Location matters: highly divergent protein levels in samples from different CNS compartments in a clinical trial of rituximab for progressive MS.

BACKGROUND: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared. METHODS: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively. RESULTS: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman's rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF. CONCLUSION: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.

A new MRI tag-based method to non-invasively visualize cerebrospinal fluid flow.

PURPOSE: Abnormal cerebrospinal fluid (CSF) dynamics can produce a number of significant clinical problems to include hydrocephalus, loculated areas within the ventricles or subarachnoid spaces as well as impairment of normal CSF movement between the cranial and spinal compartments that can result in a cerebellar ectopia and hydrosyringomyelia. Thus, assessing the patency of fluid flow between adjacent CSF compartments non-invasively by magnetic resonance imaging (MRI) has definite clinical value. Our objective was to demonstrate that a novel tag-based CSF imaging methodology offers improved contrast when compared with a commercially available application. METHODS: In a prospective study, ten normal healthy adult subjects were examined on 3T magnets with time-spatial labeling inversion pulse (Time-SLIP) and a new tag-based flow technique-time static tagging and mono-contrast preservation (Time-STAMP). The image contrast was calculated for dark-untagged CSF and bright-flowing CSF. We tested the results with the D'Agostino and Pearson normality test and Friedman's test with Dunn's multiple comparison correction for significance. Separately 96 pediatric patients were evaluated using the Time-STAMP method. RESULTS: In healthy adults, contrasts were consistently higher with Time-STAMP than Time-SLIP (p < 0.0001, in all ROI comparisons). The contrast between untagged CSF and flowing tagged CSF improved by 15 to 34%. In both healthy adults and pediatric patients, CSF flow between adjacent fluid compartments was demonstrated. CONCLUSIONS: Time-STAMP provided images with higher contrast than Time-SLIP, without diminishing the ability to visualize qualitative CSF movement and between adjacent fluid compartments.

Intrathecal lactate predicting hydrocephalus after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Evidence shows possible benefits from continuous drainage by lumbar drain after aneurysmal subarachnoid hemorrhage (SAH). Under the hypothesis that compartmentalization occurs between the ventricle and subarachnoid space after massive SAH, this study aimed to evaluate the biochemical differences between ventricular and intrathecal cerebrospinal fluid (CSF) and assess the role of CSF lactate in shunt-dependent hydrocephalus (SDHC) after aneurysmal SAH. MATERIALS AND METHODS: Patients with modified Fisher grade III/IV aneurysmal SAH who underwent early obliteration were evaluated. Intrathecal and intraventricular CSF were obtained on day 7 post-SAH to measure their biochemical composition in terms of total protein, glucose, ferritin, and lactate. The associations of SDHC with the clinical parameters and CSF data were analyzed. RESULTS: There were 28 patients (mean age, 55.4 y; males, 46.6%), including 18 (64.3%) with SDHC. Intrathecal CSF had significantly higher levels of total protein, ferritin, hemoglobin, and lactate but lower glucose level than intraventricular CSF (all P < 0.0001). By multivariate analysis of clinical and CSF parameters, elevated intrathecal CSF lactate (P = 0.036) and the presence of intraventricular hemorrhage (P = 0.05) were independent factors associated with SDHC. Moreover, intrathecal lactate >5.5 µM effectively predicted the occurrence of SDHC (odds ratio: 32, 95% confidence interval: 3.8-270.8; P = 0.0015). CONCLUSIONS: By compartmentalization of the subarachnoid space after SAH, intrathecal lactate level is a useful predictive parameter for long-term SDHC in patients with aneurysmal SAH patients.

Neuroprotein dynamics in the cerebrospinal fluid: intraindividual concomitant ventricular and lumbar measurements.

