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PubMed1999

The effects of mitotic inhibition on the spinal cord response to the superimposed injuries of spinal cord hemisection and peripheral axotomy.

The present study was carried out to test the hypothesis that dividing microglia are responsible for the depression of crossed phrenic nerve activity documented at 2 weeks postphrenicotomy in an injury model which superimposes the effects of spinal cord injury on peripheral axotomy. Crossed phenic nerve activity is defined as the respiratory activity recorded from the phrenic nerve during the crossed phrenic phenomenon (CPP) which is a respiratory reflex induced by respiratory stress following an ispsilateral spinal cord hemisection. Young adult female Sprague-Dawley rats were subjected to left intrathoracic phrenicotomies. Cytarabine (Cyt-A, a powerful antimitotic drug) or saline-filled miniosmotic pumps were then implanted into the cisterna magna and 2 weeks were allowed to pass at which time the CPP was induced by a left C2 spinal cord hemisection and transection of the contralateral phrenic nerve. Control studies including bromodeoxyuridine labeling of mitotic cells and a triple immunofluorescent protocol were carried out to verify that microglial cells were the primary cell type undergoing mitosis in the current injury model and that Cyt-A completely inhibited cellular proliferation. Quantitative electrophysiological analysis of crossed phrenic nerve activity showed that there is a statistically significant depression of activity at 2 weeks postphrenicotomy when animals were infused with saline compared to controls. Crossed phrenic nerve activity levels were not significantly different, however, from control levels when 2-week postphrenicotomized rats were infused with Cyt-A. Immunofluorescent studies showed that the majority of cells dividing in response to phrenicotomy were microglia. Furthermore, there were no astrocytes seen dividing at any time. From the results, we conclude that activated microglial cells may be responsible for the depression in crossed phrenic activity normally seen 2 weeks postphrenicotomy. Further, the activation of microglia may be related to the astrocytic response to injury. The activated microglial cell may be acting as a coordinator of various aspects of the injury response. Alternatively, the activation of microglia may be a necessary step in the cascade of multiple events that take place in the spinal cord after injury.

Animals↗
PubMed2001

Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells.

Netrins are a family of chemotropic factors that guide axon outgrowth during development; however, their function in the adult CNS remains to be established. We examined the expression of the netrin receptors DCC and UNC5H2 in adult rat retinal ganglion cells (RGCs) after grafting a peripheral nerve (PN) to the transected optic nerve and following optic nerve transection alone. In situ hybridization revealed that both Dcc and Unc5h2 mRNAs are expressed by normal adult RGCs. In addition, netrin-1 was found to be constitutively expressed by RGCs. Quantitative analysis using in situ hybridization demonstrated that both Dcc and Unc5h2 were down-regulated by RGCs following axotomy. In the presence of an attached PN graft, Dcc and Unc5h2 were similarly down-regulated in surviving RGCs regardless of their success in regenerating an axon. Northern blot analysis demonstrated expression of netrin-1 in both optic and sciatic nerve, and Western blot analysis revealed the presence of netrin protein in both nerves. Immunohistochemical analysis indicated that netrin protein was closely associated with glial cells in the optic nerve. These results suggest that netrin-1, DCC, and UNC5H2 may contribute to regulating the regenerative capacity of adult RGCs.

Animals↗
PubMed2002

Priming by muscle inflammation alters the response and vulnerability to axotomy-induced damage of the rat facial motor nucleus.

To ascertain whether signaling due to peripheral inflammation affects motoneuron vulnerability, we examined in adult rats the reaction to axonal injury of facial motoneurons primed by muscle inflammation. In this double-hit paradigm, preconditioning was achieved by injections into the facial muscles of the T cell mitogen phytohemagglutinin, which was found in a previous study ( 11 ) to elicit a retrograde response in motoneurons. Facial nerve transection was used as test lesion. Intramuscular injections of saline prior to axotomy were used as control for lectin pretreatment. In rats pretreated with phytohemagglutinin injection, upregulation of the expression of the antiapoptotic bcl-2 gene, examined with in situ hybridization, was significantly higher in facial motoneurons at 2 days postaxotomy compared with saline-injected control cases. After repeated phytohemagglutinin injections followed by nerve transection, induction in facial motoneurons of nitric oxide synthase, revealed by histochemistry and immunohistochemistry, as well as activation of the surrounding microglia, was enhanced at 14 days postaxotomy with respect to the saline-treated control cases. At the same time point, no significant intergroup difference was detected in the intensity of astrocytic activation. At 1 month postaxotomy, stereological cell counts revealed that motoneuron loss was significantly greater in the cases pretreated with phytohemagglutinin than in the saline-treated cases. The data point out that the response of the facial motor nucleus to axonal damage is altered by previous exposure to peripheral inflammation and that such preconditioning stimulus enhances motoneuron vulnerability to nerve injury.

