Clinical evaluation of anaesthetic-like effect of two dermocosmetic formulations containing Aquaphilus dolomiae extract-G3 in subjects with sensitive facial skin.

BACKGROUND: Sensitive skin is a common condition of hyper-reactivity to external stimuli, e.g. heat or abrasion. The symptoms are subjective but can be measured using validated emotional and technical methods. Avène water has several beneficial effects on the skin. In vitro studies indicated that the active component of this natural spring water, Aquaphilus dolomiae extract-G3 (ADE-G3), modulates cutaneous sensitivity via an anaesthetic-like mechanism. OBJECTIVES: To assess facial skin reactivity after repeated application of two formulations containing ADE-G3. METHODS: In open-label studies, healthy subjects with sensitive facial skin applied cream or balm twice daily for 84 days. The severity of skin sensitivity was measured using the Sensitive Scale (based on quantifying visible or subjective signs). Subjective responses associated with pain or uncomfortable feeling were assessed by measuring electrodermal response (EDR). This involves measuring variations in skin electrical resistance due to non-conscious physiological changes in activity of the sympathetic nervous system. Subjects were also evaluated for beneficial effects according to a quantitative approach using semantic assessment of a question regarding their skin quality. Evaluations were performed before and after the first application, and after 29/30, 56 and 84 days of twice daily use. RESULTS: There was a significant decrease in the EDR after stimuli immediately after the application of both ADE-G3 formulations, which continued to decrease over 84 days (40-50% decrease by D85). Likewise, all physical and functional signs of the Sensitive Scale were significantly decreased immediately after the first application and at all time points tested after treatment. Verbatim analysis revealed a semantic shift, from mainly negative terms on D1 to mainly positive terms at D85 for both tested products. CONCLUSIONS: These results demonstrated that two formulations containing ADE-G3 reduced skin sensitivity, indicating a decreased activation of the sympathetic nervous system associated with this condition.

Cutaneous sensitivity modulation by Aquaphilus dolomiae extract-G3 on in vitro models of neuro-inflammation.

BACKGROUND: Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation involving the release in blood and skin of neurotransmitters such as substance P (SP). AIMS AND METHODS: In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract-G3 (ADE-G3) on cutaneous neurogenic inflammation. RESULTS: ADE-G3 significantly inhibited SP-stimulated release of IL-1ß and TNF-α from normal human epidermal keratinocytes; significantly and dose-dependently inhibited SP-stimulated activation of human mast cells; significantly inhibited veratridine-stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine-sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL-8 and histamine release. CONCLUSIONS: Topically applied ADE-G3, once formulated, may improve neuro-inflammation in patients with inflammatory skin disorders.

Additional pharmacological activity of I-modulia and generation of two newly designed extracts of Aquaphilus dolomiae culture for dermocosmetic actives.

Aquaphilus dolomiae (AD) is a unique isolate from Avène Thermal Spring Water. I-Modulia, the first biotech extract from culture of AD, was used as immune modulator in Th2 inflammatory models. In this short publication, firstly we describe generation of two AD de novo extracts specifically designed for repairing and for neuroinflammation modulation activities which will be described, respectively, in two other articles in this supplement. Finally, for I-modulia, we describe new data on inhibition of human mast cell degranulation in vitro and its effect on substance P-induced neurogenic inflammation on ex vivo human skin explants.

Effective inhibition of Th17/Th22 pathway in 2D and 3D human models of psoriasis by Celastrol enriched plant cell culture extract.

