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PubMed1998

Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy.

To understand the role of opioids and their receptors in chronic pain following peripheral nerve injury, we have studied the mu-opioid receptor in rat and monkey lumbar 4 and 5 dorsal root ganglion neurons and the superficial dorsal horn of the spinal cord under normal circumstances and after peripheral axotomy. Our results show that many small neurons in rat and monkey dorsal root ganglia, and some medium-sized and large neurons in rat dorsal root ganglia, express mu-opioid receptor-like immunoreactivity. Most of these neurons contain calcitonin gene-related peptide. The mu-opioid receptor was closely associated with the somatic plasmalemma of the dorsal root ganglion neurons. Both mu-opioid receptor-immunoreactive nerve fibers and cell bodies were observed in lamina II of the dorsal horn. The highest intensity of mu-opioid receptor-like immunoreactivity was observed in the deep part of lamina II. Most mu-opioid receptor-like immunoreactivity in the dorsal horn originated from spinal neurons. A few mu-opioid receptor-positive peripheral afferent terminals in the rat and monkey dorsal horn were calcitonin gene-related peptide-immunoreactive. In addition to pre- and post-junctional receptors in rat and monkey dorsal horn neurons, mu-opioid receptors were localized on the presynaptic membrane of some synapses of primary afferent terminals in the monkey dorsal horn. Peripheral axotomy caused a reduction in the number and intensity of mu-opioid receptor-positive neurons in the rat and monkey dorsal root ganglia, and of mu-opioid receptor-like immunoreactivity in the dorsal horn of the spinal cord. The decrease in mu-opioid receptor-like immunoreactivity was more pronounced in the monkey than in the rat dorsal root ganglia and spinal cord. It is probable that there was a parallel trans-synaptic down-regulation of mu-opioid-like immunoreactivity in local dorsal horn neurons of the monkey. These data suggest that one factor underlying the well known insensitivity of neuropathic pain to opioid analgesics could be due to a marked reduction in the number of mu-opioid receptors in the axotomized sensory neurons and in interneurons in the dorsal horn of the spinal cord.

Animals↗
PubMed1998

gp130 cytokines, leukemia inhibitory factor and interleukin-6, induce neuropeptide expression in intact adult rat sensory neurons in vivo: time-course, specificity and comparison with sciatic nerve axotomy.

The gp130 cytokines leukemia inhibitory factor and interleukin-6 are neuroactive cytokines associated with peripheral nerve injury. Here we show that exogenous administration of these factors selectively regulates neuropeptide phenotype in intact sensory neurons in a manner consistent with their role as injury-induced factors. Intraneural injection of leukemia inhibitory factor into the intact sciatic nerve of adult rats induces a significant increase in the percentage of neuronal profiles immunoreactive for galanin in the L4 and L5 dorsal root ganglia without altering the percentage profiles immunoreactive for vasoactive intestinal polypeptide or neuropeptide Y. Galanin-immunoreactivity was predominantly confined to those neurons which retrogradely transported and accumulated leukemia inhibitory factor. The up-regulation of galanin-immunoreactivity observed in L4 and L5 dorsal root ganglia following unilateral axotomy of the sciatic nerve was significantly reduced following continuous treatment for two weeks with a monoclonal antibody against the gp130 receptor motif. Intraneural injection of interleukin-6 into the intact sciatic nerve also significantly increased the percentage of neuronal profiles which displayed galanin-immunoreactivity but not vasoactive intestinal polypeptide or neuropeptide Y-immunoreactivity. Our results indicate that cytokines which interact with the gp130 receptor at the site of peripheral nerve injury contribute to the cell body response to axotomy. Changes in the levels of such cytokines however are insufficient to account for the complete repertoire of neuropeptide phenotypic changes associated with peripheral nerve injury.

Animals↗
PubMed1998

Motoneurons innervating partially denervated rat hindlimb muscles remain susceptible to axotomy-induced cell death.

