Choline supplementation mitigates effects of bilirubin in cerebellar granule neurons in vitro.

BACKGROUND: Premature infants may suffer from high levels of bilirubin that could lead to neurotoxicity. Bilirubin has been shown to decrease L1-mediated ERK1/2 signaling, L1 phosphorylation, and L1 tyrosine 1176 dephosphorylation. Furthermore, bilirubin redistributes L1 into lipid rafts (LR) and decreases L1-mediated neurite outgrowth. We demonstrate that choline supplementation improves L1 function and signaling in the presence of bilirubin. METHODS: Cerebellar granule neurons (CGN) were cultured with and without supplemental choline, and the effects on L1 signaling and function were measured in the presence of bilirubin. L1 activation of ERK1/2, L1 phosphorylation and dephosphorylation were measured. L1 distribution in LR was quantified and neurite outgrowth of CGN was determined. RESULTS: Forty µM choline significantly reduced the effect of bilirubin on L1 activation of ERK1/2 by 220% (p = 0.04), and increased L1 triggered changes in tyrosine phosphorylation /dephosphorylation of L1 by 34% (p = 0.026) and 35% (p = 0.02) respectively. Choline ameliorated the redistribution of L1 in lipid rafts by 38% (p = 0.02) and increased L1-mediated mean neurite length by 11% (p = 0.04). CONCLUSION: Choline pretreatment of CGN significantly reduced the disruption of L1 function by bilirubin. The supplementation of pregnant women and preterm infants with choline may increase infant resilience to the effects of bilirubin. IMPACT: This article establishes choline as an intervention for the neurotoxic effects of bilirubin on lipid rafts. This article provides clear evidence toward establishing one intervention for bilirubin neurotoxicity, where little is understood. This article paves the way for future investigation into the mechanism of the ameliorative effect of choline on bilirubin neurotoxicity.

Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods.

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)-which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue-exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612.

Myrtus communis subsp. communis improved cognitive functions in ovariectomized diabetic rats.

AIM: The purpose of this study was to investigate the possible effects of Myrtus communis subsp. communis (MC) on cognitive impairment in ovariectomized diabetic rats. MATERIAL AND METHOD: Female Sprague-Dawley rats were divided into 5 groups consisting of 15 rats each; Control (C), Diabetes (D), Ovariectomy and diabetes (OVX + D), Ovariectomy, diabetes and donepezil (OVX + D + Don), Ovariectomy, diabetes and Myrtus communis subsp. communis (OVX + D + MC). Blood glucose measurements were made at the beginning and end of the experiments. The animals underwent the novel object recognition test (NORT) and their performance was evaluated. In hippocampal tissues; amyloid beta (Aß) and neprilysin levels, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities, polysialylated neural cell adhesion molecule (PSA-NCAM), α7 subunit of neuronal nicotinic acetylcholine receptor (α7-nAChR) and brain derived neurotrophic factor (BDNF) gene expressions were examined. RESULTS: Animals with ovariectomy and diabetes showed increased levels of blood glucose, AChE activity and Aß levels, and decreased neprilysin levels, ChAT activity, α7-nAChR, PSA-NCAM and BDNF gene expressions in parallel with a decrease in NORT performance score. On the other hand, in the MC-treated OVX + D group, there was a significant decrease observed in blood glucose levels and AChE activities while there was improvement in NORT performances and an increase in hippocampal ChAT activity, neprilysin levels, α7-nAChR, PSA-NCAM and BDNF expressions. CONCLUSION: These results suggest that MC extract could improve cognitive and neuronal functions with its anticholinesterase and antihyperglycemic properties.

Choline ameliorates ethanol induced alterations in tyrosine phosphorylation and distribution in detergent-resistant membrane microdomains of L1 cell adhesion molecule in vivo.

