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PubMed2001

Deterioration of axotomy-induced neurodegeneration by group IIA secretory phospholipase A2.

Phospholipase A2 (PLA2) is proposed to play a role in the repair of the ruptured membrane after axotomy. In neonatal rats, we examined the effect of Group IIA secretory PLA2 (sPLA2-IIA) on axotomy-induced cell death of motoneurons. sPLA2-IIA significantly induced death of axotomized motoneurons. Indoxam, a specific inhibitor for sPLA2-IIA, protected motoneurons from the sPLA2-IIA-induced deterioration. The present study indicated that sPLA2-IIA possessed neurotoxic effect rather than neuroprotective effect against facial nerve.

Animals↗
PubMed1997

Increased expression of extracellular signal regulated kinase 1 after axotomy in the dorsal motor nucleus of the vagus nerve and the hypoglossal nucleus.

The extracellular signal regulated kinases (Erks) cascade is a major signalling system by which cells transduce extracellular signals into intracellular responses. To obtain information about the role of Erks in retrograde neuronal reaction, we investigated the changes of Erk 1 and Erk 2 with in situ hybridization and immunohistochemical study in the dorsal motor nucleus of vagus nerve, which shows degenerative changes, and the hypoglossal nucleus, which shows regenerative changes, of adult rats after axotomy. The expression of mRNA and protein of Erk 1 increased between 7 and 28 days after axotomy both in the vagal and hypoglossal nuclei, however, there was no remarkable change in those of Erk 2. The increased expression of Erk 1 is common to both regenerative hypoglossal and degenerative vagal neurons. These findings indicate that Erk 1 is closely related with the retrograde neuronal reaction but whether neurons are destined to survive or die depends on some other factors.

Animals↗
PubMed1998

Death of transcallosal neurons after close axotomy.

The extent of cell death after axotomy may limit potential recovery after brain injury. We wished to determine the effect of axotomizing lesions on survival of transcallosally projecting cortical neurons. Transcallosal neurons were prelabeled by retrograde transport of the fluorescent dyes Fluoro-Gold and True Blue. A transcortical stab wound divided the field of labeled cortical cells into axotomized and unaxotomized groups. Little difference in labeled cell density was seen over the first few days after injury. Animals surviving at least 2 weeks after injury had clear loss of axotomized neurons. By 1 month after injury, the vast majority of axotomized labeled cells appeared to have died. Quantitative evaluation of labeled cells showed that the region of cortex within 1 mm of the axotomizing injury had less than 10% of the expected neuronal density in animals surviving at least 4 weeks after injury. Close axotomy appears to cause dramatic loss of transcallosal neurons even in adult animals.

Animals↗
PubMed1998

Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn-possible involvement of cholecystokinin-B receptors.

An increased expression of cholecystokinin (CCK) messenger RNA (mRNA) as well as CCK-B receptor mRNA in dorsal root ganglion (DRG) cells following peripheral axotomy has previously been demonstrated. In the present in vivo microdialysis study, the effect of unilateral sciatic nerve section on basal and potassium-induced release of CCK-like (CCK-LI) immunoreactivity in the rat dorsal horn was investigated. We also compared the effects of the CCK-B receptor antagonist CI988 on basal and potassium-stimulated CCK-LI release in intact animals and in chronically axotomized rats. Perfusion of the microdialysis probe with KCl (100 mM) induced a more than 6-fold increase of the extracellular level of CCK-LI in control animals. In contrast, following unilateral sciatic nerve section the same KCl stimulation failed to evoke a release of CCK-LI ipsilaterally. However, after systemic administration of CI988 (1 mg kg-1, i.v.), 100 mM KCl induced a significant increase of the extracellular CCK-LI level in axotomized rats, similar to that observed in control animals. In control animals no effect of CI988 on KCl-stimulated CCK-LI release could be detected. CI988 by itself had no influence on the extracellular CCK-LI level in either nerve injured or control animals. The present data suggest that axotomy reduces the release of CCK-like immunoreactivity in the spinal cord by a mechanism involving the CCK-B receptor binding site.