Animals↗
PubMed2002

Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats.

Heat shock proteins (hsps) are induced in a variety of cells following periods of stress, where they promote cell survival. In this study, we examined the effect of upregulating hsp expression by treatment with BRX-220, a co-inducer of hsps, on the survival of injured motoneurones. Following sciatic nerve crush at birth, rat pups were treated daily with BRX-220. The expression of hsp70 and hsp90, motoneurone survival, and muscle function was examined at various intervals later and the number of functional motor units was assessed by in vivo isometric tension recordings. Fourteen days after injury, significantly more motoneurones survived in the BRX-220-treated group (39 +/- 2.8%) compared to the saline-treated group (21 +/- 1.7%). Moreover, in the BRX-220-treated group no further loss of motoneurones occurred, so that at 10 weeks 42 +/- 2.1% of motoneurones survived compared to 15 +/- 0.6% in the untreated group. There were also more functional motor units in the hindlimb muscles of BRX-220-treated animals. In addition, treatment with BRX-220 resulted in a significant increase in the expression of hsp70 and hsp90 in glia and neurones. Thus, treatment with BRX-220, a co-inducer of hsps, protects motoneurones from axotomy-induced cell death.

Animals↗
PubMed2000

Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.

Activating transcription factor 3 (ATF3), a member of ATF/CREB family of transcription factors, is induced in a variety of stressed tissue. ATF3 regulates transcription by binding to DNA sites as a homodimer or heterodimer with Jun proteins. The purpose of this study was to examine the expression and regulation of ATF3 after axonal injury in neurons in dorsal root ganglia (DRG) and spinal cord. In naive rats, ATF3 was not expressed in the DRG and spinal cord. Following the cut of peripheral nerve, ATF3 was immediately induced in virtually all DRG neurons and motoneurons that were axotomized, and the time course of induction was dependent on the distance between the injury site and the cell body. Double labeling using immunohistochemistry revealed that the population of DRG neurons expressing ATF3 included those expressing c-jun, and in motoneurons ATF3 and c-jun were concurrently expressed after axotomy. In contrast to c-jun, ATF3 was not induced transsynaptically in spinal dorsal horn neurons. We conclude that ATF3 is specifically induced in sensory and motoneurons in the spinal cord following nerve injury and should be regarded as an unique neuronal marker of nerve injury in the nervous system.

Activating Transcription Factor 3↗
PubMed2002

Dynamic changes in gene expression profiles following axotomy of projection fibres in the Mammalian CNS.

Following postcommissural fornix transection we have investigated the postaxotomy transcriptional program in the subiculum where the injured axons originate. cDNA array hybridization revealed 125 genes that were specifically regulated as the injured neurons passed through three distinct postlesion (PL) stages comprising (i). early phase of injury and axon degeneration, (ii). sprouting phase of the proximal stump, and (iii). axonal growth arrest at the lesion scar. Numerous genes were detected which have, so far, not been associated with axotomy or axonal growth. Following the early lesion response that is characterized predominantly by down-regulation of genes at 1 day PL, neurons switch to a sprouting program with the majority of genes up-regulated at 7 days PL. However, the latter program of gene expression is not maintained but largely reversed (at 3 weeks PL) to the initial profile as axonal growth is blocked at the lesion barrier, indicating retrograde signaling that leads to down-regulation of neuronal genes previously up-regulated during axon sprouting.

Animals↗
PubMed1998

Immunolabelling of the cytoplasm and processes of apoptotic facial motoneurons following axotomy in the neonatal rat.