BACKGROUND: Exposure to ethanol during pregnancy is the cause of fetal alcohol spectrum disorder. The function of L1 cell adhesion molecule (L1), critical for proper brain development, is dependent on detergent-resistant membrane microdomains (DRM). Ethanol at low concentrations disrupts L1 function measured by inhibition of downstream signaling and alterations in L1-DRM distribution in cerebellum in vivo and in cerebellar granule neurons (CGN) in vitro. We have previously shown that choline pretreatment of CGN partially prevents ethanol toxicity through improving L1 function in vitro. Here we show that choline supplementation reduces the impact of ethanol on L1 in cerebellum in vivo. METHODS: Pregnant rat dams were placed on choline free diet on gestational Day 5 (G5). Pups were treated with saline or choline from postnatal day (P) 1-5. On P5, pups were intubated twice 2 hr apart with ethanol or Intralipid® for a total dose of 6 g/kg/d and sacrificed 1 hr after the last intubation. The cerebella were harvested and L1 phosphorylation/dephosphorylation status and distribution in DRM were analyzed. RESULTS: Ethanol reduced L1 tyrosine phosphorylation and L1-Y1176 dephosphorylation in cerebella, and caused an increase in the percent of L1 in DRM. Choline supplementation of pups reduced the ethanol-induced changes in L1 phosphorylation status and ameliorated ethanol-induced redistribution of L1 into DRM. CONCLUSION: Choline supplementation before an acute dose of ethanol ameliorates changes in L1 in vivo.

Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-ß pathologies in a mouse model of Alzheimer's disease.

The accumulation of amyloid-ß protein (Aß) in brain is linked to the early pathogenesis of Alzheimer's disease (AD). We previously reported that neuron-derived exosomes promote Aß clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aß levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aß in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aß accumulation by promoting EVs-dependent Aß clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.

Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis.

CONTEXT: Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. OBJECTIVE: We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. PATIENTS: The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. RESULTS: Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. CONCLUSION: We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.

Resveratrol Regulates BDNF, trkB, PSA-NCAM, and Arc Expression in the Rat Cerebral Cortex after Bilateral Common Carotid Artery Occlusion and Reperfusion.

The polyphenol resveratrol (RVT) may drive protective mechanisms of cerebral homeostasis during the hypoperfusion/reperfusion triggered by the transient bilateral common carotid artery occlusion followed by reperfusion (BCCAO/R). This immunochemical study investigates if a single dose of RVT modulates the plasticity-related markers brain-derived neurotrophic factor (BDNF), the tyrosine kinase trkB receptor, Polysialylated-Neural Cell Adhesion Molecule (PSA-NCAM), and Activity-regulated cytoskeleton-associated (Arc) protein in the brain cortex after BCCAO/R. Frontal and temporal-occipital cortical regions were examined in male Wistar rats randomly subdivided in two groups, sham-operated and submitted to BCCAO/R. Six hours prior to surgery, half the rats were gavage fed a dose of RVT (180 mg·kg-1 in 300 µL of sunflower oil as the vehicle), while the second half was given the vehicle alone. In the frontal cortex of BCCAO/R vehicle-treated rats, BDNF and PSA-NCAM decreased, while trkB increased. RVT pre-treatment elicited an increment of all examined markers in both sham- and BCCAO/R rats. No variations occurred in the temporal-occipital cortex. The results highlight a role for RVT in modulating neuronal plasticity through the BDNF-trkB system and upregulation of PSA-NCAM and Arc, which may provide both trophic and structural local support in the dynamic changes occurring during the BCCAO/R, and further suggest that dietary supplements such as RVT are effective in preserving the tissue potential to engage plasticity-related events and control the functional response to the hypoperfusion/reperfusion challenge.

Sialic Acid and Sialylated Oligosaccharide Supplementation during Lactation Improves Learning and Memory in Rats.

Sialic acids (Sia) are postulated to improve cognitive abilities. This study evaluated Sia effects on rat behavior when administered in a free form as N-acetylneuraminic acid (Neu5Ac) or conjugated as 6'-sialyllactose (6'-SL). Rat milk contains Sia, which peaks at Postnatal Day 9 and drops to a minimum by Day 15. To bypass this Sia peak, a cohort of foster mothers was used to raise the experimental pups. A group of pups received a daily oral supplementation of Neu5Ac to mimic the amount naturally present in rat milk, and another group received the same molar amount of Sia as 6'-SL. The control group received water. After weaning, rats were submitted to behavioral evaluation. One year later, behavior was re-evaluated, and in vivo long-term potentiation (LTP) was performed. Brain samples were collected and analyzed at both ages. Adult rats who received Sia performed significantly better in the behavioral assessment and showed an enhanced LTP compared to controls. Within Sia groups, 6'-SL rats showed better scores in some cognitive outcomes compared to Neu5Ac rats. At weaning, an effect on polysialylated-neural cell adhesion molecule (PSA-NCAM) levels in the frontal cortex was only observed in 6'-SL fed rats. Providing Sia during lactation, especially as 6'-SL, improves memory and LTP in adult rats.

Seasonal reorganization of hypothalamic neurogenic niche in adult sheep.

Neurogenesis is the process by which new neurons are generated. This process, well established during development, persists in adulthood owing to the presence of neural stem cells (NSCs) localized in specific brain areas called neurogenic niches. Adult neurogenesis has recently been shown to occur in the hypothalamus, a structure involved in the neuroendocrine regulation of reproduction and metabolism, among others. In the adult sheep-a long-lived mammalian model-we have previously reported the existence of such a neurogenic niche located in the hypothalamic arcuate nucleus and the median eminence. In addition, in this seasonal species, the proliferation as well as neuroblasts production varies depending on the time of the year. In the present study, we provide a better characterization of the hypothalamic neurogenic niche by identifying the main components (NSCs, migrating cells, glial cells and blood vessels) using immunohistochemistry for validated markers. Then, we demonstrate the strong sensitivity of these various neurogenic niche components to the season, particularly in the arcuate nucleus. Further, using an electron microscopic approach, we reveal the cellular and cytoarchitectural reorganization of the arcuate nucleus niche following exposure to contrasting seasons. This study provides evidence that the arcuate nucleus and the median eminence contain two independent niches that react differently to the season. In addition, our results support the view that the cytoarchitectural organization of the sheep arcuate nucleus share comparable features with the structure of the subventricular zone in humans and non-human primates.

Electro-Acupuncture Modulates L1 Adhesion Molecule Expression After Mouse Spinal Cord Injury.

Spinal cord injury is a devastating neurological disease in desperate need of a cure. We have previously shown that overexpression of the adhesion molecule L1 contributes to locomotor recovery after injury and were therefore interested in how electro-acupuncture would influence the expression of this molecule. Here, we investigated the effects of electro-acupuncture at "Jiaji" points (EX-B2), newly established by us, in young adult mice to determine whether improved recovery via electro-acupuncture could be due to enhanced L1 expression. Locomotor function, as evaluated by the Basso Mouse Scale score and by catwalk gait parameters, was improved by electro-acupuncture at different time points after injury in parallel with enhanced levels of L1 expression. Interestingly, the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) were also increased, but only in the early phase after injury, being reduced at later stages during recovery. Acupuncture alone showed less pronounced changes in expression of these molecules. We propose that electro-acupuncture improves regeneration in part by promoting the L1 expression and beneficial activation of stem cells, and by differentially modulating the expression of GFAP by promoting regeneration-conductive astrocytic responses at initial stages and reducing regeneration-adversive activation in the secondary stages. Expression of the stem cell marker nestin was upregulated by electro-acupuncture in the acute stage. The combined observations show for the first time in mice the beneficial functions of electro-acupuncture at Jiaji points in the spinal cord injury mouse model and provide novel insights into some molecular mechanisms underlying electro-acupuncture in spinal cord injury.

Choline partially prevents the impact of ethanol on the lipid raft dependent functions of l1 cell adhesion molecule.

BACKGROUND: Fetal alcohol spectrum disorder, the leading known cause of mental retardation, is caused by alcohol exposure during pregnancy. One mechanism of ethanol (EtOH) teratogenicity is the disruption of the functions of L1 cell adhesion molecule (L1). These functions include enhancement of neurite outgrowth, trafficking through lipid rafts, and signal transduction. Recent data have shown that choline supplementation of rat pups reduces the effects of EtOH on neurobehavior. We sought to determine whether choline could prevent the effect of EtOH on L1 function using a simple experimental system. METHODS: Cerebellar granule neurons (CGN) from postnatal day 6 rat pups were cultured with and without supplemental choline, and the effects on L1 signaling, lipid raft distribution, and neurite outgrowth were measured in the presence or absence of EtOH. RESULTS: Choline significantly reduced the effect of EtOH on L1 signaling, the distribution of L1 in lipid rafts and L1-mediated neurite outgrowth. However, choline supplemented EtOH-exposed cultures remained significantly different than controls. CONCLUSIONS: Choline pretreatment of CGN significantly reduces the disruption of L1 function by EtOH, but does not completely return L1 function to baseline. This experimental system will enable discovery of the mechanism of the neuroprotective effect of choline.

