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Rat islet homogenates display both phosphoglycerate 2,3-mutase and enolase activities. When phosphoglycerate 2,3-mutase is activated by 2,3-diphosphoglycerate, the reaction velocity becomes close to that of enolase. The islet content in 2,3-diphosphoglycerate is sufficiently high to allow virtually full activation of phosphoglycerate 2,3-mutase.
The highly sialylated isoform of the neural cell adhesion molecule is thought to be expressed predominantly in the developing nervous system, where it is implicated in a variety of dynamic events linked to neural morphogenesis. It has become increasingly evident, however, that this "embryonic" neural cell adhesion molecule isoform continues to be expressed in certain adult neuronal systems, and in particular, in those that can undergo structural plasticity. In the present study, we performed light microscopic immunocytochemistry with an antibody specific for polysialylated neural cell adhesion molecule and confirmed our earlier observations [Bonfanti L. et al. (1992) Neuroscience 49, 419-436] showing polysialylated neural cell adhesion molecule-immunoreactive cells in the subependymal layer of the lateral ventricle of the adult rat, a region where cell proliferation continues into the postnatal period. In addition, we used an antibody raised against the proliferating cell nuclear antigen and found that proliferating cells continue to be visible in this area, even in the adult. Double immunolabeling showed that many of these newly generated cells displayed high polysialylated neural cell adhesion molecule immunoreactivity. Cells from a portion of the subependymal layer migrate to the olfactory bulb and contribute to the continual replacement of its granule neurons [Luskin M. B. (1993) Neuron 11, 173-189]. We found polysialylated neural cell adhesion molecule-immunoreactive cells all along the pathway purported to be followed by the newly generated cells to their final destination and in neurons corresponding to granular and periglomerular cells in the olfactory bulb. Our present observations thus support the contention that polysialylation is a feature of neurons capable of dynamic change and may contribute to the molecular mechanisms permitting cell proliferation and migration not only during development but also in the adult.
The role of taurine in the process of neuronal migration was studied in a microwell cell culture system. Immunocytochemical analysis of the cellular composition of this culture system revealed the presence of the astrocytic marker GFAP in some structures such as the aggregates of neuronal bodies and in those cables used for migration, resembling what is described in vivo. The neuronal marker gamma-enolase stained practically all structures, including the aggregates and all cables. The intracellular taurine concentration was reduced by 60% in mouse cerebellar granule cells treated with a blocker of taurine transport, guanidinoethane sulfonate (GES). Under these conditions cell migration was markedly reduced to approximately 50% of that in untreated cultures. Both, taurine depletion and impairment of cell migration induced by GES were prevented by adding taurine to the culture medium. Taurine deficiency similarly affected different morphological parameters such as the number of cables suitable for neuronal migration as well as the number of migrating neurons. The number of aggregates of neuronal bodies was significantly increased, by about 30%, as a consequence of the reduced migration. Taurine alone did not exert any effect on the parameters evaluated. GES treatment of granule cells did not affect mitochondrial metabolism or K(+)-stimulated Ca(2+)-dependent [3H]-D-aspartate release. This suggests that the described effects of taurine deficiency were not due to an alteration of neuronal viability and that the action of GES was not simply due to unspecific and deleterious effects. These results are in agreement with those obtained in in vivo studies. This approach represents a useful model to investigate the role played by taurine in the process of neuronal migration.
We have previously shown that electrolytic lesion-induced neurogenesis in the ventromedial nucleus of the hypothalamus (VMN) is significantly correlated with the recovery of courtship behavior in adult male ring doves. Here we revealed that reduction of lesion-induced neurogenesis in VMN impaired the behavioral recovery suggesting therefore a causal link between neurogenesis and behavioral recovery. Our results lend support that adult neurogenesis is latent in repair of injured brain.
We determined whether pentobarbital anesthetic is required to culture postmortem adult rat neurons. Pentobarbital treatment resulted in two-fold increases in neuron survival in culture after 2 and 4 h postmortem compared to non-anesthetic controls, but was not as effective as simple postmortem treatment on ice and therefore not essential.
Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders than men. The course of a depression is thought to be positively influenced by social support. We have used a chronic stress model in which rats received foot-shocks daily for 3 weeks. Since rats are social animals we hypothesised that 'social support' might reduce the adverse effects of chronic stress. To test this hypothesis, male and female rats were housed individually or socially in unisex groups of four rats. The proliferation marker bromodeoxyuridine (BrdU) was injected 2 weeks before the sacrifice to investigate if stress and social housing influenced the survival of proliferating cells in the dentate gyrus (DG). To investigate changes in proliferation, another group of rats was sacrificed the day after the last BrdU injection. Stress significantly decreased BrdU labelling in individually housed males and not significantly in socially housed males. In individually housed females stress increased BrdU labelling, which was prevented by social housing. The increase found in females is most likely caused by differences in survival rate, since cell proliferation was not affected by stress or housing conditions. These results indicate that social support can affect neurogenesis in both female and male rats, however in a different way.
Most regions of the mature mammalian brain, including the cerebral cortex, appear to be unable to support the genesis of new neurons. Here, we report that a low level of neurogenesis occurs in the cerebral cortex of the infant mouse brain and is enhanced by chronic perinatal hypoxia. When mice were reared in a low-oxygen environment from postnatal days 3 to 11, approximately 30% of the cortical neurons were lost after the insult; yet this damage was transient. The loss of cortical neuron number, cortical volume, and brain weight were all reversed during the recovery period. At P18, 7 days after the cessation of hypoxia, there was a marked increase in astroglial cell proliferation within the SVZ, as assessed by 5-bromodeoxyuridine (BrdU) incorporation in S-phase cells. One month after BrdU incorporation, 40% more BrdU-positive cells were found in the cerebral cortex of hypoxic-reared as compared to normoxic control mice. Among these newly generated cortical cells, approximately 45% were oligodendrocytes, 35% were astrocytes, and 10% were neurons in both hypoxic and normoxic mice. However, twice as many BrdU-labeled cells expressed neuronal markers in the neocortex in mice recovering from hypoxia as compared to controls. In both hypoxic-reared and normoxic infant/juvenile mice, putative neuroblasts could be seen detaching from the forebrain subventricular zone, migrating through the subcortical white matter and entering the lower cortical layers, 5 to 11 days after their last mitotic division. We suggest that cortical neurogenesis may play a significant role in repairing neuronal losses after neonatal injury.
Neuroblastoma (NB) is uncommon in the adolescent age group. It is located at any site containing sympathetic neural tissue, with retroperitoneal and adrenal lesions being the most common. Cutaneous and subcutaneous metastases of NB in children are infrequent. Primary thyroid NB with regional lymph node and distant multiple subcutaneous metastases was diagnosed in an 11-year-old boy. The differential diagnosis was primitive neuroectodermal tumor. Our case demonstrates the unique presentation of NB in an adolescent.
Electroconvulsive therapy is considered one of the most effective treatments of major depression, but controversy still exists on whether it may be brain damaging. The aim of this work was to evaluate the cerebrospinal fluid (CSF) levels of neuron specific enolase (NSE), protein S100B and lactate of rats submitted to acute and chronic models of ECS. Rats were submitted to either one shock (acute) or a series of eight shocks, applied one at every 48 h (chronic). CSF samples were collected at 0, 3, 6, 12, 24, 48 and 72 h after the shock in the acute model and at these same time intervals after the last shock in the chronic model. Both models did not produce significant alterations in the levels of NSE. S100B levels were significantly increased at 6 h in the chronic model (p<0.0001). There was a significant increase in the levels of lactate at 0 h in both models (p<0.001). These results support the proposition that ECS does not produce neural damage, and suggest that the alterations in the levels of S100B and lactate may reflect an astrocytic activity of a protective nature.
The tremor rat is a spontaneous epilepsy model with a seizure phenotype caused by a deletion in the aspartoacylase (ASPA) gene. The absence of ASPA expression in these animals results in undetectable levels of enzyme activity and the accumulation of the substrate N-acetyl-aspartate (NAA) in brain, leading to generalized myelin vacuolation and severe motor and cognitive impairment. In support of human gene therapy for CD, recombinant adeno-associated viral vector (AAV-2) expressing ASPA was stereotactically delivered to the tremor rat brain and effects on the mutant phenotype were measured. AAV-ASPA gene transfer resulted in elevated aspartoacylase bioactivity compared to untreated mutant animals and elicited a significant decrease in the pathologically elevated whole-brain NAA levels. Assessment of motor function via quantitative rotorod testing demonstrated that rats injected with AAV-ASPA significantly improved on tests of balance and coordinated locomotion compared to animals receiving control vectors. This study provides evidence that AAV-2-mediated aspartoacylase gene transfer to the brain improves biochemical and behavioral deficits in tremor rat mutants (tm/tm) and supports the rationale of human gene transfer for Canavan disease.