OBJECTIVE: The measurement of neuromarker/neuroproteins in the cerebrospinal fluid (CSF) is gaining increased popularity. However, insufficient information is available on the rostrocaudal distribution of neuroproteins in the CSF to guarantee an appropriate interpretation of ventricular versus lumbar concentrations. METHODS: In 10 patients treated with both an external ventricular and a lumbar CSF drain, we collected concomitant CSF samples. We measured CSF concentrations of the glial S100B protein, the neuron-specific enolase (Cobas e411®; Roche Diagnostics), the leptomeningeal ß-trace protein (BN Pro Spec®; Dade Behring/Siemens), and the blood-derived albumin (Immage; Beckman Coulter). Statistical analysis was performed with a paired Wilcoxon signed ranks test. RESULTS: In patients with a free CSF circulation without any recent neurosurgical procedure, S100B and neuron-specific enolase concentrations did not differ between the ventricular and lumbar CSF while ß-trace and albumin levels were significantly higher in the lumbar than in the ventricular CSF (p=0.008 and p=0.005). Following posterior fossa tumor surgery, all proteins accumulate in the lumbar CSF. CONCLUSION: For brain-derived proteins, we could not confirm a rostrocaudal CSF gradient while lepto-meningeal and blood-derived proteins accumulate in the lumbar CSF. We conclude that for the interpretation of protein CSF concentrations, the source of the sample is of crucial importance.

GABA(A) receptor characterization and subunit localization in the human sub-ventricular zone.

It is now well established that the human brain continuously produces new stem cells until well into old age. One of these stem-cell rich areas in the human brain is the sub-ventricular zone (SVZ). The human SVZ is organized in four distinctive layers containing type A, B and C cells. To date, no studies have investigated the distribution of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) and their respective receptors on the different cell types in the human SVZ. GABA(A) receptors (GABA(A)R) are ubiquitously expressed, inhibitory heteropentameric chloride ion channels comprised of a variety of subunits that are targeted by many prescribed drugs. In this study we present detailed immunohistochemical data on the regional and cellular localization of α1, α2, α3, ß2,3 and γ2 subunits of GABA(A)R in the human SVZ. The results from our double and triple labeling studies demonstrate that the cell types and subunit composition throughout the SVZ is heterogeneous; the thickness of the SVZ and GABA(A)R α2 and γ2 expression is increased especially in the vicinity of large SVZ blood vessels. GABA(A)R γ2 is the most specific to the SVZ and present on various cells that express, either glial fibrillary acidic protein (GFAPδ) or polysialic acid-neural cell adhesion molecule (PSA-NCAM) separately, or together in a respective ratio of 7:6:2. Proliferating (type C) cells in the SVZ express GAD65/67, GFAPδ and GABA(A)R ß2,3 receptor subunits. Within the SVZ the majority of cells have an unexpected nuclear GABA(A)R ß2,3 expression that is inversely proportional to that of PCNA (proliferating cell nuclear antigen marker), which is a very different pattern of expression compared with underlying caudate nucleus cells. Taken together our results provide a detailed description of the chemo-architecture of the adult human SVZ demonstrating the importance of GABA and GABA(A) receptors on the various cell types in the SVZ.

Manual drainage of the zebrafish embryonic brain ventricles.

Cerebrospinal fluid (CSF) is a protein rich fluid contained within the brain ventricles. It is present during early vertebrate embryonic development and persists throughout life. Adult CSF is thought to cushion the brain, remove waste, and carry secreted molecules(1,2). In the adult and older embryo, the majority of CSF is made by the choroid plexus, a series of highly vascularized secretory regions located adjacent to the brain ventricles(3-5). In zebrafish, the choroid plexus is fully formed at 144 hours post fertilization (hpf)(6). Prior to this, in both zebrafish and other vertebrate embryos including mouse, a significant amount of embryonic CSF (eCSF) is present . These data and studies in chick suggest that the neuroepithelium is secretory early in development and may be the major source of eCSF prior to choroid plexus development(7). eCSF contains about three times more protein than adult CSF, suggesting that it may have an important role during development(8,9). Studies in chick and mouse demonstrate that secreted factors in the eCSF, fluid pressure, or a combination of these, are important for neurogenesis, gene expression, cell proliferation, and cell survival in the neuroepithelium(10-20). Proteomic analyses of human, rat, mouse, and chick eCSF have identified many proteins that may be necessary for CSF function. These include extracellular matrix components, apolipoproteins, osmotic pressure regulating proteins, and proteins involved in cell death and proliferation(21-24). However, the complex functions of the eCSF are largely unknown. We have developed a method for removing eCSF from zebrafish brain ventricles, thus allowing for identification of eCSF components and for analysis of the eCSF requirement during development. Although more eCSF can be collected from other vertebrate systems with larger embryos, eCSF can be collected from the earliest stages of zebrafish development, and under genetic or environmental conditions that lead to abnormal brain ventricle volume or morphology. Removal and collection of eCSF allows for mass spectrometric analysis, investigation of eCSF function, and reintroduction of select factors into the ventricles to assay their function. Thus the accessibility of the early zebrafish embryo allows for detailed analysis of eCSF function during development.