Tibialis anterior and extensor digitorum longus muscles were partially denervated by cutting the L4 spinal nerve in three-day-old rats. The ultrastructure of the intact axons to these muscles in the L5 spinal nerve was examined in nine-day-old rats. In the control L5 spinal nerve, myelinated and unmyelinated axons were intermingled throughout the cross-section of the nerve, while on the operated side the nerve contained areas with predominantly small unmyelinated immature axons. The number of motoneurons innervating the partially denervated muscles was established by retrograde labelling with Diamidino Yellow. In nine- and 21-day-old rats, the number of labelled motoneurons on the partially denervated side, expressed as a percentage of the control side, was 26.1 +/- 5.5% and 20.7 +/- 3.0%, respectively. The response of these uninjured motoneurons to axotomy was tested. The axons of the motoneurons to the partially denervated muscles were crushed at nine days and the numbers of labelled motoneurons in the spinal cord of these rats counted at 21 days of age. Only 4.9 +/- 2.0% labelled motoneurons were seen on the operated side, as opposed to 20.7 +/- 3.0% present in animals without sciatic nerve injury. In normal animals, nerve injury at nine days does not cause motoneuron death. Thus, motoneurons to partially denervated muscles (i) have axons with several immature features and (ii) remain susceptible to axotomy-induced death for much longer than normal.

Animals↗
PubMed2003

Evidence for dopamine-derived hydroxyl radical formation in the nigrostriatal system in response to axotomy.

We have evaluated the ability of the injured nigrostriatal dopaminergic system to produce highly reactive hydroxyl radicals ((*)OH) by the electrochemical detection of salicylate hydroxylation. Unilateral transection of the medial forebrain bundle transiently increased the formation of (*)OH in substantia nigra (SN) but not in striatum during the first 48 h postlesion, when most relevant changes in terms of oxidatively modified proteins take place. Short-term adaptive axotomy-induced changes in substantia nigra included downregulation of nigral tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression and more intense TH immunoreactivity. Maintained inhibition of monoamine oxidase activity with deprenyl totally prevented the axotomy-induced formation of (*)OH, thus demonstrating the dopaminergic nature of these radicals. In contrast, deprenyl treatment, which is associated with a diminution in free radical production, failed to delay the onset of dopaminergic degeneration. This observation highlights the importance of being extremely cautious when analyzing parameters of oxidative stress and extrapolating them as a primary cause of cell death in the context of neurodegeneration. Long-term adaptive changes included a dramatic downregulation of DAT mRNA expression along with a moderate decrease in TH mRNA levels in SN. We anticipate a key regulatory role of the DAT to maximally optimize dopaminergic transmission in the synaptic cleft under conditions of degeneration.

Animals↗
PubMed1999

Retinal ganglion cells lose trophic responsiveness after axotomy.

Whereas PNS neurons in culture are intrinsically responsive to peptide trophic factors, retinal ganglion cells (RGCs) are not unless they are depolarized, or their intracellular levels of cyclic AMP (cAMP) are elevated. We show here that depolarization increases cAMP in cultured RGCs sufficiently to enhance their responsiveness and that the trophic responsiveness of developing RGCs in intact retinas depends on physiological levels of activity and cAMP elevation. Responsiveness is lost after axotomy but is restored by cAMP elevation. The death of axotomized RGCs can be prevented if they are simultaneously stimulated by several trophic factors together with cAMP elevation. Thus, the death of RGCs after axotomy is not caused solely by the loss of retrograde trophic stimuli but also by a profound loss of trophic responsiveness.

Adenylyl Cyclase Inhibitors↗
PubMed1999

Microglial motility in the rat facial nucleus following peripheral axotomy.

Microglial motility was studied in living mammalian brain tissue using infrared gradient contrast microscopy in combination with video contrast enhancement and time lapse video recording. The infrared gradient contrast allows the visualization of living cells up to a depth of 60 microm in brain slices, in regions where cell bodies remain largely uninjured by the tissue preparation and are visible in their natural environment. In contrast to other techniques, including confocal microscopy, this procedure does not require any staining or labeling of cell membranes and thus guarantees the investigation of tissue which has not been altered, apart from during preparation. Microglial cells are activated and increase in number in the facial nucleus following peripheral axotomy. Thus we established the preparation of longitudinal rat brainstem slices containing the axotomized facial nucleus as a source of activated microglial cells. During prolonged video time lapse recordings, two different types of microglial cell motility could be observed. Microglial cells which had accumulated at the surface of the slice remained stationary but showed activity of the cell soma, developing pseudopods of different shape and size which undulated and which were used for phagocytosis of cell debris. Microglial phagocytosis of bacteria could be documented for the first time in situ. In contrast, ameboid microglia which did not display pseudopods but showed migratory capacity, could be observed exclusively in the depth of the tissue. Some of these cells maintained a close contact to neurons and appeared to move along their dendrites, a finding that may be relevant to the role of microglia in "synaptic stripping", the displacement of synapses following axotomy. This approach provides a valuable opportunity to investigate the interactions between activated microglial cells and the surrounding cellular and extracellular structures in the absence of staining or labeling, thus opening a wide field for the analysis of the cellular mechanisms involved in numerous pathologies of the CNS.