A polyclonal antibody intended to recognize c-Jun (Oncogene Science, c-jun/AP-1, Ab-2) has previously been shown to recognize an apparently novel "apoptosis-specific protein" (ASP) in the cytoplasm of cells undergoing apoptotic cell death in vitro. We have investigated whether this antibody would also serve as a reliable marker for apoptotic motoneurons in vivo. Following transection of the left facial nerve in anesthetized neonatal rat pups, which results in over 90% death of the facial motoneurons, we performed immunohistochemistry on frozen brain stem sections with Oncogene Science Ab-1 and Ab-2 antibodies which are raised against different peptide fragments of c-Jun. While Ab-1/c-Jun labelling was seen in the nuclei of the majority of axotomized motoneurons, Ab-2/ASP immunoreactivity was present only in scattered cells, all of which had characteristic apoptotic morphology. Furthermore, Ab-2/ASP immunoreactivity was cytoplasmic and frequently included the dendrites and axons of dying neurons. Some cerebellar granule cells undergoing postnatal developmental cell death were also Ab-2/ASP positive. The time course of the number of Ab-2/ASP-labelled motoneurons corresponded relatively closely with our previous data on DNA fragmentation in these cells, as assessed by an in situ end labelling (ISEL) technique. When facial nerve axotomy was performed at 7 and 14 days postnatum, resulting in reduced cell death, the number of Ab-2/ASP immunoreactive cells decreased correspondingly. Although the exact identity of the epitope recognized by Ab-2 is unclear, we conclude that, by labelling the cytoplasmic and neuritic components of apoptotic motoneurons, Ab-2/ASP immunohistochemistry is a valuable complementary technique to existing in situ methods based on the detection of fragmented DNA in the cell nucleus.

Animals↗
PubMed2004

Peripheral axotomy induces depletion of the vesicular glutamate transporter VGLUT1 in central terminals of myelinated afferent fibres in the rat spinal cord.

Myelinated primary afferent axons use glutamate as their principal neurotransmitter. We have shown previously that central terminals of myelinated tactile and proprioceptive afferents contain the vesicular glutamate transporter VGLUT1. Peripheral nerve injury is known to induce changes in the anatomy, neurochemistry, and physiology of primary afferents. In this study, we have examined the effect of peripheral axotomy on VGLUT1 expression in central terminals of myelinated afferents in laminae III-V and lamina IX of the rat spinal cord. Bilateral injections of cholera toxin B subunit (CTb) were made into the sciatic nerves of rats that had undergone unilateral sciatic nerve transection 1, 2, 4, or 8 weeks previously. Immunofluorescence staining and confocal microscopy were used to compare levels of VGLUT1 in CTb-labelled boutons on the intact and sectioned sides at each postoperative survival time. VGLUT1 was depleted from central terminals of transected myelinated afferents in rats injected with CTb 1 week after nerve section, and this depletion became more severe in animals with longer postaxotomy survival times. By 4 weeks, the level of VGLUT1 in CTb-labelled boutons in lamina IX was reduced by over 80% compared to that seen in intact (contralateral) afferents, while for boutons in laminae III-V, VGLUT1 levels were reduced by 50-70%. This suggests that loss of VGLUT1 is more severe in proprioceptive than cutaneous afferents. Depletion of VGLUT1 may lead to a decrease in levels of transmitter glutamate in these afferents and thus to a reduction in synaptic efficacy.

Afferent Pathways↗
PubMed2005

AAV2/5-mediated NGF gene delivery protects septal cholinergic neurons following axotomy.

Nerve growth factor (NGF) therapy has been proposed to treat cognitive impairments in aged patients including those with Alzheimer's disease. Various viral vectors, including adeno-associated virus serotype 2 (AAV2), have been investigated for their ability to deliver NGF in brain. In this study, hybrid vectors (AAV2/5) consisting of the genome of recombinant AAV2 and the capsid of AAV serotype 5 were evaluated for their ability to deliver NGF and green fluorescent protein (GFP) genes into brain. Compared to AAV2, AAV2/5 consistently led to more septal neurons being transduced with GFP over a wider range of distribution. However, both types of vector provided similar levels of long-term (17 weeks) protection of septal cholinergic neurons from axotomy and led to similar levels of NGF accumulation in this region. These results demonstrate that rAAV-mediated NGF gene delivery is neuroprotective for an extended period of time, but that factors other than transduction efficiency appear to determine transgenic NGF expression in septum.

Animals↗
PubMed2006

Enriched environment during adolescence changes brain-derived neurotrophic factor and TrkB levels in the rat visual system but does not offer neuroprotection to retinal ganglion cells following axotomy.

The purpose of the present experiment was to characterize changes in TrkB signaling in the rat visual system resulting from exposure to enriched environment. Female Sprague-Dawley rats were placed in enriched or impoverished conditions for 1, 7 or 28 days. Levels of BDNF protein and its predominant receptor TrkB were examined in the retina, superior colliculus and visual cortex. In the retina, 1 day of enrichment increased full-length TrkB and after 28 days increased BDNF. In the superior colliculus, enrichment for 7 days reduced full-length TrkB and after 28 days increased BDNF and full-length TrkB. One day of enrichment significantly increased BDNF, reduced full-length TrkB and increased truncated TrkB in the visual cortex. Consequently, we further investigated whether exposure to enriched environment and the subsequent changes in BDNF and TrkB translates into a neuroprotective effect on retinal ganglion cells (RGCs) following transection of the optic nerve. Although exogenous intraocular application of BDNF provides neuroprotection to RGCs after axotomy, the endogenous increase in BDNF in the retina after 28 days of enrichment had no effect on RGC survival. While enriched housing conditions offer a model of non-invasive rehabilitation treatment for injury and modulates changes in BDNF and TrkB levels, these molecular changes did not translate into a neuroprotective effect on RGCs following transection of the optic nerve.

Analysis of Variance↗
PubMed2004

Suppressive silver methods--a tool for identifying axotomy-induced neuron degeneration.

Suppressive silver methods evolved from empirical observations about 50 years ago that argyrophilia of normal nerve fibers can be suppressed by a short period of oxidation of tissue sections, whereas degenerating nerve fibers in the same preparations were still clearly visible. Based on this property, suppressive silver impregnation became the main technique for investigating pathways in the central nervous system until the early 1970s. Suppressive silver methods were also found to visualize degenerating nerve cell bodies, in addition to degenerating nerve fibers. This possibility has given these methods an important place among current tools for identifying neuronal degeneration in trauma, disease and toxicity. In this article we demonstrate and review the usefulness of suppressive silver methods in identifying neurons undergoing degeneration as a result of peripheral or central axon injury in immature animals. The documentation is based on previously published data from experiments in which silver impregnation was used to demonstrate degeneration of motoneurons following pure motor axon injury or mixed peripheral nerve injury, as well as on new results on degeneration-induced argyrophilia in the inferior olive following cerebellar lesions. We find that silver precipitates resulting from these injuries are localized either to the entire neuronal cytoplasm, to a few (typically two) intranuclear bodies, or to both sites. The findings are discussed in relation to morphological features of apoptosis, necrosis and retrograde neuronal responses. We suggest that suppressive silver methods allow visualization of different processes of neuronal degeneration, and therefore may be a useful adjunct for identifying axotomy-induced neuronal degeneration.

Animals↗
PubMed2004

Axotomy abolishes NeuN expression in facial but not rubrospinal neurons.

The neuronal nuclei (NeuN) antibody, which binds to a poorly characterized antigen/antigens, is increasingly being used in several areas of study as a specific marker to identify neuronal populations. Despite the increasing reliance on NeuN as a panneuronal marker, changes of NeuN expression following axonal injury have not yet been examined. In the present study, NeuN immunoreactivity was analyzed in adult rodent facial motoneurons [peripheral nervous system (PNS) model] following nerve resection or crush and in rubrospinal neurons [central nervous system (CNS) model] after lesion of the dorsal lateral funiculus at the cervical level of the spinal cord. Peripheral nerve resection in the rat and mouse resulted in an almost complete loss of NeuN immunoreactivity in facial motoneurons by 3 days postinjury and remained absent at 28 days post-resection despite the survival of the neurons as evidenced by neuronal tracing. These results were confirmed with Western blot. In the peripheral nerve crush model of injury, there was an initial decline in NeuN immunoreactivity in facial motoneurons, but unlike the resection model, NeuN immunoreactivity began to return within 7 days postinjury and returned to the uninjured level of expression by 28 days. In contrast, axotomy in the CNS model resulted in little decline in NeuN immunoreactivity in the rubrospinal neurons, even after 28 days postaxotomy. These results indicate that NeuN expression in response to axonal injury is different in separate neuronal populations (PNS and CNS), and that care must be taken when addressing cell survival based on NeuN staining alone.

Animals↗
PubMed2004

Modification of the regenerative response of dorsal column axons by olfactory ensheathing cells or peripheral axotomy in adult rat.