Innervation of ventricular and periventricular brain compartments.

Synaptic transmission is divided into two broad categories on the basis of the distance over which neurotransmitters travel. Wiring transmission is the release of transmitter into synaptic clefts in close apposition to receptors. Volume transmission is the release of transmitters or modulators over varying distances before interacting with receptors. One case of volume transmission over potentially long distances involves release into cerebrospinal fluid (CSF). The CSF contains neuroactive substances that affect brain function and range in size from small molecule transmitters to peptides and large proteins. CSF-contacting neurons are a well-known and universal feature of non-mammalian vertebrates, but only supra- and subependymal serotonergic plexuses are a commonly studied feature in mammals. The origin of most other neuroactive substances in CSF is unknown. In order to determine which brain regions communicate with CSF, we describe the distribution of retrograde neuronal labeling in the rat brain following ventricular injection of Cholera toxin, ß subunit (CTß), a tracer frequently used in brain circuit analysis. Within 15 to 30 min following intraventricular injection, there is only diffuse, non-specific staining adjacent to the ventricular surface. Within 2 to 10 days, however, there is extensive labeling of neuronal perikarya in specific nuclear groups in the telencephalon, thalamus, hypothalamus and brainstem, many at a considerable distance from the ventricles. These observations support the view that ventricular CSF is a significant channel for volume transmission and identifies those brain regions most likely to be involved in this process.

Immunohistochemical distribution of somatostatin and somatostatin receptor subtypes (SSTR1-5) in hypothalamus of ApoD knockout mice brain.

In the present study, the expression of somatostatin (SST) and somatostatin receptor subtypes (SSTR1-5) was determined in the hypothalamus of wild-type (wt) and apolipoprotein D knockout (ApoD(-/-)) mice brain. SST-like immunoreactivity, while comparable in most regions of hypothalamus, diminished significantly in arcuate nucleus of ApoD(-/-) mice. SSTR1 strongly localized in all major hypothalamic nuclei as well as in the median eminence and ependyma of the third ventricle of wt mice brain. SSTR1-like immunoreactivity increases in hypothalamus except in paraventricular nucleus of ApoD(-/-) mice. SSTR2 was well expressed in most of the hypothalamic regions whereas it decreases significantly in ventromedial and arcuate nucleus of ApoD(-/-) mice. SSTR3 and SSTR4-like immunoreactivity increases in ApoD(-/-) mice in all major nuclei of hypothalamus, median eminence, and ependymal cells of third ventricle. SSTR5 is well expressed in ventromedial and arcuate nucleus whereas weakly expressed in paraventricular nucleus. In comparison to wt, ApoD(-/-) mice exhibit increased SSTR5-like immunoreactivity in paraventricular nuclei and decreased receptor expression in ventromedial hypothalamus and arcuate nucleus. In conclusion, the changes in hypothalamus of ApoD(-/-) mice may indicate potential role of ApoD in regulation of endocrine functions of somatostatin in a receptor-dependent manner.

The effect of reductive ventricular osmotherapy on the osmolarity of artificial cerebrospinal fluid and the water content of cerebral tissue ex vivo.

The purpose of this study was to explore a novel treatment involving removal of free water from ventricular cerebrospinal fluid (CSF) for the reduction of cerebra]l edema. The hypothesis is that removal of free water from the CSF will increase the osmolarity of the CSF, which will favor movement of tissue-bound water into the ventricles, where the water can be removed. Reductive ventricular osmotherapy (RVOT) was tested in a flowing solution of artificial CSF (aCSF) with two end-points: (1) the effect of RVOT on osmolarity of the CSF, and (2) the effect of RVOT on water content of ex vivo cerebral tissue. RVOT catheters are made up of membranes permeable only to water vapor. When a sweep gas is drawn through the catheter, free water in the form of water vapor is removed from the solution. With RVOT treatment, aCSF osmolarity increased from a baseline osmolarity of 318.8 ± 0.8 mOsm/L to 339.0 ± 3.3 mOsm/L (mean ± standard deviation) within 2 h. After 10 h of treatment, aCSF osmolarity approached an asymptote at 344.0 ± 4.2 mOsm/L, which was significantly greater than control aCSF osmolarity (p <<0.001 by t-test, n = 8). Water content at the end of 6 h of circulating aCSF exposure was 6.4 ± 0.9 g H2O (g dry wt)⁻¹ in controls, compared to 6.1 ± 0.7 g H2O (g dry wt)⁻ after 6 h of RVOT treatment of aCSF (p = 0.02, n = 24). The results support the potential of RVOT as a treatment for cerebral edema and intracranial hypertension.

Hypothalamic arcuate neuropeptide Y-neurons decrease periventricular somatostatin-neuronal activity before puberty in the female lamb: morphological arguments.

It is assumed that hypothalamic somatostatin plays a dominant role in the regulation of growth of developing lambs. On the other side, neuropeptide Y (NPY) neurons of the arcuate (ARC) nucleus are potentially involved in the control of gonadotrophins in prepubertal lambs and also of growth hormone (GH) secretion in adults. This study therefore investigated whether the transition from the prepubertal to the peripubertal period is accompanied by changes in NPY-ir and NPY mRNA content in neurons of the ARC nucleus and their putative projections to somatostatin neurons in both the ARC and periventricular (PEV) nuclei. The hypothalami of prepubertal (17-week-old) and peripubertal (32-week-old) female lambs were compared using single and double-labelling immunohistochemistry, and hybridisation in situ for NPY. Single-labelling for NPY mRNA and NPY-ir was quantified by image analysis using a light microscope and expressed as the percent area stained and/or the integral density of the reaction. Double-labelling for NPY-somatostatin relationships was analysed by confocal microscopy. Our data suggest that there are no detectable changes in NPY-ir in the PEV nucleus in the period leading up to puberty, whereas both the distributional area and intensity of NPY-labelling in the ARC are significantly higher in peripubertal compared to prepubertal sheep. In contrast, NPY mRNA levels are higher in prepubertal than in peripubertal ewes in the ARC nucleus. Confocal microscopy suggests the existence of NPY-somatostatin axo-somatic contacts in both PEV and ARC nuclei. In the PEV nucleus, the number of close appositions between NPY-ir fibres and somatostatin-ir perikarya is higher in prepubertal than in peripubertal ewes, but in the ARC no such difference was observed. In conclusion, our observations suggest that there is decreased activity of the NPY neurons of the ARC nucleus closely related to somatostatin neurons in the PEV nucleus at the onset of puberty. The withdrawal of this NPY effect may allow a higher release of somatostatin, which consequently inhibits GH secretion and stops growth. Both peptides are involved in the transmission of signals leading to stop growth at puberty.

Characteristic features of a nerve primo-vessel suspended in rabbit brain ventricle and central canal.

Bonghan theory was proposed by Bonghan Kim to illustrate the anatomy and physiology of the acupuncture meridian system. One of his astonishing claims was the physical presence of the nerve primo-vessel, which can be involved with a regenerating system of nerves. Our previous work has shown that there is a nerve primo-vessel in brain ventricles and the central canal of the spine of a rabbit. In this study, confocal laser scanning microscopy, transmission electron microscopy, and high voltage electron microscopy demonstrated that a nerve primo-vessel comprised DNA particles, other microparticles, and rod-shaped nuclei encircled by helix-shaped actins. The nerve primo-vessel had acridine orange-stained DNA particles that varied in size and were in parallel. These characteristics of the nerve primo-vessel are crucial for a comprehensive understanding of their function in the central nervous system, which may be associated with nerve regeneration.

Pharmacokinetics and distribution of linezolid in cerebrospinal fluid in children and adolescents.

BACKGROUND: Two studies in hydrocephalic children and adolescents were performed to assess the penetration of linezolid into cerebrospinal fluid and its relation to meningeal inflammation. METHODS: Each patient was administered intravenous linezolid 10 mg/kg every 12 hours for 3 days (study 1) or every 8 hours for 2 days (study 2). Pharmacokinetic indices (Cmax, Cmin, Tmax, AUC) were determined for plasma and ventricular fluid (VF) after the first and last doses. RESULTS: In study 1, after the last dose, the mean Cmax values for plasma and VF were 10.30 microg/mL (range, 3.95-16.6 microg/mL) and 7.54 microg/mL (range, 2.26-12.6 microg/mL), respectively; mean Cmin values were 1.32 microg/mL (range, 0.08-3.66 microg/mL) and 1.26 microg/mL (range, 0.19-2.58 microg/mL), respectively. The VF:plasma ratio based on last dose AUC0-12 was 0.98 microg h/mL (range, 0.64-1.22 microg h/mL). In study 2, after the last dose, the mean plasma and VF Cmax levels were 9.83 microg/mL (range, 3.19-16.5 microg/mL) and 5.84 microg/mL (range, 1.82-9.34 microg/mL), respectively; mean plasma and VF Cmin levels were 1.12 microg/mL (range, 0.10-3.39 microg/mL) and 1.94 microg/mL (range, 0.34-4.62 microg/mL), respectively. The VF:plasma ratio based on last dose AUC0-8 was 0.95 microg h/mL (range, 0.62-1.31 microg h/mL). Inflammation of the meninges did not seem to influence penetration of linezolid to the VF. CONCLUSIONS: : Both studies showed that VF concentrations were variable. Further investigation of the role of linezolid in the treatment of CNS infection is needed.

Abnormalities of tau-protein and beta-amyloid in brain ventricle cerebrospinal fluid.

OBJECTIVE: Determination of various biomarkers, such as beta-amyloid, tau-protein, phosphorylated tau-protein in CSF and their sensitivity and specificity in neurodegenerative brain processes, in particular Alzheimer Dementia (AD), has been recently investigated to monitor their abnormalities in the CSF at early stages of diseases before the clinical manifestation. DESIGN AND SETTING: In the pilot group of our patients (10 men / 5 women) who underwent a drainage neurosurgical procedure for diagnosis of hydrocephalus, CSF was obtained from the brain ventricles and the influence of a different compartment of the CSF on the level of biomarkers, tau-protein and beta-amyloid, was investigated. RESULTS: The mean tau-protein level for all 15 patients was 812.0 pg/ml, with median value 363.7 pg/ml; while mean beta-amyloid level for all 15 patients was 526.7 pg/ml, with median value 239.5 pg/ml, respectively. The abnormal tau-protein and beta-amyloid levels were found in the subgroup of patients in whom hydrocephalus was caused by a severe pathological process, such as brain tumor. The beta-amyloid values were significantly lower also in comparison with our previously published results in patients with AD in the CSF obtained by lumbar puncture in the spinal canal. CONCLUSIONS: CSF in the brain ventricles is theoretically more stable and the values in this CSF probably provide more reliable informations for clinical diagnostic procedure than those for the CSF obtained by lumbar puncture in the spinal canal.

MALDI-tandem mass spectrometry imaging of astemizole and its primary metabolite in rat brain sections.

BACKGROUND: Matrix-assisted laser desorption/ionization (MALDI)-tandem mass spectrometry (MS)/MS is a proven reliable tool for visualizing the spatial distribution of dosed drugs and their primary metabolites in animal tissue sections. MATERIALS & METHODS: The rat brain tissue sections coated with dihydroxybenzoic acid as matrix, were analyzed by MALDI-MS/MS imaging experiments. The potential metabolites of astemizole in rat brain homogenate selected for MALDI-MS/MS imaging experiments were first identified by high-performance liquid chromatography coupled to an electrospray ionization source and a hybrid-quadrupole-linear-ion-trap mass spectrometer. RESULTS: Astemizole was observed to be heterogeneously distributed to most parts of the brain tissue slices including the cortex, hippocampus, hypothalamic, thalamus and ventricle regions, while its major metabolite, desmethylastemizole, was only found around ventricle sites. CONCLUSION: The results indicated that the dosed compound alone might be responsible for the CNS side-effects when drug exposures became elevated.

Immunohistochemical changes related to ageing in the mouse hippocampus and subventricular zone.