Animals↗
PubMed2004

Neurosurgery: functional regeneration after laser axotomy.

Understanding how nerves regenerate is an important step towards developing treatments for human neurological disease, but investigation has so far been limited to complex organisms (mouse and zebrafish) in the absence of precision techniques for severing axons (axotomy). Here we use femtosecond laser surgery for axotomy in the roundworm Caenorhabditis elegans and show that these axons functionally regenerate after the operation. Application of this precise surgical technique should enable nerve regeneration to be studied in vivo in its most evolutionarily simple form.

Animals↗
PubMed2001

Emergence of axons from distal dendrites of adult mammalian neurons following a permanent axotomy.

The distinctive features of axons and dendrites divide most neurons into two compartments. This polarity is fundamental to the ability of most neurons to integrate synaptic signals and transmit action potentials. It is not known, however, if the polarity of neurons in the adult mammalian nervous system is fixed or plastic. Following axotomy, some distal dendrites of neck motoneurons in the adult cat give rise to unusual processes that, at a light microscopic level, resemble axons (Rose, P.K. & Odlozinski, M., J. Comp. Neurol., 1998, 390, 392). The goal of the present experiments was to characterize these unusual processes using well-established ultrastructural and molecular criteria that differentiate dendrites and axons. These processes were immunoreactive for growth-associated protein-43 (GAP-43), a protein that is normally confined to axons. In contrast, immunoreactivity for a protein that is widely used as a marker for dendrites, microtubule-associated protein (MAP)-2a/b, could not be detected in the unusual distal arborizations. At the electron microscopic level, unusual distal processes contained dense collections of neurofilaments and were frequently myelinated. These molecular and structural characteristics are typical of axons and suggest that the polarity of adult neurons in the mammalian nervous system can be disrupted by axotomy. If this transformation in neuronal polarity is common to other types of neurons, axon-like processes emerging from distal dendrites may represent a mechanism for replacing connections lost due to injury. Alternatively, the connections formed by these axons may be aberrant and therefore maladaptive.

Animals↗
PubMed1998

Differential time course of neuronal and glial apoptosis in neonatal rat dorsal root ganglia after sciatic nerve axotomy.

Sensory neurons in neonatal rat lumbar dorsal root ganglia die after sciatic nerve axotomy, and previous studies have estimated the total cell loss to be 40-95%. We have used the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) technique, combined with immunohistochemistry, to investigate the contribution of apoptosis to the cell loss that occurs after unilaterally transecting the sciatic nerve of new-born rats. TUNEL-positive cells were detected 1 day post-lesion, and their number peaked 3 days after the injury. Combining TUNEL labelling with immunohistochemistry, for neuron-specific neurofilament 150 kDa, or glial-specific S-100beta, enabled us to identify dying neurons and dying glia. One day after axotomy, most of the TUNEL-positive cells (58%) were neurons, whereas 3 days post-injury, only a small number of dying cells (6%) were neuronal. This lower incidence was due to a decrease in neuronal death and an increase in glial death. The glia in the dorsal root ganglia therefore die subsequent to the neurons. The apoptotic nature of the cell death was confirmed by electron microscopy, with fine structural features of apoptotic cell death, e.g. chromatin compaction and membrane blebbing, being observed in both glia and neurons. Our results confirm that extensive apoptosis occurs in the neonatal lumbar dorsal root ganglia after sciatic nerve section, and show that neurons and glial cells die with different time-courses. The results suggest a neuron-glia trophic interdependence in the dorsal root ganglia.

Animals↗
PubMed2000

Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT).

Nerve injury leads to the release of a number of cytokines which have been shown to play an important role in cellular activation after peripheral nerve injury. The members of the signal transducer and activator of transcription (STAT) gene family are the main mediators in the signal transduction pathway of cytokines. After phosphorylation, STAT proteins are transported into the nucleus and exhibit transcriptional activity. Following axotomy in rat regenerating facial and hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3 and STAT5 was detected using in situ hybridization and semi-quantitative polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3 protein was significantly increased. In addition, activation of STAT3 by phosphorylation on position Tyr705 and enhanced nuclear translocation was found within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine phosphorylation was obvious for more than 3 months. In contrast, none of these changes was found in response to axotomy of non-regenerating Clarke's nucleus neurons, although all the investigated models express c-Jun and growth-associated protein-43 (GAP-43) in response to axonal injury. Increased expression of Janus kinase (JAK) and STAT molecules after peripheral nerve transection suggests changes in the responsiveness of the neurons to signalling molecules. STAT3 as a transcription factor, which is expressed early and is activated persistently until the time of reinnervation, might be involved in the switch from the physiological gene expression to an 'alternative program' activated only after peripheral nerve injury.