Animals↗
PubMed1998

Expression of c-jun, junB, c-fos, fra-1 and fra-2 mRNA in the rat brain following seizure activity and axotomy.

The present study has investigated the congruence of mRNA induction and protein expression of inducible transcription factors (ITFs). The patterns of c-jun, junB, c-fos, fra-1 and fra-2 mRNAs were studied by radioactive and non-radioactive in situ hybridization in the adult rat brain following kainate-induced seizure activity and axotomy. In the same animals, the expression of c-Jun, JunB and c-Fos proteins was compared with the respective mRNA signals. Using radioactive labeled probes all investigated mRNAs showed an onset within 1 h after systemic kainate application and the maximal levels were generally reached after 3 h. Each mRNA displayed a specific temporo-spatial expression pattern. Whereas fra-1 and fra-2 were restricted to the hippocampus, c-jun, junB and c-fos were additionally induced in the cortex, amygdala and thalamus. The areas with maximal labeling were the dentate gyrus and the hippocampal CA1 and CA3 subfields. The expression patterns between c-jun, junB and c-fos mRNA were virtually congruent with the respective protein. Labeling of the junB and fra-2 probes with digoxigenin yielded similar results. Twenty-four hours, 3 and 10 days following transection of the medial forebrain bundle and the mamillo-thalamic tract, high levels of c-jun mRNA (either digoxigenin or radioactive labeled probes) and protein were seen in the axotomized neurons of the substantia nigra pars compacta and mamillary body whereas the other mRNAs studied and the JunB or c-Fos proteins could not be detected. These findings demonstrate that mRNAs encoding for ITFs are translated into the respective proteins following excitotoxic seizures and axotomy, and that the antisera used for immunocytochemistry yield specific expression patterns of homologous proteins.

Animals↗
PubMed1998

The microglia/macrophage response in the neonatal rat facial nucleus following axotomy.

Microglia represent a population of brain macrophage precursor cells which are intrinsic to the CNS parenchyma. Transection of the facial nerve in the newborn rat causes death of the affected motor neurons which is accompanied by massive activation of local microglia. Many of these cells develop into macrophages as can be shown by immunocytochemistry for OX-42 and ED1. Using the new polyclonal microglial marker ionized calcium binding adapter molecule 1, iba1, in combination with immunocytochemical double-labeling for the proliferating cell nuclear antigen (PCNA), or [3H]thymidine autoradiography, and confocal microscopy, qualitative as well as quantitative differences can be demonstrated between the newborn and the adult axotomized rat facial nucleus. While microglial cells are the only cell population which responds to axotomy by cell division in the adult facial nucleus, GFAP positive reactive astrocytes can be shown to undergo mitosis following axotomy in the newborn rat. Furthermore, ED1 immunoreactivity, early expression of MHC class II molecules and morphological transformation of microglia into macrophages can only be observed under conditions of neuronal degeneration, i.e., in the neonatal rat facial nucleus. Thus, the combination of cellular markers described here should be useful for studies employing the neonatal rat facial nucleus as an in vivo assay system to test the efficacy of neurotrophic factors.

Age Factors↗
PubMed1999

Prevention by insulin-like growth factor-I and riluzole in motor neuron death after neonatal axotomy.

Transection of the sciatic nerve in neonatal rats results discernable loss of motor neurons in the spinal cord. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors, since some of these factors have been shown to be effective in injury induced motor neuron death. Another hypothesis suggests that glutamate and its receptors has been implicated as possible mechanism for motor neuron death, because inhibitor of glutamate release and antagonists of glutamate receptors are effective in preventing axotomized motor neuron death. To investigate the effect of insulin-like growth factor-I (IGF-I) and riluzole, a drug that inhibits glutamate release, on axotomy induced motor neuron death. Newborn rats were anesthetized with hypothermia. Sciatic nerve was cut near the obturator tendon in the left thigh. Animals were then treated daily with different doses of IGF-I and riluzole for 14 days with intraperitoneal injections. Control rats received PBS in the same fashion. After the treatment, the number of surviving motor neurons and the motor neuron diameter in the L(4) was assessed. Both IGF-I (1.0 mg/kg) and riluzole (5.0 mg/kg) rescued motor neuron death in a similar way. Co-administration of IGF-I (1.0 mg/kg) and riluzole (5.0 mg/kg) was more effective than either agent alone and there was a statistically significant difference between co-administration and IGF-I alone. However there was no significant difference between simultaneous treatment and riluzole alone. As for diameter of motor neurons, riluzole (5.0 mg/kg) preserved the motor neuron diameter in the lesion side. Nonetheless, no further increase in motor neuron diameter was seen when riluzole (5 mg/kg) and IGF-I (1.0 mg/kg) were applied in combination. Both agents did not affect diameter of motor neurons in the non-axotomy side. Riluzole is available in amyotrophic lateral sclerosis (ALS) and the positive results of clinical trials with IGF-I suggests that combination treatment of IGF-I and riluzole in ALS remains to be determined.