We investigated mainly immunohistochemical changes of nestin (a marker of neuroepithelial stem cells) and Ki-67 (a marker of proliferating cells) proteins related to ageing in the mouse hippocampus and subventricular zone (SVZ) using young adult (8 weeks old) and middle-aged (40 weeks old) mice. In the present study, no significant changes in neurons and astrocytes of the hippocampal CA1 sector were found in a middle-aged male ICR mice without severe senile weakness, as compared with young adult animals. In contrast, a significant change in the number of microglia was found in the hippocampal CA1 sector of the middle-aged mice. Furthermore, no significant changes in the number of nestin- and Ki-67-positive cells were observed in the hippocampal CA1 sector of the middle-aged mice. On the other hand, decreases in the number of nestin- and Ki-67-immunopositive cells were observed in the SVZ of the middle-aged mice. Furthermore, a migration of nestin- and Ki-67-immunoreactive cells in the corpus callosum was not observed in the SVZ of the middle-aged mice. In the dentate gyrus, significant decreases in the number of Ki-67-immunopositive cells were observed in the middle-aged mice. Our study also showed that nestin immunoreactivity was observed in both Ki-67-postive cells and astrocytes in the SVZ of young adult mice. These findings emphasize the need to recognize ageing as important factors in studies of microglia, which may help to clarify the role of glial cell structure and function during ageing processes. Furthermore, the present findings suggest that ageing processes may decrease neurogenesis in the corpus callosum, SVZ and dentate gyrus. Thus our present findings provide valuable information for the neurogenesis during ageing processes.

Musashi1 antigen expression in human fetal germinal matrix development.

Musashi1 is a highly conserved protein found in neural progenitor cells. We examined the expression dynamics of Musashi1 in conjunction with other representative neural progenitor antigenic determinants (Ki-67 and nestin) during 8 different stages of the developing human fetal germinal matrix. Our results indicate that Musashi1 is a useful marker for immature cells in periventricular areas inhabited by stem cells, progenitor cells, and differentiating cells.

The subventricular zone releases factors which can be protective in oxygen/glucose deprivation-induced cortical damage: an organotypic study.

A number of studies have already established the role of the subventricular zone in sustaining adult neurogenesis in different brain regions and under different pathological conditions, but nothing is reported about the role of this germinal area in preserving cell viability. In this work, we developed an organotypic culture model of the forebrain structures that comprise the neocortex, striatum, subventricular zone, and corpus callosum. With this model, we investigated the role of the subventricular zone in modulating cell viability in the cortex after oxygen/glucose deprivation. Here we have demonstrated that soluble heat-labile factors released by the subventricular zone in the media can lead to protection specifically in the cortical area. No protection was observed when medium, conditioned with factors released during the insult was administered to the hippocampal slices. Moreover, the use of different modifications of the slice cultures showed that the removal of the subventricular zone increased the cellular damage induced by oxygen/glucose deprivation. Furthermore, by using pharmacological experiments to investigate the possible mechanisms that regulate this subventricular function, we found evidence of purinergic involvement. We postulate that extracellular ATP signaling in the subventricular zone exacerbates cortical damage induced by hypoxia/hypoglycemia. For the first time, we demonstrate in vitro that the germinal subventricular zone can release factors that can be protective after exposure to a metabolic stressor. These released factors are not yet characterized but we identified in the extracellular ATP a factor that may interfere with the protective role of the subventricular zone during metabolic cortical damage.

Presence of nerve growth factor and TrkA expression in the SVZ of EAE rats: evidence for a possible functional significance.

Nerve growth factor (NGF) is a well-characterized neurotrophic factor that plays a crucial role during development in the growth, differentiation, and maintenance of brain neurons as well as in the reparative response of the adult brain to neuronal damage. Recent studies have shown that acute axonal loss occurs in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), and that NGF suppresses clinical symptoms of EAE in nonhuman primates. Aim of the present study was to investigate the role of NGF in the regenerative response of the adult brain to neuronal damage occurring in EAE. Using EAE rats, we have found that exogenous NGF injection and NGF deprivation (NGF autoimmunization) can act on growth and differentiation of brain precursor cells in the subventricular zone (SVZ) of EAE rats. Moreover, NGF administration in brain of EAE rats stimulates the expression of early neuronal markers on proliferating precursor cells of the SVZ. The data obtained demonstrated that NGF and its antibody affect bromodeoxyuridine (BrdU) incorporation and NGF receptor expression by SVZ progenitor cells in the brain of EAE rats.