Animals↗
PubMed2002

Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain.

Phenotypic modification of dorsal root ganglion (DRG) neurons represents an important mechanism underlying neuropathic pain. However, the nerve injury-induced molecular changes are not fully identified. To determine the molecular alterations in a broader way, we have carried out cDNA array on the genes mainly made from the cDNA libraries of lumbar DRGs of normal rats and of rats 14 days after peripheral axotomy. Of the 7,523 examined genes and expressed sequence tags (ESTs), the expression of 122 genes and 51 expressed sequence tags is strongly changed. These genes encompass a large number of members of distinct families, including neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, and others. Of particular interest is the up-regulation of gamma-aminobutyric acid(A) receptor alpha5 subunit, peripheral benzodiazepine receptor, nicotinic acetylcholine receptor alpha7 subunit, P2Y1 purinoceptor, Na(+) channel beta2 subunit, and L-type Ca(2+) channel alpha2delta-1 subunit. Our findings therefore reveal dynamic and complex changes in molecular diversity among DRG neurons after axotomy. Sequences reported in this paper have been deposited in the GenBank database (accession numbers BG 662484-BG 673712)

Animals↗
PubMed2002

Anti-semaphorin 3A antibodies rescue retinal ganglion cells from cell death following optic nerve axotomy.

Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A., Ziv, I., Fleminger, G., Shina, R., He, Z., Brudo, I., Melamed, E., and Brazilai, A. (1999) J. Neurochem. 73, 961-971). In this study, we examined the involvement of semaphorins in an in vivo experimental animal model of complete axotomy of the rat optic nerve. We demonstrate that a marked induction of type III semaphorin proteins takes place in ipsilateral retinas at early stages following axotomy, well before any morphological signs of RGC apoptosis can be detected. Time course analysis revealed that a peak of expression occurred after 2-3 days and then declined. A small conserved peptide derived from semaphorin 3A that was previously shown to induce neuronal death in culture was capable of inducing RGC loss upon its intravitreous injection into the rat eye. Moreover, we demonstrate a marked inhibition of RGC loss when axotomized eyes were co-treated by intravitreous injection of function-blocking antibodies against the semaphorin 3A-derived peptide. Marked neuronal protection from degeneration was also observed when the antibodies were applied 24 h post-injury. We therefore suggest that semaphorins are key proteins that modulate the cell fate of axotomized RGC. Neutralization of the semaphorin repulsive function may serve as a promising new approach for treatment of traumatic injury in the adult mammalian central nervous system or of ophthalmologic diseases such as glaucoma and ischemic optic neuropathy that induce apoptotic RGC death.

Animals↗
PubMed2004

Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2.

Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective activity upon reduced oxygenation or ischemia of brain, retina, and spinal cord. To examine whether Epo has an impact on the retrograde degeneration of retinal ganglion cells (RGCs) following optic nerve transection in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo preferentially in neuronal cells without inducing polycythemia. We show that the tg21 retina expresses human Epo and that RGCs in this mouse line carry the Epo receptor. Upon axotomy, the RGCs of Epo transgenic tg21 mice were protected against degeneration, as compared with wild-type control animals. Western blot analysis revealed decreased phosphorylation levels of STAT-5 and reduced expression of Bcl-XL in RGCs of axotomized tg21 animals, suggesting that the corresponding pathways are not crucial for Epo's neuroprotective activity. Increased phosphorylation levels of ERK-1/-2 and Akt, as well as decreased caspase-3 activity, however, were observed in injured tg21 retinae. Injection of selective inhibitors of ERK-1/-2 (PD98059) or Akt (Wortmannin) pathways into the vitreous space revealed that transgenic Epo protected the RGCs by a pathway involving ERK-1/-2 but not Akt. In view that axotomy-induced degeneration of RGC occurs slowly, and considering the earlier data on the safety and efficacy of Epo in human stroke patients, we predict the clinical implementation of recombinant human Epo not only in patients with acute ischemic stroke, but also with more delayed degenerative neurological diseases.

Animals↗
PubMed1998

Differential macrophage responses following pre- and postganglionic axotomy.

