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Mammalian L1 and avian Ng-CAM are homologous neural cell adhesion molecules (CAMs) that promote neurite outgrowth and cell adhesion in most neurons. Previous attempts to map these activities to discrete regions in the CAMs have suggested the involvement of a variety of different domains. However, these studies mainly used bacterially expressed proteins that were much less active on a molar basis than the native molecules. To define regions that are critical for maximal neurite outgrowth, we constructed and tested a panel of eukaryotically expressed proteins containing various extracellular segments of human L1 (hL1) or Ng-CAM. Our results indicate that Ig domains 1-4 of hL1 are critical for homophilic binding and neurite outgrowth; however this segment is less potent than the entire extracellular region. Optimal neurite outgrowth activity was seen with proteins containing all six Ig domains of hL1 or Ng-CAM. The adhesive properties of hL1 fragments correlated tightly with their neurite outgrowth activities, suggesting that these two processes are closely linked. These results suggest that Ig domains 1-4 form a structural cassette responsible for hL1 homophilic binding, while Ig domains 1-6 represent a functional region for optimal promotion of neurite outgrowth in vitro and possibly in vivo.

IntroductionEsmirtazapine is evaluated as a novel drug for treatment of insomnia.PurposeThe present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control.MethodsTreatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of “weaving”. All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine.ResultsOverall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected.ConclusionIt is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving.

In order to gain insight into the events that take place when serotonergic growth cones are remodeled into synapses, we tested the hypothesis that neurotransmitter-related properties of presynaptic terminals are already present in these growth cones before synaptogenesis begins. The ontogeny of markers for the specific reuptake of 5-HT and for 5-HT-storing synaptic vesicles was studied in isolated growth cone (IGC) fractions from developing rat brain. High- affinity 3H-imipramine binding (a marker for the plasma membrane 5-HT transporter) was significantly enriched in IGC fractions prepared before the beginning of cortical synaptogenesis [embryonic day 15 (E15) and E20]. Radioautography with 3H-imipramine or 3H-paroxetine (another marker for the transporter) confirmed that the 5-HT transporter is present in the cerebral cortex when it contains serotonergic growth cones, but not serotonergic synapses. Specific uptake of 3H-5-HT was found in IGC fractions as early as E15; this uptake was inhibited by fluoxetine. Electron microscopic radioautography demonstrated directly that growth cones were the structures in IGC fractions that took up 3H- 5-HT. The synaptic vesicle protein synaptophysin and a 45 kDa protein found specifically in serotonergic synaptic vesicles, serotonin-binding protein (SBP), were each enriched in IGC fractions from E15 to postnatal day 5; SBP immunoreactivity increased approximately 10-fold between E15 and E20. Endogenous 5-HT was detected in IGC fractions at E15 and increased in amount as development proceeded. The ratio of 5-HT to 5-hydroxyindole acetic acid suggested that 5-HT within growth cones is protected from catabolism by monoamine oxidase. Reserpine-induced depletion of 5-HT, a marker for the vesicular carrier of 5-HT, was apparent in IGC fractions at E20, but not at E15. These data suggest that properties that characterize the presynaptic components of mature serotonergic synapses develop in growth cones before synapses are formed. The early development of these properties may permit neurotransmission to be established rapidly during synaptogenesis or, alternatively, enable 5-HT to play a role in ontogeny.

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The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient-reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P ≤ 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P ≤ 0.0001) and latency to persistent sleep also improved vs placebo (P ≤ 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P ≤ 0.01 and P ≤ 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P < 0.05), although this effect was limited to the first night of each 2-night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects.