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PubMed2001

Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders.

It has been shown previously that the synthetic corticosteroid dexamethasone induces apoptosis of granule cells in the dentate gyrus and striatopallidal neurons in the dorsomedial caudate-putamen. We investigated whether or not dexamethasone can induce damage to other neuronal populations. This issue was addressed using OX42 immunohistochemistry to visualise activated microglia and thereby gauge the extent of dexamethasone-induced neuronal death. A single dose of dexamethasone (20mg/kg, i.p.) administered to young male Sprague-Dawley rats induced a strong microglial reaction which was restricted to the striatum, the dentate gyrus and all of the CA subfields of the hippocampus. Some OX42-immunoreactive cells were also seen in the lateral septal nucleus. Subsequent quantitative analysis of silver/methenamine-stained sections confirmed that acute administration of dexamethasone induced apoptosis in the striatum and all regions of the hippocampus at doses as low as 0.7mg/kg. In contrast, dexamethasone failed to induce apoptosis in the lateral septal nucleus at doses up to 20mg/kg. The levels of dexamethasone-induced striatal and hippocampal apoptosis were attenuated by pretreatment with the corticosteroid receptor antagonist RU38486 (Mifepristone), which implies that the cell death was mediated by a corticosteroid receptor-dependent process. We further determined whether dexamethasone induced sublethal damage to neurons by quantifying reductions in the number of microtubule-associated protein-2-immunoreactive striatal and hippocampal cells following injection of the corticosteroid. Dexamethasone induced dramatic decreases in the striatum, with the dorsomedial caudate-putamen being particularly affected. Similar damage was seen in the hippocampus, with the dentate gyrus and CA1 and CA3 subfields being particularly vulnerable.Equivalent corticosteroid-induced neuronal damage may occur in mood disorders, where the levels of endogenous corticosteroids are often raised. Corticosteroid-induced damage of striatal and hippocampal neurons may also account for some of the cognitive deficits seen following administration of the drugs to healthy volunteers.

Animals↗
PubMed2002

Acute administration of haloperidol induces apoptosis of neurones in the striatum and substantia nigra in the rat.

Chronic administration of typical neuroleptics is associated with tardive dyskinesia in some patients. This dyskinetic syndrome has been associated with loss of GABAergic markers in the basal ganglia but the cause of these GABAergic depletions remains uncertain. Haloperidol, a commonly prescribed typical neuroleptic, is known to be toxic in vitro, possibly as a consequence of its conversion to pyridinium-based metabolites and potentially by raising glutamate-mediated transmission. We report here that the in vivo, acute administration of a large dose of haloperidol resulted in a microglial response indicative of neuronal damage. This was accompanied by an increase in the number of apoptotic cells in the striatum (especially in the dorsomedial caudate putamen) and in the substantia nigra pars reticulata. These apoptotic cells were characterised by the stereotaxic injection of a retrograde neuroanatomical tracer into the projection targets of the striatum and substantia nigra pars reticulata prior to the systemic injection of haloperidol. This procedure confirmed that the dying cells were neurones and demonstrated that within the striatum the majority were striatopallidal neurones though relatively high levels of apoptotic striatoentopeduncular neurones were also seen.The possibility that chronic administration of haloperidol could induce cumulative neuronal loss in the substantia nigra pars reticulata and thereby induce the pathological changes which lead to tardive dyskinesia is discussed.

Animals↗
PubMed2000

Microglial activation in the developing rat olfactory bulb.

The development of the olfactory bulb, the primary central relay of the olfactory system, is characterized by a striking susceptibility to alterations in the amount of afferent input. For example, blocking airflow through one half of the nasal cavity during early life results in a number of dramatic changes in the bulb, including increased cell death. Previous studies reveal high levels of microglia in the olfactory bulb. Microglia function as phagocytes, aid in synaptogenesis, and produce important trophic and cytotoxic factors. In response to a number of tissue perturbations, microglia undergo an activation process that includes, among other changes, the up-regulation of complement receptor 3. Interestingly, a previous study reported that naris closure had no effect on microglia in the bulb; however, the research did not distinguish the functional activation state of microglia. We further examined the role of microglia in the normally developing and olfactory-deprived rat bulb using immunohistochemical detection of complement receptor 3 as a measure of microglial activation. Expression of the receptor in the bulb is relatively high during postnatal development, in particular when compared to levels in cortical regions caudal to the olfactory bulb. In addition, naris closure performed on the day after birth (but not after the first postnatal month) increases levels of the receptor in an age and laminar-dependent fashion. The presence of an inducible pool of activated microglia in the olfactory bulb may be important for normal development and contribute to the plethora of changes seen after early olfactory deprivation.

Animals↗
PubMed2001

Glial reaction to volkensin-induced selective degeneration of central neurons.

Volkensin, a highly toxic protein retrogradely transported through axons, was used to target primary neuronal death in brainstem precerebellar relays after injection in the cerebellar cortex of rats. The reaction of astrocytes and microglia was studied with immunohistochemistry in the inferior olivary and pontine nuclei from 6 h to 14 days. Neurodegenerative features were evident since the first hours, especially in the pontine nuclei, and neuronal loss reached a plateau at 7 days in the inferior olive and at 10 days in the pons. Astrocytic activation, revealed by glial fibrillary acidic protein immunoreactivity, was concomitant with early signs of neuronal death and gradually increased. Microglia activation, revealed by OX-42 immunoreactivity, was evident at 2 days and became rapidly intense in precerebellar relays. At 1 week, marked ED-1 immunoreactivity also revealed phagocytic features of microglia, which persisted during the second week. In addition, major histocompatibility complex antigens (MHC) class I and II were induced in cells exhibiting microglial features. In the inferior olive, MHC I immunoreactivity was evident since 4 days and persisted at 14 days, whereas MHC II induction was intense at 7 days and subsided at 2 weeks. In the pontine nuclei high expression of both MHC antigens persisted instead at 14 days, probably reflecting the progression of neuronal death. Thus, targeted lethal injury of central neurons elicited prompt activation of both astrocytes and microglia; the marked microglia activation resulted in phagocytic features and immunophenotypic changes, with a temporal regulation that paralleled the evolution of neurodegenerative phenomena.

Animals↗
PubMed2003

Cycloheximide inhibits neurotoxic responses induced by kainic acid in mice.

In the present study, we examined the effect of cycloheximide on various pharmacological responses induced by kainic acid (KA) administered intracerebroventricularly (i.c.v.) in mice. In a passive avoidance test, a 20-min cycloheximide (200mg/kg, i.p.) pretreatment prevented the memory impairment induced by KA. The morphological damage induced by KA (0.1microg) in the hippocampus was markedly concentrated in the CA3 pyramidal neurons and cycloheximide effectively prevented the KA-induced pyramidal cell death in CA3 hippocampal region. In immunohistochemical study, KA dramatically increased the phosphorylation of extracellular signal-regulated protein kinase (p-ERK), c-Jun N-terminal kinase 1 (p-JNK1), and calcium/calmodulin-dependent protein kinase II (p-CaMK II). Cycloheximide attenuated the increased p-ERK, p-JNK1, and p-CaMK II levels induced by KA. Furthermore, cycloheximide inhibited the increased c-Fos and c-Jun protein expression levels induced by KA in the hippocampus. The activation of microglia was detected in KA-induced CA3 cell death region by immunostaining with a monoclonal antibody against the OX-42. Cycloheximide inhibited KA-induced increase of OX-42 immunoreactivity. Our results suggest that the increased expression of the c-Fos, c-Jun, and phosphorylation of ERK, JNK1, and CaMK II proteins may play important roles in the memory impairment and the cell death in CA3 region of the hippocampus induced by i.c.v. KA administration in mice. Furthermore, the activated microglia may be related to phagocytosis of degenerated neuronal elements induced by KA.

Animals↗
PubMed2002

Characterization of the promoter of human extracellular matrix metalloproteinase inducer (EMMPRIN).

Monocyte-derived macrophages play a central role in atherosclerotic lesion formation and potentially plaque destabilization by expression of matrix metalloproteinases (MMPs); however, mechanisms associated with stimulating MMP production are not clearly understood. EMMPRIN, which is expressed by human cancer cells and macrophages, present in human, mouse and rabbit atherosclerosis and noted to induce MMPs may be involved. A DNA fragment containing 1797 bp 5' upstream of the EMMPRIN gene and the transcription start site was generated by polymerase chain reaction and cloned into a luciferase reporter gene vector, pGL3-basic. The relative luciferase activities driven by this 5'-upstream fragment and a series of deletion mutants were measured in transiently transfected human and mouse macrophage THP-1 and Raw264.7 cells, respectively. A fragment 471 bp upstream of the EMMPRIN coding region was sufficient to promote transcription, while a region from -1413 to -1024 bp suppressed activity. Further deletion analysis of the 471 bp fragment indicated that a 30 bp element from -142 to -112 bp, which contains binding sites for Sp1, AP1TFII and EGR-2, was important for EMMPRIN transcription in both THP-1 and Raw264.7 macrophages. Using electrophoretic mobility shift assays, the Sp1 element within 30 bp region specifically bound Sp1 and Sp3 transcription factors. Mutation of the Sp1 element at -122 to -116 bp of the EMMPRIN promoter significantly diminished promoter activity and formation of DNA-nuclear protein complex. Transient expression of Sp1 and/or Sp3 transcription factors in insect cells lacking the Sp family of transcription factors, stimulated EMMPRIN promoter activity in a synergistic manner. Together, these results indicate that both Sp1 and Sp3 associate with the functional Sp1 element on the EMMPRIN promoter and cooperate in the regulation of EMMPRIN gene expression in macrophages.

Animals↗
PubMed2001

Alteration of Bcl-2 expression in the nigrostriatal system after kainate injection with or without melatonin co-treatment.

In order to understand further the role of the anti-apoptotic Bcl-2 proto-oncogene protein in excitotoxin-induced brain injury and possible interaction between Bcl-2 and the antioxidant melatonin, the expression of Bcl-2 in various brain parts was studied after intrastriatal injection of kainate (KA, 2.5 nmol) with or without co-treatment of melatonin (10 mg/kg, intraperitoneally (i.p.)). Three days after unilateral injection of KA to the striatum in the rat, a dramatic direct cytotoxic effect was observed, as indicated an expression of Bcl-2 immunoreactivity in TUNEL- and OX-42-positive cells in the KA-injected striatum and traumatized cortical region. A less severe detrimental effect was also observed in the ipsilateral substantia nigra and peritraumatic cortex, as reflected by an upregulation of Bcl-2-immunostained neurons. Surprisingly, a reduction in Bcl-2-immunoreactive neurons that was accompanied by a less severe loss of tyrosine hydroxylase-immunoreactive neurons in the nigrostriatal pathway was observed after co-treatment with melatonin. Western blot analysis confirmed that Bcl-2 expression is elevated in striatum and cortex on the lesioned side, and that its expression was attenuated substantially after systemic administration of melatonin. The results showing an upregulation of Bcl-2 in nigral neurons and reactive microglia after KA lesion are consistent with the view that Bcl-2 is protective in function in the central nervous system.

Actins↗
PubMed2000

Survival of hippocampal and cortical neurons in a mixture of MEM+ and B27-supplemented neurobasal medium.

Serum-free B-27 supplemented neurobasal (NB) and a 10% fetal bovine serum-supplemented Eagle's minimum essential medium (MEM+) are used to culture rat embryonic hippocampal neurons for different purposes. Although NB medium leads to enhanced cell survival, it contains biological antioxidants and is not suitable for the study of free radical damage and oxidation in cultured neurons. MEM+ without additional antioxidants has been used widely in the study of free radical damage and oxidation, although it does not support optimum neuronal survival in culture. Serum in MEM+ leads to enhanced cell survival but also promotes glial cell proliferation. In this study, we used a new combination medium (NM-2) that consists of both NB and MEM+ for growing primary hippocampal and cortical neuronal cultures. NM-2 enhanced neuronal survival 78.9% for dissociated neurons at a density of 50 cells/mm(2) and 83.1% for 100 cells/mm(2), while decreasing glial cell proliferation to 2-3% and completely inhibiting oligodendrocytes. The NM-2 minimized the effectiveness of antioxidants in the medium to the neurotoxin 4-hydroxynonenal. It also decreased neuronal clumping and provided a more even distribution of neurons. Neurons survived for 4 weeks in NM-2 without changing the original medium. NM-2 provides a good environment for studies of free radical damage and oxidation of neurons. The combination incorporates the best of both NB and MEM+ that results in high neuron survival rate, low glial cell proliferation, reduced antioxidant level, and provides relatively pure cultures of hippocampal and cortical neurons.

Animals↗
PubMed2000

Expression patterns of chondrocyte genes cloned by differential display in tibial dyschondroplasia.

Tibial dyschondroplasia (TD) appears to involve a failure of the growth plate chondrocytes within growing long bones to differentiate fully to the hypertrophic stage, resulting in a mass of prehypertrophic chondrocytes which form the avascular TD lesion. Many biochemical and molecular markers of chondrocyte hypertrophy are absent from the lesion, or show reduced expression, but the cause of the disorder remains to be identified. As differentiation to the hypertrophic state is impaired in TD, we hypothesised that chondrocyte genes that are differentially expressed in the growth plate should show altered expression in TD. Using differential display, four genes, B-cadherin, EF2, HT7 and Ex-FABP were cloned from chondrocytes stimulated to differentiate to the hypertrophic stage in vitro, and their differential expression confirmed in vivo. Using semi-quantitative RT-PCR, the expression patterns of these genes were compared in chondrocytes from normal and TD growth plates. Surprisingly, none of these genes showed the pattern of expression that might be expected in TD lesion chondrocytes, and two of them, B-cadherin and Ex-FABP, were upregulated in the lesion. This indicates that the TD phenotype does not merely reflect the absence of hypertrophic marker genes, but may be influenced by more complex developmental mechanisms/defects than previously thought.

Animals↗
PubMed2003

Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration.

The present study was designed to examine whether expression of iNOS was involved in LPS-induced neurodegeneration in rat substantia nigra (SN) and to study the role of NO in the loss of the SN dopaminergic neurons. In Western blot analysis, iNOS was induced in the SN after injection of LPS in a time- and dose-dependent manner. Immunofluorescence and immunohistochemical analyses revealed that the iNOS is located in a fully activated microglia with the characteristic amoeboid morphology. Furthermore, LPS-induced loss of dopaminergic neurons was significantly inhibited by the administration of L-N(G)-nitroarginine, a selective inhibitor of NOS, and the glucocorticoid dexamethasone. These inhibiting agents for iNOS reduced LPS-induced microglial activation, suggesting that NO has a role in inflammatory-mediated microglial activation. These results demonstrate that LPS induces the expression of iNOS in activated microglia in the SN, and that NO and/or its metabolites may play a crucial role in inflammation-mediated degeneration of dopaminergic neurons.

Animals↗
PubMed2003

Microglial activation and cell death induced by the mitochondrial toxin 3-nitropropionic acid: in vitro and in vivo studies.

Metabolic impairment of neurons has been implicated in several neurological disorders, but it is not at present known whether such metabolic impairment has deleterious effects on microglia, the phagocytic cells of the central nervous system (CNS). In the present study, we examined whether metabolic impairment induced by 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, affects the function and viability of microglia in vitro and in vivo. Treatment of HMO6 human microglia cell line with 3-NP induced the elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) and activation of microglia with production of reactive oxygen species (ROS). Exposure of HMO6 cells to 3-NP also induced cell death as indicated by nuclear fragmentation in a dose- and time-dependent manner. Trolox, an antioxidant agent, was effective in reduction in ROS production and cell death caused by 3-NP. Consistent with in vitro findings, intrastriatal injection of 3-NP in adult rats resulted in an increase in ROS production in microglia in vivo, as evidenced by the oxidation of the reduced MitoTracker probe. ROS production induced by 3-NP was inhibited when trolox was coinjected with 3-NP. Caspase-3 immunoreactivity was demonstrated in OX-42+ microglia in the core and penumbra area of the 3-NP-injected striatum. Apoptotic cell death of microglia was also demonstrated by terminal deoxynucleotidyl- transferase-mediated biotin-dUTP nick end labeling reaction in the 3-NP-induced lesion area. The present results indicate that metabolic impairment in the CNS could involve both activation and cell death of microglia and contribute to pathology in neurodegenerative diseases.

Animals↗
PubMed2002

Acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system.

BACKGROUND: A cascade of inflammatory reactions characterize acute vascular rejection after heart transplantation. This study was undertaken to test the hypothesis that acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system. METHODS: Acute vascular rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of acute vascular rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for alphavbeta3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN). RESULTS: Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p < 0.001), tissue factor (1.8-fold, p < 0.001), and EMMPRIN (1.5-fold, p < 0.001). All patients in the AVR group received plasmapheresis; 11 of 14 patients had evidence of ischemic necrosis on biopsy specimens, and 3 of 14 patients experienced hemodynamic compromise and graft dysfunction and died within 3 weeks of transplant. Another patient died at 10 months after transplant. CONCLUSIONS: Acute vascular rejection is associated with up-regulation of alphavbeta3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.

Acute Disease↗
PubMed2000

An improved method for avulsion of lumbar nerve roots as an experimental model of nitric oxide-mediated neuronal degeneration.

A root avulsion lesion on the spinal nerve of adult animals is a useful technique to make a model for axotomy-induced motoneuronal degeneration, which is thought to be mediated by nitric oxide (NO). Here, we show a simplified version of extravertebral avulsion in the young adult rat. The L4 nerve always runs under the transverse process of the L5 vertebra, which is located just rostral to the delineation of the iliac crest. We used the iliac crest as a clue for the identification of the L4 nerve during surgery, including before skin incision. In almost all animals the L4 nerve was successfully avulsed at the exit point from the spinal cord. This experimental result was similar to that shown in the previous literature; the number of either Nissl-stained or ChAT-immunoreactive (-ir) motoneurons (MN) gradually decreased, while NOS immunoreactivity was induced in the MN after avulsion. Furthermore, a combined method of confocal laser scanning microscopy and double fluorescent procedures carried out in this model suggested the existence of cellular interaction between NOS-ir MN and OX42-ir or ED1-ir microglia. It is concluded that this simple and fast method of spinal root avulsion is very useful for making a reproducible model of NO-mediated MN cell death, with which the mechanism of neuronal cell death, including neuron-glia interaction, can be further explored.

Animals↗
PubMed2002

EMMPRIN-mediated MMP regulation in tumor and endothelial cells.

Tumor invasion and metastasis are multistep processes which require extracellular matrix remodeling by proteolytic enzymes such as matrix metalloproteinases (MMPs). The production of these enzymes is stimulated by many soluble or cell-bound factors. Among these factors, extracellular matrix metalloproteinase inducer (EMMPRIN) is known to increase in vitro stromal cell production of MMP-1, MMP-2 and MMP-3. In this study, we demonstrated that EMMPRIN-transfected MDA-MB-436 tumor cells displayed a more invasive capacity than vector-transfected cells in a modified Boyden chamber invasion assay. Using gelatin zymography and protein analyses, we showed that EMMPRIN-transfected cancer cells produced significantly more latent and active MMP-2 and MMP-3 than vector-transfected cancer cells. We found that EMMPRIN did not regulate MMP-1, MMP-9, membrane type-1 MMP (MT1-MMP) expression and had also no effect on the production of the specific tissue inhibitors of MMPs (TIMPs), TIMP-1 and TIMP-2. We also demonstrated that tumor-derived EMMPRIN stimulated MMP-1, -2, and -3 without modification of MMP-9, MT1-MMP, TIMP-1 and TIMP-2 production in human umbilical vein endothelial cells (HUVEC). These data provide support for the role of EMMPRIN in tumor invasion, metastasis, and neoangiogenesis by stimulating extracellular matrix remodeling around tumor cell clusters, stroma, and blood vessels.

Antigens, CD↗
PubMed2002

Microglial changes accompanying the promotion of retinal ganglion cell axonal regeneration into peripheral nerve grafts.

Intravitreal injection of the microglia inhibitor tuftsin 1-3 leads to an increase in retinal ganglion cell axonal regeneration into peripheral nerve grafts and a decrease in phagocytic cells in the retina. However, the relation of phagocytic cells and particularly microglia towards axonal regeneration remains unclear. Initially, to assess this, tuftsin 1-3's effect on axonal regeneration was reexamined by doing a dose-response study. Optimal doses were found to be 2.5 microg/ml and 250 microg/ml in rats and hamsters respectively. We then studied retinal phagocytic cells in rats. Microglial cells were classified as resting or activated based on their morphology following OX42 immunolabelling. In controls, most microglial cells were in the resting state. Optic nerve cut led to an increase in the total number of microglia and a ten-fold elevation in the proportion of activated cells; changes were more pronounced at the optic nerve stump. Anastomosis of an autologous segment of sciatic nerve to the stump of the freshly cut optic nerve minimized the overall increase in microglia, and combined with 2.5 microg/ml tuftsin 1-3, lead to a marked blunting of activation. Preservation within the retina of a higher proportion of resting over active form of microglia, and not the prevention of microglial proliferation per se, may be a crucial factor in allowing additional retinal ganglion cell axons to regenerate into peripheral nerve grafts.

Animals↗
PubMed2003

EMMPRIN (extracellular matrix metalloproteinase inducer) is a novel marker of poor outcome in serous ovarian carcinoma.

EMMPRIN is a member of the immunoglobulin superfamily of adhesion molecules and has a role in the activation of several matrix metalloproteinases (MMP). The objective of this study was to investigate the expression of EMMPRIN in effusions, primary and metastatic tumors of serous ovarian carcinoma patients, as well as to evaluate its association with clinicopathologic parameters and with MMP and integrin expression. Eighty effusions and eighty-three solid lesions were evaluated for expression of EMMPRIN mRNA using in situ hybridization (ISH). Protein expression was studied in 75 effusions and 55 biopsies using immunohistochemistry (IHC). EMMPRIN mRNA and protein were detected in carcinoma cells in 63/80 (79%) and 64/75 (85%) effusions, respectively. Expression was similar in peritoneal and pleural effusions. EMMPRIN was co-expressed with MMP-1 (P < 0.001), MMP-9 (P = 0.006) and the alphav (P = 0.013) and beta1 (P = 0.029) integrin subunits. In solid lesions, EMMPRIN localized most often to tumor cells (51/83 using ISH, 51/55 using IHC), but was also expressed in stromal and endothelial cells in approximately one third of the cases. EMMPRIN mRNA expression in tumor cells was most frequent in peritoneal metastases (P = 0.03). EMMPRIN expression in carcinoma cells of solid tumors showed an association with that of MMP-9 (P = 0.018), while labeling of stromal cells showed co-localization with the beta1 integrin subunit (P = 0.043). In survival analysis, EMMPRIN protein expression in stromal cells of primary tumors (P = 0.012) and in endothelial cells of all solid tumors (P = 0.023) correlated with poor survival. In conclusion, EMMPRIN is a novel prognostic marker in ovarian carcinoma, and is co-expressed with other metastasis-associated molecules in this malignancy. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence to our theory that cells at these sites share similar genotypic and phenotypic profiles.

Adult↗
PubMed2000

Topographic representation of the sciatic nerve motor neurons in the spinal cord of the adult rat correlates to region-specific activation patterns of microglia.

The frequent use of the adult rat sciatic nerve as a model to study the neuronal responses to injury, nerve regeneration and in transplantation studies, requires a detailed knowledge of the projection pattern of motor neurons into this nerve. Thus, as a first goal we determined this topographical projection of motor neurons and labelled small contingents by applying the fluorescent dye DiI in localised incisions made in the dorsal, rostral, ventral or caudal quadrants of the nerve. As a second goal we analysed with immunohistochemical methods the response of microglial cells within the topographical area corresponding to the incision and within areas outside this location. Uptake of the dye occurred only within the area confined to the incision, thus allowing the identification of the corresponding motor neuron perikarya within the ventral horn, eight to ten days later. In serial transverse sections of the lumbosacral spinal cord the number of labelled cells, their position within the ventral horn, and their longitudinal extent have been determined. The data suggest that the gross projection of the lumbosacral motor neuron column at the mid-thigh level of the sciatic nerve is topographic. In accordance, microglial cells showed fast activation within the injured topographic area, and a less pronounced and delayed response within the non-injured areas of the ventral horn. The graded response of microglial cells suggests that these cells possess a potential of local activation by sensing whether neurons are axotomised or just irritated by axotomy of their neighbours. The topographic organisation proves to be useful in studies on local injuries to the sciatic nerve and when analysing retrograde responses within the lumbosacral spinal cord.

Animals↗