Animals↗
PubMed1997

N-methyl-D-aspartate receptors in motoneurones after unilateral axotomy in the neonatal rat.

Quantitative autoradiography was used to characterise the binding of the N-methyl-D-aspartate receptor antagonist [3H]dizocilpine maleate in the ventral horns of the lumbar spinal cord of normal, sham-operated, and axotomized neonatal rats. Specific binding sites were revealed on the cell membranes of the motoneurones. In the normal neonate both the Bmax and the Kd values for the binding declined over the first 14 days of life. At 14 days the Kd value was similar to that in adult rats. Unilateral sciatic nerve section was performed in neonates on the day of birth. Axotomy caused the death of approximately 53% of motoneurones. The Bmax and Kd values for [3H]dizocilpine maleate binding declined in the first 2 weeks on operated and contralateral sides in both axotomized and sham-operated animals. However, the specific binding per motoneurone was significantly higher on the sectioned side in axotomized animals at all times examined after the day of birth. The results are consistent with two populations of NMDA receptors with different binding affinities being present in motoneurones at birth, and the lower affinity receptor gradually disappearing over the first few days. The lower affinity receptor may be responsible for the plasticity of motoneurones during embryonic and neonatal life, and for determining which motoneurones die after axotomy.

Animals↗
PubMed1998

Evidence for two populations of N-methyl-D-aspartate receptors in neonatal rat spinal cord. The effect of peripheral nerve axotomy.

Quantitative autoradiography was used to characterise the binding of the N-methyl-D-aspartate (NMDA) receptor antagonist [3H]dizocilpine maleate (MK801) in the white matter and dorsal, intermediate and ventral subregions of the grey matter in the lumbar spinal cord of neonatal rats. The effect on the binding of unilateral sciatic nerve section on the day of birth was examined. In unoperated animals the Bmax and Kd of the binding had decreased in all subregions by two weeks, when the values were similar to those in the adult. After axotomy the Bmax values declined during the first 14 days in all subregions although the density appeared higher in the grey matter in the ventral horn compared to sham operated control. In the axotomised animals, the Kd values for the white matter and ventral horn grey matter had declined by two weeks but in the dorsal and intermediate subregions of the grey matter the values remained elevated. The results are consistent with the presence of two populations of NMDA receptor at birth. In the normal animals the lower affinity receptor disappears in all subregions, but after axotomy it is retained in the dorsal and intermediate subregions for at least 2 weeks.

Animals↗
PubMed2000

Identification of oxidized galectin-1 as an initial repair regulatory factor after axotomy in peripheral nerves.

Various neurotrophic factors that promote axonal regeneration have been investigated in vivo, but the signals that prompt the axons to send out processes in peripheral nerves after axotomy are not well understood. We have shown using two specific strategies that galectin-1 can play an important role in this initial stage. One used an in vitro nerve regeneration model that allowed us to monitor the initial axon and support cell outgrowth from the proximal nerve stump comparable to the initial stages of nerve repair. The other strategy was to clarify the axonal regeneration-promoting factor from kidney-derived cells. Using these strategies, we discovered that oxidized galectin-1 from the cell (COS1 cell) conditioned media acts as an axonal regeneration-promoting factor without the lectin activity. Oxidized recombinant human galectin-1 (rhGAL-1/Ox) showed the same activity at low concentrations (pg/ml range). A similarly low concentration also effectively promoted axonal regeneration in both transection and crush experiments in vivo. Moreover, the application of functional anti-galectin-1 antibody strongly inhibited the regeneration in vivo. Since galectin-1was shown to be secreted and localized in the regenerating sciatic nerve, this suggests that secreted galectin-1 may be oxidized and change its molecular structure to regulate initial repair after axotomy as a kind of cytokine.