[Promotion of compound fujian tablet on the motor function rehabilitation and neurotization in rats with cerebral infarction].

OBJECTIVE: To study the effects of Compound Fujian Tablet (FJT)on the neurotization in the cerebral infarction rats and to explore its mechanisms for promoting the motor skills. METHODS: Totally 90 Wistar rats were randomly divided into the drug group, the model group, and the sham-operation group, 30 in each group. The rat model of middle cerebral artery occlusion (MCAO) was successfully established by electrocoagulation. Six hours after successful modeling, the rats of the drug group were orally administered with 9 g/kg FJT water solution, and the other groups were orally administered with equal volume of normal saline, once a day for two weeks. The motor skills of rats were examined by beam walking test. The expressions of nestin, polysialic acid neural cell adhesion molecule (PSA-NCAM), microtubule-associated protein 2 (MAP-2), growth-associated protein (GAP-43), and synaptophysin (Syn) in the brain tissue around the infarction were observed by in immunohistochemical assay. The mean staining gray or the optical density value were detected. RESULTS: The 86 rats were recruited in the result analysis. After two weeks of administration, the neural function scoring was obviously higher in the drug group than in the model group with statistical difference (P < 0.01). The expressions of nestin, PSA-NCAM, MAP-2, GAP-43, and Syn in the brain tissue around the infarction were more obviously enhanced in the drug group than in the model group, showing statistical difference (P < 0.01). CONCLUSION: FJT can promote neurotization and improve the motor skill recovery after cerebral infarction.

Photoperiodic variations of the polysialylated form of neural cell adhesion molecule within the hypothalamus and related reproductive output in the ewe.

Cellular mechanisms induced by melatonin to synchronise seasonal reproduction in several species, including sheep, remain unclear. We sought to evaluate the scale and physiological significance of neural plasticity in order to explain the delay between the change of duration of melatonin secretion and the change of reproductive status following a transition from long days (LD, 16 h light/24 h) to short days (SD, 8 h light/24 h) and from SD to LD. Using Western blots in ovariectomised oestradiol-replaced ewes, we evaluated the content of the polysialylated form of neural cell adhesion molecule (PSA-NCAM), a plasticity marker, in the hypothalamus. From day 15 following a transition to SD, most hypothalamic areas showed a decrease of PSA-NCAM level that was particularly significant in the preoptic area (POA). Following a transition to LD, PSA-NCAM content increased at day 15 in most regions except in the premammillary hypothalamic area (PMH) in which a significant decrease was noted. The functional importance of PSA-NCAM variations for seasonal reproduction was assessed for the PMH and POA. PSA-NCAM was degraded by stereotaxic injections of endoneuraminidase N and luteinising hormone (LH) secretion was recorded in treated and control ewes. Degradation of PSA-NCAM in the PMH in SD-treated ewes failed to produce a significant effect on LH secretion, whereas a similar treatment in the POA before a transition to SD delayed activation of the gonadotroph axis in two-thirds of the ewes. Our results suggest that the photoperiod controls variations of the hypothalamic content of a plasticity marker and that these might be important for the regulation of seasonal reproduction, particularly in the POA.

Promotion of compound fujian tablet on the motor function rehabilitation and neurotization in rats with cerebral infarction / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effects of Compound Fujian Tablet (FJT)on the neurotization in the cerebral infarction rats and to explore its mechanisms for promoting the motor skills.</p><p><b>METHODS</b>Totally 90 Wistar rats were randomly divided into the drug group, the model group, and the sham-operation group, 30 in each group. The rat model of middle cerebral artery occlusion (MCAO) was successfully established by electrocoagulation. Six hours after successful modeling, the rats of the drug group were orally administered with 9 g/kg FJT water solution, and the other groups were orally administered with equal volume of normal saline, once a day for two weeks. The motor skills of rats were examined by beam walking test. The expressions of nestin, polysialic acid neural cell adhesion molecule (PSA-NCAM), microtubule-associated protein 2 (MAP-2), growth-associated protein (GAP-43), and synaptophysin (Syn) in the brain tissue around the infarction were observed by in immunohistochemical assay. The mean staining gray or the optical density value were detected.</p><p><b>RESULTS</b>The 86 rats were recruited in the result analysis. After two weeks of administration, the neural function scoring was obviously higher in the drug group than in the model group with statistical difference (P < 0.01). The expressions of nestin, PSA-NCAM, MAP-2, GAP-43, and Syn in the brain tissue around the infarction were more obviously enhanced in the drug group than in the model group, showing statistical difference (P < 0.01).</p><p><b>CONCLUSION</b>FJT can promote neurotization and improve the motor skill recovery after cerebral infarction.</p>

[Structural plasticity of the adult central nervous system: insights from the neuroendocrine hypothalamus]. / Plasticité structurale du système nerveux central adulte: apport des connaissances sur l'hypothalamus neuroendocrine.