The regeneration of sciatic-dorsal column (DC) axons following DC crush injury and treatment with olfactory ensheathing cells (OECs) and/or sciatic axotomy ("conditioning lesion") was evaluated. Sciatic-DC axons were examined with a transganglionic tracer, cholera toxin conjugated to horseradish peroxidase, and evaluated at chronic time points, 2-26 weeks post-lesion. With DC injury alone (n = 7), sciatic-DC axons were localized to the caudal border of the lesion terminating in reactive end bulbs with no indication of growth into the lesion. In contrast, treatment with either a heterogeneous population of OECs (equal numbers of p75- and fibronectin-positive OECs) (n = 9) or an enriched population of OECs (75% p75-positive OECs) (n = 6) injected either directly into the lesion or 1-mm rostral and caudal to the injury, stimulated DC axon growth into the lesion. A similar regenerative response was observed with a conditioning lesion either concurrent to (n = 4) or 1 week before (n = 4) the DC injury. In either of the latter two paradigms, some DC axons grew across the injury, but no axons grew into the rostral intact spinal cord. Upon combining OEC treatment with the conditioning lesion (n = 21), the result was additive, increasing DC axon growth beyond the rostral border of the lesion in best cases. Additional factors that may limit DC regeneration were tested including formation of the glial scar (immunoreactivity to glial fibrillary acidic protein in astrocytes and to chondroitin sulfate proteoglycans), which remained similar between treated and untreated groups.

Animals↗
PubMed2004

Axotomy dependent purinergic and nitrergic co-expression.

Different lines of evidence indicate that ATP and nitric oxide (NO) play key roles in mediating neuronal responses after cell damage. Purinergic and nitrergic interactions have been proposed in non neural tissues physiological functions and, in different experimental models of brain injury, both purinergic and nitrergic activations have been reported. The present study was planned to ascertain possible relations of these two systems after brain damage. Variations in the expression of the nitric oxide synthase neuronal isoform (nNOS) enzyme, and of two subunits of purinergic ionotrophic receptors (P2X) namely P2X(1) and P2X(2) in precerebellar stations after cerebellar lesion in rats were analyzed and compared. After the lesion nNOS positive cells presented a clear increment followed by a decrement. Conversely, nNOS negative cells presented a rapid decrement in the first postlesional weeks that continued less pronounced afterward. Postlesional nNOS activation was related with time course of P2X(1) and P2X(2) activations. The capacity of the same cells to express both nNOS and P2X markers was investigated immunocytochemically. Confocal microscopy of double immunofluorescence showed a high percentage of co-localization among P2X(1)/nNOS, P2X(2)/nNOS and P2X(1)/P2X(2) in olivary and pontine neurons. In addition, NeuN/P2X(1) and NeuN/P2X(2) double immunofluorescence showed P2X(1) expressed only in neurons while P2X(2) expressed by both neurons and glia. Present data demonstrate that after cerebellar lesion nitrergic and purinergic systems are activated with similar time courses in precerebellar stations. Further, time differences in the relation between nNOS expression and cell survival suggest a multifarious role of NO in mediating cell reaction to axotomy. The tight cellular co-localization and temporal co-activation of purinergic and nitrergic markers indicate possible interactions between these two systems also in the CNS.

Animals↗
PubMed2005

Differential effect of p75 neurotrophin receptor on expression of pro-apoptotic proteins c-jun, p38 and caspase-3 in dorsal root ganglion cells after axotomy in experimental diabetes.

We have hypothesized that p75 neurotrophin receptor (p75(NTR))-mediated activation of the pro-apoptotic proteins c-jun, p38 and caspase-3 underlies the neuronal cell loss in dorsal root ganglia (DRG) neurons after axotomy in normal mice, and that this activation is exaggerated in experimental diabetes. To test this hypothesized relationship, we compared the expression of pro-apoptotic proteins in fifth lumbar DRG (L5DRG) neurons of wildtype Balb/c (p75+/+) mice and p75(NTR) knockout (p75-/-) mice, assigned to either non-diabetic control groups or to diabetic (1 month) groups, all with a unilateral sciatic nerve crush produced 10 days before tissue preparation. The absolute number of L5DRG neurons expressing immunoreactivities (IR) for phosphorylated c-jun (P-c-jun-IR), phosphorylated p-38 (P-p38-IR) and cleaved caspase-3 (caspase-3-IR) were estimated in semi-thick sections using the optical fractionator. Nerve crush increased the numbers of P-c-jun-IR and caspase-3-IR neurons in all four groups. On the crush side, diabetes did not exaggerate the increase of P-c-jun-IR or caspase-3-IR neurons in p75+/+ mice, whereas in p75-/- mice diabetes reduced the increase of P-c-jun-IR neurons. Also, in p75-/- mice there was fewer caspase-3-IR cells on the intact and crushed side in comparison with p75+/+ mice independent of the presence of diabetes. This study demonstrates that (1) diabetes of 1 month's duration does not potentiate the expression of three pro-apoptotic markers p38, caspase-3 and P-c-jun neither in intact neurons nor after nerve crush, and that (2) p75(NTR) is required for activation of the pro-apoptosis signal caspase-3 after nerve crush in both diabetic and non-diabetic mice.