Animals↗
PubMed2001

Localization of mRNAs for six ARFs (ADP-ribosylation factors) in the brain of developing and adult rats and changes in the expression in the hypoglossal nucleus after its axotomy.

ADP-ribosylation factors (ARFs) play crucial roles in the intracellular vesicular transport and in regulation of phospholipid-modifying enzyme activities and cytoskeletons. Using in situ hybridization histochemistry, the gene expression for six isoforms of ARF was examined during normal development of rats and in the hypoglossal nucleus following its axotomy. In the embryonic brain, the expression for ARF-1, -4, -5, -6 mRNAs was distinct in the ventricular germinal zone while that for ARF-3, -4, -5 in the mantle zone. In early postnatal brain, the expression for six ARFs was seen widely in various loci of the gray matter with different intensity, and the expression of ARF-4, -5, -6 mRNAs was evident in the cerebellar external granule cell layer. In the adult brain, the gene expression for all ARF isoforms decreased more or less in most gray matters and the distinct expression was maintained mainly in the hippocampal and dentate neuronal layers and cerebellar cortex. The expression levels of ARF-2 and -4 mRNAs in affected hypoglossal nucleus increased after 24 h up to 7 days following axotomy of the hypoglossal nerve, while no such changes were seen in the expression levels for the other ARFs. The present findings suggest that ARFs are differentially involved in some processes essential to nerve regeneration as well as neuronal differentiation and maturation.

ADP-Ribosylation Factor 1↗
PubMed1999

Differential regulation of alpha- and beta-CGRP mRNAs within oculomotor, trochlear, abducens, and trigeminal motoneurons in response to axotomy.

Spinal and cranial motoneurons express alpha- and beta-calcitonin gene-related peptide (CGRP) mRNAs constitutively at variable ratios, and these two mRNAs are differentially regulated following axotomy in spinal, facial, and hypoglossal motoneurons. The purpose of this study was to investigate the change in CGRP mRNA expression following nerve injury in oculomotor, trochlear, abducens, and trigeminal motor nuclei in which beta-CGRP mRNA is predominantly expressed under normal conditions. Using male Sprague-Dawley rats, either the left eyeball and the orbital contents including the bulbar muscles were removed, or the left masseter nerve was ligated and transected. The rats were allowed to survive for 1, 3, 7, 14, 28, 56 days following these procedures. The levels of mRNAs for alpha- and beta-CGRP and growth-associated protein (GAP)-43 were analyzed by in situ hybridization histochemistry using 35S-labeled oligonucleotide probes. Following nerve injury, the expression of alpha-CGRP mRNA rapidly increased on the directly-injured side in all of these nuclei. Thereafter, it gradually decreased and returned to about the control level at postoperative day 56 within oculomotor, trochlear, and abducens motoneurons, but it sustained at a high level within trigeminal motoneurons. The expression of beta-CGRP was quite variable among these nuclei, and significant changes were also seen on the side contralateral to the directly-injured side. These data indicate that the up-regulation of alpha-CGRP mRNA may be a common response of cranial motor neurons following axotomy even if the constitutive expression of beta-CGRP mRNA exceeds that of alpha-CGRP mRNA in these neurons.

Abducens Nerve↗
PubMedDate not supplied

Facial nerve axotomy in aged and young adult rats: analysis of the glial response.

