, until it reached the adult level. Denervation caused a rapid decrease in the ANP content to half of the intact SCG level after 3 h, which then fell to 10% of the control value on day 2 after operation. The time course of ANP content reduction after denervation was similar but rather faster than that of activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, an observation suggesting that ANP may partly contribute to cholinergic synaptic transmission. On the other hand, axotomy produced a rather slower decrease in the ANP content than did denervation. Enucleation and sialoadenectomy also caused a considerable reduction of the ANP content. Thus, part of the ANP found in the ganglion is apparently transported from sympathetically innervated extraganglionic organs via retrograde axoplasmic flow.

Aging↗

PubMed1990

Effects of axotomy on distribution and concentration of elements in rat sciatic nerve.

X-ray microprobe analysis was used to determine the effects of axotomy on distribution and concentration (millimoles of element per kilogram dry weight) of Na, P, Cl, K, and Ca in frozen, unfixed sections of rat sciatic nerve. Elemental concentrations were measured in axoplasm, mitochondria, and myelin at 8, 16, and 48 h after transection in small-, medium-, and large-diameter fibers. In addition, elemental composition was determined in extraaxonal space (EAS) and Schwann cell cytoplasm. During the initial 16 h following transection, axoplasm of small fibers exhibited a decrease in dry weight concentrations of K and Cl, whereas Na and P increased compared to control values. Similar changes were observed in mitochondria of small axons, except for an early, large increase in Ca content. In contrast, intraaxonal compartments of larger fibers showed increased dry weight levels of K and P, with no changes in Na or Ca concentrations. Both Schwann cell cytoplasm and EAS at 8 and 16 h after injury had significant increases in Na, K, and Cl dry weight concentrations, whereas no changes, other than an increase in Ca, were observed in myelin. Regardless of fiber size, 48 h after transection, axoplasm and mitochondria displayed marked increases in Na, Cl, and Ca concentrations associated with decreased K. Also at 48 h, both Schwann cell cytoplasm and EAS had increased dry weight concentrations of Na, Cl, and K. The results of this study indicate that, in response to nerve transection, elemental content and distribution are altered according to a specific temporal pattern. This sequence of change, which occurs first in small axons, precedes the onset of Wallerian degeneration in transected nerves.

Animals↗

PubMed1976

Degeneration secretion and noradrenaline disappearance in rat salivary glands following proximal or distal axotomy.

The noradrenaline (NA) content and the degeneration secretion of saliva were studied in rat salivary glands, following proximal or distal sympathetic denervation. Proximal denervation was obtained by removal of the cervical superior ganglion, which left a long stump of adrenergic axons attached to the gland. Distal denervation was achieved by crushing the perihilar tissue, including the adrenergic axons, close to the gland, leaving only short axon stumps connected with the gland. Onset of both NA decrease and degeneration secretion occurred first in the distally denervated glands and about 2 h later on the proximally denervated sides. Except for the delay of 2 h the pattern of NA decrease and saliva secretion was similar after the two denervation procedures. The length of the attached axon stumps was estimated to be about 15-20 mm longer on the proximally denervated side. Therefore, the delay of 2 h caused by this length of axons corresponds to the proximo-distal intra-axonal transport distal to the "axotomy" of some protecting factors at the rate of 8-10 mm/h. Onset of degeneration secretion was observed between 11 and 12 h after proximal denervation when the NA content was decreased by about 10%. The maximum of saliva secretion occurred about 14 1/2 h after denervation when only 45% of the NA remained in the gland. The correlation between the degeneration secretion of saliva and the decrease in NA probably was due to 1) the amount of NA leaking from degenerating nerve terminals, and 2) the inactivation of this escaped NA by the re-uptake mechanism in the membrane of still intact nerve terminals.

Animals↗

PubMed1972

Some quantitative observations upon the responses of neuroglial cells which follow axotomy of adjacent neurones.

1. The dry mass and nucleic acid content of freshly isolated neuroglial cells and of their nucleoli were measured by interference microscopy and ultraviolet absorption microspectrography. The incorporation of tritiated nucleosides and of an amino acid was followed autoradiographically.2. After hypoglossal axotomy in the adult rat hypertrophy of astrocytes of the hypoglossal nucleus occurred in a biphasic manner. The first phase lasted from days 1-10 and was accompanied by a small degree of astrocytic hyperplasia, and the second from days 20-80. Hypertrophy of oligodendrocytes accompanied the second phase of the astrocytic response.3. When severed axons failed to reinnervate denervated muscle, the second phase of the astrocytic response was markedly reduced and the hypertrophy of oligodendrocytes did not occur.4. If the severed axons re-innervated denervated muscle after a controlled delay, the second phase of the astrocytic response and the oligodendroglial hypertrophy was also delayed.5. Injection of botulinum toxin into the tongue caused changes in astrocytes and oligondendrocytes closely resembling those found after axotomy.6. Transient astrocytic hypertrophy occurred in the uninjured right hypoglossal nucleus, and had a different time course to the changes occurring on the injured side.7. The results are discussed in relation to changes in the metabolism and to alterations in the dendritic fields of injured neurones, previously measured in these circumstances.