Accumulating evidence renders the dogma obsolete according to which the structural organization of the brain would remain essentially stable in adulthood, changing only in response to a need for compensatory processes during increasing age and degeneration. It has indeed become clear from investigations on various models that the adult nervous system can adapt to physiological demands by altering reversibly its synaptic circuits. This potential for structural and functional modifications results not only from the plastic properties of neurons but also from the inherent capacity of the glial cellular components to undergo remodeling as well. This is currently known for astrocytes, the major glial cells in brain which are well-recognized as dynamic partners in the mechanisms of synaptic transmission, and for the tanycytes and pituicytes which contribute to the regulation of neurosecretory processes in neurohemal regions of the hypothalamus. Studies on the neuroendocrine hypothalamus, whose role is central in homeostatic regulations, have gained good insights into the spectacular neuronal-glial rearrangements that may subserve functional plasticity in the adult brain. Following pioneering works on the morphological reorganizations taking place in the hypothalamo-neurohypophyseal system under certain physiological conditions such as dehydration and lactation, studies on the gonadotropic system that orchestrates reproductive functions have re-emphasized the dynamic interplay between neurons and glia in brain structural plasticity processes. This review summarizes the major contributions provided by these researches in the field and also addresses the question of the morphological rearrangements that occur on a 24-h basis in the central component of the circadian clock responsible for the temporal aspects of endocrine regulations. Taken together, the reviewed data highlight the close cooperation between neurons and glia in developing strategies for functional adaptation of the brain to the changing conditions of the internal and external environment.

L1 and CHL1 Cooperate in Thalamocortical Axon Targeting.

Neural cell adhesion molecule close homolog of L1 (CHL1) is a regulator of topographic targeting of thalamic axons to the somatosensory cortex (S1) but little is known about its cooperation with other L1 class molecules. To investigate this, CHL1(-/-)/L1(-/y) double mutant mice were generated and analyzed for thalamocortical axon topography. Double mutants exhibited a striking posterior shift of axons from motor thalamic nuclei to the visual cortex (V1), which was not observed in single mutants. In wild-type (WT) embryos, L1 and CHL1 were coexpressed in the dorsal thalamus (DT) and on fibers along the thalamocortical projection in the ventral telencephalon and cortex. L1 and CHL1 colocalized on growth cones and neurites of cortical and thalamic neurons in culture. Growth cone collapse assays with WT and mutant neurons demonstrated a requirement for L1 and CHL1 in repellent responses to EphrinA5, a guidance factor for thalamic axons. L1 coimmunoprecipitated with the principal EphrinA5 receptors expressed in the DT (EphA3, EphA4, and EphA7), whereas CHL1 associated selectively with EphA7. These results implicate a novel mechanism in which L1 and CHL1 interact with individual EphA receptors and cooperate to guide subpopulations of thalamic axons to distinct neocortical areas essential for thalamocortical connectivity.

The intimate relationship of gonadotropin-releasing hormone neurons with the polysialylated neural cell adhesion molecule revisited across development and adult plasticity.

The neurohormone gonadotropin-releasing hormone (GnRH) is critical for all the aspects of reproductive life in vertebrates. GnRH is secreted by a small number of neurons dispersed within the preoptic-hypothalamic region. These neurons are derived from the embryonic olfactory pit. They then migrate along olfactory, vomeronasal and terminal nerves to their final destination. Classical approaches to study the regulation of GnRH secretion during the reproductive cycle have focused on the various neuronal inputs on GnRH neurons and their regulation by ovarian steroids. However, it is well known that steroids will change the microenvironment of neuronal networks and can induce plasticity and functional changes. In this review, we will focus on the intimate relationship of developing and adult GnRH neurons with the polysialylated form of neural cell adhesion molecule (PSA-NCAM), a major molecular actor in the morphogenesis and adult plasticity of the nervous system. We will first recapitulate the spatiotemporal relationship between PSA-NCAM and migrating GnRH neurons during embryogenesis of various vertebrate species and discuss its importance for GnRH neuron development as shown by various loss of function studies. In the adult, we will review the relationships between PSA-NCAM and GnRH neurons across various physiological states, and open the discussion to the use of new model systems that can help to unravel the function and mechanism of action of PSA-NCAM on GnRH neuronal network activity and GnRH release.