Animals↗
PubMed2006

Axotomy-induced motoneuron death is delayed in mice overexpressing PrPc.

The normal function of the cellular prion protein, PrP(c), remains largely unknown. Recently, PrP(c) has been implicated in the regulation of neuronal survival and was shown to confer neuroprotection in the brain. To pursue investigation of the role of PrP(c) in the CNS, we used the facial nerve section, a well-established experimental model of motoneuronal stress. Nerve sections were performed in 2- and 7-day-old newborn mice and in 2 month-old adult mice expressing different levels of PrP(c). We observed no differences in motoneuronal death triggered by facial nerve section between Prnp-/- and wild-type mice, whether in neonatal or adult mice. By contrast, overexpression of PrP(c) in Tga20 newborn mice was correlated with a better survival of motoneurons in the few days following axotomy. The protection was, however transient since motoneuron number in lesioned facial nuclei of Tga20 mice became identical to that of wild-type mice 7 days and 14 days following the lesion when performed in 2- and 7-day-old mice respectively. In Tga20 adult mice, no protection was observed 2 months after the lesion, a time with a significant degree of motoneuron death in adult control mice. These results, while providing further evidence that PrP(c) is endowed with neuroprotective capacity in vivo, also suggest that PrP(c) does not play a physiological role in the regulation of motoneuronal survival.

Age Factors↗
PubMed2006

Increased sodium channel immunofluorescence at myelinated and demyelinated sites following an inflammatory and partial axotomy lesion of the rat infraorbital nerve.

The localization of sodium channels (NaChs) change following nerve lesions and this change may contribute to the development of increased pain states. Here we examine the change in distribution of NaChs within the rat infraorbital nerve (ION) two weeks after a combined inflammatory/partial axotomy lesion that results in behavior showing increased sensitivity to mechanical stimuli. Sections from experimental and normal control IONs were double-stained for indirect immunofluorescence using an antibody that identifies all NaCh isoforms and caspr-antibody to identify nodes of Ranvier, and a confocal microscope z-series of optically sectioned images were then obtained. ImageJ (NIH) software was used to quantify the area of pixels showing maximum NaCh intensity within both caspr and non-caspr associated accumulations. Analysis showed that the lesioned IONs had many more split nodes, heminodes and caspr-negative "naked" accumulations, a significantly increased area of NaCh staining within typical nodes and "naked" accumulations, as well as an increased density and size of significant accumulations when compared to normal IONs. This study demonstrates a dramatic redistribution and increased immunofluorescence of NaChs especially at myelinated and demyelinated sites in fibers located just proximal to the lesion. The remodeling of NaChs seen in this study may represent an important event associated with the development of increased nerve excitability after lesions.

Animals↗
PubMed2000

Nerve growth factor applied onto the olfactory epithelium alleviates degenerative changes of the olfactory receptor neurons following axotomy.

The olfactory neuroepithelium of the mammalian nervous system manifests continuous neurogenesis throughout life. Recent studies suggest that neurotrophic factors and their receptors may play a role in the regulation of development and regeneration in the olfactory system. However, there have been very few in vivo studies investigating the effect of exogenous neurotrophic factors in the olfactory system. In the present study, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were administered into the rat olfactory mucosa for 5 days just after the transection of the olfactory nerve. We then examined the effect of exogenous neurotrophic factors on the degenerative changes in axotomized olfactory receptor neurons (ORNs). Further, we examined the location of their receptors, Trk A and Trk B. We found that both mature and immature ORNs expressed more intense signals for olfactory marker protein and beta-tubulin mRNAs, respectively, when NGF was applied to the axotomized olfactory neuroepithelium for 5 days, compared to the ORNs of saline-treated controls. BDNF at a 10 microg total dose did not show this effect. The effect of NGF applied onto the olfactory epithelium is consistent with the immunohistochemical finding that Trk A was present in the dendrites and axon bundles in normal and axotomized ORNs. These results suggest that NGF may protect the degenerative changes in mature and immature ORNs following axotomy through the binding to the Trk A receptor located on the surface of the olfactory epithelium.

Animals↗