With increasing age, there is a trend towards greater morbidity and injury extent with brain injury. Because several reports have suggested that microglia and astrocytes have an exacerbated response to brain injury in the aged, we set out to explore glial responses to facial nerve axotomy. This model was chosen because the glial responses are well-characterized in young rats and there is no perturbation of the blood-brain barrier (BBB). Immunohistochemistry was performed for glial fibrillary acidic protein (GFAP), leukocyte common antigen, type 3 complement receptor, and major histocompatability complex classes I and II. Quantitative analysis showed that age does not affect the glial response to axotomy in the lesioned facial nucleus; however, an aging-related contralateral effect with enhanced GFAP-labeling was observed. Interestingly, despite a lack of infiltrating neutrophils, a T cell influx was observed in both young and aged rats. Overall, these results suggest that neutrophil extravasion and BBB breakdown are underappreciated with regards to aging and injury exacerbation.

Aging↗
PubMed2002

Differential tyrosine kinase C mRNA distribution in extensor digitorum longus and soleus motoneurons in adult rats: effect of axotomy and neurotrophin-3 treatment.

Delivery of neurotrophin-3 (NT-3) to severed sciatic nerves results in specific normalization of atrophied fast 2b gastrocnemius muscle fibres, and promotes preferential neuromuscular junction maturation of fast extensor digitorum longus (EDL). To investigate the selective influence on fast muscle reinnervation due to NT-3 delivery, we analyzed tyrosine kinase C (trkC) mRNA differential expression in EDL and slow soleus motor pools of unoperated rats and at 1-week post-axotomy. Motoneurons (Mns) were identified using retrograde tracers. TrkC mRNA quantification was estimated by silver grain counting. TrkC mRNA expression was higher in EDL than in soleus Mns in unoperated rats. Axotomy decreased trkC mRNA expression only in EDL Mns, this downregulation being prevented by NT-3. These results suggest that differential expression of trkC receptor is the morphological correlate of the preferential effect of NT-3 upon EDL Mns.

Animals↗
PubMed1997

Expression and regulation of galanin-R2 receptors in rat primary sensory neurons: effect of axotomy and inflammation.

Using in situ hybridization, we studied galanin-R2 receptor (GAL-R2-R) mRNA in rat lumbar 5 dorsal root ganglia (DRGs) at different time points after peripheral tissue inflammation and sciatic nerve transection (axotomy). About 25% of all normal DRG neuron profiles were GAL-R2-R mRNA-positive, and the majority was of the small type. In normal DRGs GAL-R2-R mRNA often (approximately 80%) colocalized with CGRP mRNA and sometimes (approximately 20%) with GAL-R1-R mRNA. There was a strong increase in the number and labeling intensity of GAL-R2-R mRNA-positive neuron profiles after peripheral tissue inflammation with a peak at 3 days, as well as a long-lasting decrease after axotomy. These results, together with the previously shown regulation of GAL and the GAL-R1-R, suggest that GALergic mechanisms participate in complex adaptive responses in DRGs after inflammation and nerve injury.

Animals↗
PubMed2000

Axotomy-induced change in the properties of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor channels in rat motoneurons.

Properties of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor channels were studied in fluorescence-labelled control and axotomized motoneurons in spinal cord slices using a patch-clamp technique. Axotomy performed on the third postnatal day resulted in motoneuron death. Application of AMPA or kainate induced large whole-cell currents, but outside-out patches isolated from control motoneurons were either unresponsive or displayed only single-channel activity in response to rapid application of AMPA. Measurement of AMPA receptor channel openings in outside-out patches revealed multiple single-channel conductance levels: 12.2+/-1.0, 21. 9+/-1.5 and 32.6+/-3.2pS. In control motoneurons dialysed with spermine, the current-voltage relationship of responses induced by activation of AMPA receptor channels exhibited various degrees of inward rectification. The rectification index, the ratio of responses at +40 and -60mV, was used to compare the degree of inward rectification. The mean values of rectification index of responses to focal application of AMPA and AMPA receptor-mediated excitatory postsynaptic currents induced by focal electric stimulation were 0. 64+/-0.17 and 0.50+/-0.27, respectively. In axotomized motoneurons, the degree of rectification was significantly less for both responses induced by application of AMPA and for excitatory postsynaptic currents (0.91+/-0.09 and 0.95+/-0.12, respectively). Deactivation of AMPA receptors assessed from motoneuron excitatory postsynaptic currents at -70 mV was independent of postnatal age, with tau(fast)=0.88+/-0.35ms (A(fast)=78.2+/-11.8%) and tau(slow)=6. 3+/-3.2ms. In axotomized motoneurons, the decay time constants of excitatory postsynaptic currents were similar, tau(fast)=0.91+/-0. 42ms (A(fast)=85.8+/-12.6%) and tau(slow)=5.9+/-3.4ms. However, the mean amplitude of excitatory postsynaptic currents was only 43% of the amplitude recorded in control motoneurons. The results show that the current induced by activation of AMPA receptors in neonatal motoneurons is mediated by opening of both Ca(2+)-permeable and Ca(2+)-impermeable channels. As a result of axotomy, an experimental model of neurodegeneration, AMPA receptor channels in injured motoneurons destined to die become predominantly Ca(2+) impermeable. These findings suggest phenotypic control of AMPA receptor channel properties, presumably by affecting their subunit composition.