Na(+)-K(+)-Cl(-) cotransporter has been proposed to play an important role in the regulation of intracellular Cl(-) concentration in neurons during development. In this study, the expression pattern of the cotransporter in different regions of rat brain was examined at birth (P0), postnatal days 7 (P7), P14, P21, and adult by Western blotting analysis. In cortex, thalamus, cerebellum and striatum, the cotransporter expression level was low at P0 and significantly increased at P14 (P<0.05). The expression peaked at P21 and was maintained at the same level in adulthood. However, in hippocampus, a peak level of the cotransporter expression was detected in adult brain. The immunocytochemistry study of adult rat brain revealed that an intense staining of the Na(+)-K(+)-Cl(-) cotransporter protein was observed in dendritic processes of CA1-CA3 hippocampal pyramidal neurons. In contrast, abundant immuno-reactive signals of the cotransporter were found in somata of thalamic nucleus. Immunofluorescence double staining demonstrates that the Na(+)-K(+)-Cl(-) cotransporter was expressed in astrocytes within cortex, corpus callosum, hippocampus and cerebellum. In addition, co-localization of the cotransporter and glial fibrillary acidic protein (GFAP), or with aquaporin 4, was found in perivascular astrocytes of cortical cortex and white matter. The results indicate that a time-dependent expression of the Na(+)-K(+)-Cl(-) cotransporter protein occurs not only in cortex but also in hippocampus, striatum, thalamus and cerebellum. In addition, the cotransporter is expressed in astrocytes and perivascular astrocytes of adult rat brain.
Leukocyte infiltration of the CSF and brain parenchyma and other parameters of inflammation during pneumococcal meningitis were investigated after reduction of meningeal macrophages in rabbits by intracisternal injection of dichloromethylene-diphosphonate (Cl2MDP)-containing liposomes. Macrophages in the meninges were reduced, in median, by approximately 77% after three intrathecal injections of 100 microl of liposomes containing Cl2MDP at 12 h intervals. Production of the cytokines interleukin-1 and tumor necrosis factor-alpha as well as infiltration of the CSF and nervous tissue by leukocytes was not significantly altered in infected animals after treatment with Cl2MDP-containing liposomes. The median CSF concentration of neuron specific enolase (NSE) as a parameter of neuronal damage was higher in infected Cl2MDP-treated animals (median [median (25th/75th percentiles): 44.7 (33.2/54.3) microg/l vs. 13.9 (10.4/23.9) microg/l; P = 0.01]). Therefore, the reduction of meningeal macrophages does not appear to attenuate inflammation in the subarachnoid space in experimental pneumococcal meningitis. Meningeal macrophages seem, however, to be important for the protection of neuronal tissue in bacterial meningitis.
The neuroendocrine (NE) cell is a minor cell population in normal human prostate glands. The number of NE cells is increased in advanced hormone-refractory prostate carcinomas (PCA). The mechanism of increased NE cell population in these advanced tumors is poorly understood. We examined molecular mechanisms which may be involved in the regulation of the transdifferentiation process of human PCA cells leading to a NE phenotype. We compared PCA cell lines LNCaP and PC-3 in the following medium conditions: steroid-reduced (SR), interleukin-6 (IL-6)-supplemented, or dibutyrate cAMP (db-cAMP)-supplemented. We found that androgen-responsive C-33 LNCaP cells responded to all treatments, having a neuronal-like morphology. In contrast, C-81 LNCaP cells, having a decreased androgen responsiveness, had a less pronounced effect although followed a similar trend. Androgen-unresponsive PC-3 cells showed little change in their morphology. Grown in the SR condition, the level of neuron-specific enolase (NSE), a marker of neuronal cells, was upregulated in C-33 LNCaP cells, while to a lesser degree in the presence of IL-6. In the presence of db-cAMP, the NSE level in C-33 cells was decreased, lower than that in control cells. An opposite effect was observed for C-81 LNCaP cells. Nevertheless, the NSE level was only elevated in db-cAMP-treated PC-3 cells, but no change was found in PC-3 cells grown in the SR- or IL-6-supplemented medium. Thus, a similar gross phenotypic change may correlate with differential molecular expressions. We also analyzed the expression of protein tyrosine phosphatase alpha (RPTPalpha) since it plays a critical role in normal neuronal differentiation and signaling. Our results showed that the expression of RPTPalpha correlates with the NE phenotypic change of LNCaP cells in the SR condition. In summary, our data clearly show that the molecular process by which cultured human prostate cancer cells undergo a transdifferentiation process to a NE cell-like phenotype is accompanied by differential expressions of different markers, and a gross NE cell-like phenotype can occur by exposing PCA cells to different pharmacological agents.
Developing human fetal salivary glands of gestational age from 10 to 40 weeks (n = 100) and normal adult glands (n = 10) were examined for immunoreactivity to S-100 protein and its subunits S-100 alpha, S-100 beta, glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE). In the early intermediate developmental stage (19-32 weeks) some acinar basal cells showed immunoreactivity to S-100 protein which rapidly disappeared in the late developmental stage (33-40 weeks). Adult salivary glands were negative for S-100 protein. The S-100 alpha subunit was strongly positive in the glandular ducts and acini of both fetal and adult glands. The S-100 beta, although present in some acini and ductal cells during the late intermediate developmental stage, was rarely seen in the adult glands. GFAP and NSE was positive at the developing salivary epithelium in the early developmental stage (15-18 weeks). The above findings indicated that the developing salivary epithelia showed transient appearance of the neuronal phenotype during active cytodifferentiation stage of glandular acini and ducts. Therefore, after evaluation of normal developmental and neoplastic transformation of the salivary glands a suggestion that neuronal differentiation of ductal reserve cells is responsible for the production of modified myoepithelial cells in both normal developmental salivary gland and neoplastic transformation is made.
The histological, immunohistochemical and electron microscopic features of a rare malignant granular cell tumor (GCT) arising in the left radial nerve of a 54-year-old man are reported. Despite a lack of local recurrence following extirpation, the tumor metastasized to the skull five years later. Light-microscopically, both primary and metastatic tumors consisted of markedly atypical or pleomorphic neoplastic cells with abundant cytoplasm containing diastase-resistant periodic acid Schiff reaction-positive granules. These tumor cells were arranged in a sheet-like pattern with mitotic figures including atypical ones, and were frequently immunopositive for proliferating cell nuclear antigen and c-MET, the c-met proto-oncogene product. These findings reflect high-grade malignancy of the present tumor. In addition, the tumor cells were positive for S-100 protein and neuron-specific enolase. Ultrastructurally, a large number of intracytoplasmic granules featuring secondary lysosomes as well as long interdigitating cytoplasmic processes, intercellular intermediate junctions, discontinuous basal lamina-like structures, and stromal long-spacing collagen were observed. These findings indicated schwannian differentiation of the present tumor. In addition, based on a review of previously reported cases, the overall clinicopathological characteristics of malignant GCT were summarized.
Two cases of TS associated with brain tumors had severe psychomotor retardation and early onset of long-term intractable convulsions, compared with cases without tumors. In one case, the tumor was partially cystic and progressed rapidly. Immunohistochemical studies of neuron specific enolase, glial fibrillary acidic protein and myelin basic protein revealed differences in positivity between cell types and between cases. These results suggested that the origin of the tumor cells could be variably differentiated cells.
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It has been proposed that the therapeutic benefits of treatment with antidepressants and mood stabilizers may arise partially from their ability to stimulate neurogenesis. This study was designed to examine the effects of chronic antipsychotic treatment on cell proliferation and survival in the adult rat hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU, 200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h following BrdU administration and BrdU-positive cells were quantified to assess the effects of drug treatment on cell proliferation. The remaining animals continued on antipsychotic medication for an additional 3 weeks following BrdU administration to assess the effects of antipsychotics on cell survival. Our results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus (DG) by two-fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell proliferation in DG. Moreover, neither drug at either dose had an effect on the number of newly generated neurons surviving in the DG 3 weeks following BrdU administration. These preliminary findings suggest that clozapine may influence the number of cells which divide, but antipsychotics do not promote the survival of the newly generated neurons at 3 weeks after a BrdU injection.