Animals↗

PubMed1977

Membrane properties and conduction velocity in sensory neurones following central or peripheral axotomy.

1. The properties of dorsal root ganglion cells in the lumbosacral segments were examined with intracellular electrodes about 3 weeks after section of the central (dorsal roots) or peripheral processes in the cat.2. Chronic section of the peripheral nerve in the hind limb resulted in a reduction in conduction velocity of both the central and peripheral processes of sensory neurones.3. Sensory neurones arising from the triceps surae and plantaris muscles were subject to ;disuse' conditions for about 3 weeks by section of the ventral roots combined with severance of the Achilles tendon. Under such conditions, the central and peripheral conduction velocities of these sensory neurones tended to decrease, but the decrease was significantly less than that following peripheral nerve section.4. Chronic section of the dorsal roots produced no significant changes in conduction velocity of the central processes of muscle sensory neurones but caused a significant increase in the peripheral conduction velocity.5. The only electrophysiological property of dorsal root ganglion cells which altered following axotomy was the time-dependent membrane rectification in response to hyperpolarizing current pulses. The rectification characteristics were modified by chronic section of the peripheral nerve but not by chronic section of the dorsal root.6. It is concluded that injuries in nerve fibres per se do not necessarily result in a decrease of their conduction velocity and that a decrease in their conduction velocity is associated with changes in the properties of the cell bodies.7. It is suggested that a decrease in conduction velocity following nerve section may require the participation of changes in the neurone cell body.

Animals↗

PubMed1994

Calcium-dependent chloride current induced by axotomy in rat sympathetic neurons.

1. Seven to ten days after sectioning their axons, rat sympathetic neurons were studied using intracellular recording techniques in an in vitro preparation of the superior cervical ganglion. 2. In 75% of axotomized cells, an after-depolarization (ADP) was observed following spike firing or depolarization with intracellular current pulses. Discontinuous single-electrode voltage-clamp techniques were employed to study the ADP. When the membrane potential was clamped at the resting level just after an action potential, a slow inward current was recorded in cells that showed an ADP. 3. In the presence of TTX and TEA, inward peaks and outward currents were recorded during depolarizing voltage jumps, followed by slowly decaying inward tail currents accompanied by large increases in membrane conductance. The inward peak and tail currents activated between -10 and -20 mV and reached maximum amplitudes around 0 mV. With depolarizing jumps to between +40 and +50 mV, net outward currents were recorded during the depolarizing jumps but inward tail currents were still activated. 4. In the presence of the Ca2+ channel blocker cadmium, or when Ca2+ was substituted by Mg2+, the ADP disappeared. In voltage-clamped cells, cadmium blocked the inward tail currents. The reversal potential for the inward tail current was approximately -15 mV. Substitution of the extracellular NaCl by sucrose or sodium isethionate increased the amplitude of the inward tail current, and displaced its equilibrium potential to more positive values. Changes in extracellular [K+] did not appreciably affect the inward tail current amplitude or equilibrium potential. Niflumic acid, a blocker of chloride channels activated by Ca2+, almost completely blocked the tail current. 5. No ADPs were observed in non-axotomized neurons, and when depolarizing pulses were applied while in voltage clamp no inward tail currents were evoked in these normal cells. 6. It is concluded that axotomy of sympathetic ganglion cells produces the appearance of a Ca(2+)-dependent chloride current responsible for the ADP observed following spike firing.

Animals↗

PubMed1990

Flunarizine protects neurons from death after axotomy or NGF deprivation.

Systemically administered flunarizine enhanced neuronal survival in lumbar sensory ganglia in newborn rats after axotomy. Flunarizine-treated rats lost 71 percent fewer neurons than the untreated control rats at the end of 1 week. In cell culture, flunarizine at 30 to 40 microM also prevented neuronal death in nerve growth factor-dependent embryonic sensory and sympathetic neurons after the abrupt withdrawal of neurotrophic support. The drug may cause this effect by acting at an intracellular site, one distinct from its blockade of voltage-dependent calcium channels.

Animals↗