Animals↗
PubMed2002

Relationship between sprouting axons, proteoglycans and glial cells following unilateral nigrostriatal axotomy in the adult rat.

Proteoglycans may modulate axon growth in the intact and injured adult mammalian CNS. Here we investigate the distribution and time course of deposition of a range of proteoglycans between 4 and 14 days following unilateral axotomy of the nigrostriatal tract in anaesthetised adult rats. Immunolabelling using a variety of antibodies was used to examine the response of heparan sulphate proteoglycans, chondroitin sulphate proteoglycans and keratan sulphate proteoglycans. We observed that many proteoglycans became abundant between 1 and 2 weeks post-axotomy. Heparan sulphate proteoglycans were predominantly found within the lesion core (populated by blood vessels, amoeboid macrophages and meningeal fibroblasts) whereas chondroitin sulphate proteoglycans and keratan sulphate proteoglycans were predominantly found in the lesion surround (populated by reactive astrocytes, activated microglia and adult precursor cells). Immunolabelling indicated that cut dopaminergic nigral axons sprouted prolifically within the lesion core but rarely grew into the lesion surround. We conclude that sprouting of cut dopaminergic nigral axons may be supported by heparan sulphate proteoglycans but restricted by chondroitin sulphate proteoglycans and keratan sulphate proteoglycans.

Animals↗
PubMed2003

A lipoxygenase product, hepoxilin A(3), enhances nerve growth factor-dependent neurite regeneration post-axotomy in rat superior cervical ganglion neurons in vitro.

Hepoxilins are 12-lipoxygenase metabolites of arachidonic acid found in the CNS. They can modulate neuronal signaling but their functions are not known. We examined the effects of hepoxilin A(3) on neurite outgrowth post-axotomy in an in vitro model of spinal cord transection using superior cervical ganglion neurons. In the absence of nerve growth factor, hepoxilin A(3) did not support neuronal survival, or regeneration post-axotomy but did significantly enhance neurite regeneration in the presence of nerve growth factor. As early as 1 h post-injury hepoxilin A(3)-treated cultures (+nerve growth factor) had significantly more neurites than controls (nerve growth factor alone). Average hourly rates of outgrowth in hepoxilin A(3)-treated cultures were significantly higher than in controls for at least 12 h post-injury, suggesting that the effect of hepoxilin A(3) is maintained in vitro for several hours post-injury. In uninjured neurons hepoxilin A(3) caused a rapid but transient increase in intracellular calcium in the somata; by 2 min post-addition, calcium levels decreased to a new stable plateau significantly higher than pre treatment levels. In injured neurons, hepoxilin A(3) addition immediately post-transection caused a rapid transient increase in intracellular calcium in cell bodies; however, peak calcium levels were significantly lower than in uninjured neurons and the new baseline lower than in uninjured cells. In uninjured cells hepoxilin A(3) addition in zero calcium produced the same pattern, a transient elevation and subsequent decline to a new stable baseline significantly above rest but in injured cells levels fell rapidly to pretreatment values. Taken overall, these findings demonstrate a novel role for hepoxilins as a potentiator of neurite regeneration. They also provide the first evidence that this lipoxygenase metabolite can alter intracellular calcium in neurons by causing release of calcium from intracellular stores and modulating calcium influx mechanisms.

8,11,14-Eicosatrienoic Acid↗