Here we report that macrophages in the rat superior cervical ganglia (SCG) respond differently to pre- and postganglionic axotomy. Postganglionic axotomy results in a rapid activation of resident macrophages, as measured by inducible nitric oxide synthase (iNOS) immunoreactivity, and a massive invasion by macrophages. Following preganglionic lesion there was no such rapid activation and the macrophage invasion was of much lower magnitude. A subpopulation of the macrophages also expressed haem oxygenase-1 (HO-1). The results are compatible with a model in which macrophages or their products, including nitric oxide (NO) and carbon monoxide (CO) could be important for induction of early changes in the nerve cell body, like an altered neuropeptide synthesis, which has been shown to accompany the regenerative response in peripheral ganglia.

Animals↗
PubMed1998

Neurturin protects dopaminergic neurons following medial forebrain bundle axotomy.

To determine whether neurturin (NTN), a recently identified homologue of glial cell line-derived neurotrophic factor (GDNF), is able to preserve tyrosine hydroxylase immunoreactivity (TH-IR) in a rat model of Parkinson's disease, polymer encapsulated cells genetically engineered to release NTN were implanted near the substantia nigra 1 week before a unilateral medial forebrain bundle axotomy. Animals were allowed to survive for 1 week post-axotomy. Upon sacrifice, animals that received a NTN capsule had a significantly higher percentage of TH-IR (lesioned side vs non-lesioned side) than animals that had received a capsule containing non-transfected parent cells. However, in contrast to GDNF, no reduction of turning was observed upon amphetamine rotation with NTN. Nevertheless, these results suggest that NTN might have a therapeutic value for the treatment of Parkinson's disease.

Analysis of Variance↗
PubMed1999

Up- and down-regulation of BDNF mRNA in distinct subgroups of rat sensory neurons after axotomy.

Anterograde transport of BDNF is enhanced by axotomy in the rat sciatic nerve. However, the changes in BDNF gene expression in dorsal root ganglion (DRG) neurons after axotomy are not known. We examined this issue using in situ hybridization histochemistry. BDNF mRNA was detected in 35-40% of DRG neurons (L5) of control rats. Most of these neurons are small. BDNF gene expression in these neurons was down-regulated after application of capsaicin to the sciatic nerve. Transection of the sciatic nerve induced the up-regulation of BDNF mRNA. The intensely labeled neurons were mainly large and immunoreactive for neuropeptide Y. These results suggest that up- and down-regulation of BDNF gene expression in distinct subgroups of rat DRG neurons are caused by damage to the peripheral nerve.

Afferent Pathways↗
PubMed2001

Changes in spinal cholecystokinin release after peripheral axotomy.

The gene expression of cholecystokinin (CCK), a neuropeptide with anti-opioid properties, has been reported to be upregulated in some primary sensory neurons after a peripheral nerve lesion. We have recently demonstrated that the upregulation of CCK mRNA is not accompanied by an increased potassium-evoked release CCK-like immunoreactivity (CCK-LI) 2-4 weeks after a complete transection of the sciatic nerve. The potassium-evoked release of CCK-LI at earlier and later time points has, however, not been studied. The aim of the present in vivo microdialysis study was to monitor how the basal and stimulated extracellular level of CCK in the dorsal horn of the spinal cord is affected at various time points after a complete transection of the sciatic nerve (axotomy). During the first week after transection of the sciatic nerve a tendency towards an elevation of the potassium-induced (100 mM in the perfusion fluid) release of spinal CCK-LI was observed. In contrast, no potassium-induced release of CCK-LI could be detected 2-3 weeks and 2 months after axotomy. No significant effect was observed on the basal extracellular levels of CCK-LI in the dorsal horn. The present study provides further support for the notion that the adaptive changes in the dorsal horn 2 weeks and later after a deafferentiation injury do not include an increased release of CCK.

Animals↗
PubMed2003

Axotomy induces cytochrome c release in retinal ganglion cells.

Activation of caspase-3 and -9 has been implicated in the death of axotomized retinal ganglion cells (RGCs). The upstream pathways involved in the activation of these caspases, however, remain unknown. The aim of the current study is to examine the role of cytochrome c release in axotomized RGC death using immuno-histochemistry. We found that while only a low level of cytochrome c immunoreactivity was evident in normal retina, cytochrome c immunoreactivity increased markedly at 1 day post-axotomy, peaked at 3 days post-axotomy, and decreased thereafter. In addition, cytochrome c immunoreactivity localized almost exclusively to RGCs, suggesting that the cytochrome c release observed was injury-related. Our data indicate that cytochrome c release potentially contributes to the death of axotomized RGCs.

Animals↗