Chronic effects of venlafaxine on synaptophysin and neuronal cell adhesion molecule in the hippocampus of cerebral ischemic mice.

Venlafaxine, a novel antidepressant, inhibits serontonin and norepinephrine reuptake in the presynaptic cleft. Unlike typical selective serontonin reuptake inhibitors (SSRIs), venlafaxine may have modulatory effects on nerve terminals and neuronal plasticity. Our preliminary data found that 5 mg.kg-1.d-1 of venlafaxine treatment prevented decreased synaptophysin (SYP) in the hippocampus, which results from chronic restrained stress in the rat model. The present study investigates whether venlafaxine regulates alterations of synaptophysin and neuronal cell adhesion molecule (NCAM) in a post-stroke depression mouse model. We compared the expression level of SYP and NCAM in the hippocampus of global cerebral ischemic (GCI) mice treated with different doses of venlafaxine using immunohistological and Western blot analysis. Pre-treatment with intraperitoneal injection of venlafaxine (2.5 and 5.0 mg.kg-1.d-1) for 14 days significantly prevented the decrease of SYP in the hilus area of the hippocampus in vehicle-treated GCI mice. NCAM was significantly higher in the hippocampus of vehicle-treated GCI mice, and pretreatment with venlafaxine prevented alterations of NCAM, with the high-dose venlafaxine group comparable with vehicle-sham mice. The results suggest the alteration of neuronal remodeling proteins in the hippocampus may be an underlying mechanism of venlafaxine in treating post-stroke depression.

Inhibition of cell proliferation, adhesion, and invasion with an anti-L1-cell adhesion molecule monoclonal antibody in an in vitro endometriosis model.

The use of anti-L1-cell adhesion molecule monoclonal antibodies (anti-L1CAM-mAb) in an endometriosis epithelial cell line Z12 led to a statistically significant decrease in cell proliferation and cell invasion and to an inhibition of the adhesion compared with unspecific IgG-Ab treated and untreated cells. Because it increases the cell invasion and adhesion which consequently aggravates the disease, L1 could possibly promote endometriosis development; thus, further studies should evaluate the possible use of anti-L1-mAb in an animal endometriosis model.

Role of polysialylated neural cell adhesion molecule in rapid eye movement sleep regulation in rats.

Recent evidence suggests that synaptic plasticity occurs during homeostatic processes, including sleep-wakefulness regulation, although the underlying mechanisms are not well understood. Polysialylated neural cell adhesion molecule (PSA NCAM) is a transmembrane protein that has been implicated in various forms of plasticity. To investigate whether PSA NCAM is involved in the neuronal plasticity associated with spontaneous sleep-wakefulness regulation and sleep homeostasis, four studies were conducted using rats. First, we showed that PSA NCAM immunoreactivity is present in close proximity to key neurons in several nuclei of the sleep-wakefulness system, including the tuberomammillary hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. Second, using western blot analysis and densitometric image analysis of immunoreactivity, we found that 6 h of sleep deprivation changed neither the levels nor the general location of PSA NCAM in the sleep-wakefulness system. Finally, we injected endoneuraminidase (Endo N) intracerebroventricularly to examine the effects of polysialic acid removal on sleep-wakefulness states and electroencephalogram (EEG) slow waves at both baseline and during recovery from 6 h of sleep deprivation. Endo N-treated rats showed a small but significant decrease in baseline rapid eye movement (REM) sleep selectively in the late light phase, and a facilitated REM sleep rebound after sleep deprivation, as compared with saline-injected controls. Non-REM sleep and wakefulness were unaffected by Endo N. These results suggest that PSA NCAM is not particularly involved in the regulation of wakefulness or non-REM sleep, but plays a role in the diurnal pattern of REM sleep as well as in some aspects of REM sleep homeostasis.