BACKGROUND: Psoriasis is an immune-mediated inflammatory disease in which the Th17 pathway is mainly involved. Systemic interventions with biologics that specifically block the Th17 pathway are effective to treat severe psoriasis. However, for efficient topical treatment, small molecules are more suitable than antibodies to penetrate and target epidermal keratinocytes, the key players in psoriasis. Celastrol, a well-described triterpene, is present in low amounts in Tripterygium wilfordii roots. By using plant cell culture (PCC), we were able to boost Celastrol production in bioreactors. Here, we evaluated immune modulator effect of Celastrol enriched extract (CEE) in Th17/Th22 psoriasis induced in 2D and 3D human models in vitro in view of its dermatological usage. METHODS: Human CD4+ T cells (hCD4), Normal Human Epidermal Keratinocytes (NHEK), micro-epidermis and reconstructed human epidermis (RHE) were preincubated with CEE and reference controls. Then, hCD4 were stimulated by anti-[CD3/CD28] while others were stimulated by Th17/22 cytokines cocktails. Psoriasis biomarkers were assessed by ELISA (hCD4 and RHE), by RT-qPCR (NHEK) or by ICH/ELISA (micro-epidermis). RESULTS: In 2D stimulated models (hCD4 and NHEK), CEE dose dependently inhibited, respectively, the expression of Th17 cytokines and psoriasis induced biomarkers. In 3D models (RHE and micro-epidermis), IL-8 expression was significantly reduced (RHE) and native phenotype was restored by CEE (micro-epidermis). CONCLUSION: These results clearly showed that Th17/Th22 cytokines, main inflammatory parameters, and psoriasis associated key biomarkers were inhibited by CEE in both 2D and 3D human in vitro models. Therefore, skin homeostasis could be restored by these modulator effects. Moreover, this high added value CEE was obtained by an ecofriendly bioprocess in contrast to traditional roots extracts. This is the first time that a well-defined CEE immune modulator has been proposed for psoriasis adjuvant care to reduce inflammation.

Bell-shaped agonist activation of 5-HT1A receptor-coupled Gαi3 G-proteins: Receptor density-dependent switch in receptor signaling.

A previous study observed bell-shaped concentration-response isotherms for activation of Gαi3 G-protein subunits by high efficacy 5-HT1A receptor agonists in a Chinese hamster ovary (CHO) cell line expressing high levels of these receptors. This suggested that a signaling switch took place in that cell line (from Gαi3 to activation of other G-proteins) but it was unclear if such effects are observed for 5-HT1A receptors in other cellular environments. Here, using an antibody capture-based [35S]GTPγS binding assay for Gαi3 activation, we investigated whether efficacious 5-HT1A receptor agonists (5-HT, F13714, befiradol, NLX-101), prototypical agonists ((+) and (-)8-OH-DPAT), and partial agonist, antagonists, inverse agonists (pindolol, WAY100635, spiperone) produced similar effects on 5 cell lines expressing different levels of human 5-HT1A receptors. In membranes from cell lines (HeLa, C6-glia and CHO-low) expressing moderate receptor levels (between 1 and 4 pmol/mg of protein), 5-HT, F13714, befiradol and NLX-101 elicited classical sigmoid concentration-response isotherms. In contrast, in cell lines (CHO-high, HEK-293F) expressing high receptor levels (>9 pmol/mg) these agonists elicited bell-shaped concentration-response isotherms that peaked at nanomolar-range concentrations and then returned to baseline or below. Spiperone elicited inverse agonist inhibitory sigmoid isotherms in all membrane preparations while WAY100635 was mostly 'silent' for Gαi3 activation. The other compounds elicited diverse responses in the different cell lines suggesting that other factors, in addition to receptor expression levels, could be influencing Gαi3 activation. These data indicate that Gαi3 G-protein activation by 5-HT1A receptor ligands is highly dependent on receptor expression levels and on cellular background. Moreover, the induction of bell-shape concentration-response isotherms by 5-HT and other high-efficacy agonists is consistent with a switch in signaling to other G-protein-mediated signaling cascades, possibly elicited by receptor conformational changes.

Impact of defoliation intensity and frequency on N uptake and mobilization in Lolium perenne.

The aim of the study was to evaluate the impact of defoliation intensity, defoliation frequency, and interactions with N supply on N uptake, N mobilization from and N allocation to roots, adult leaves, and growing leaves. Plants of Lolium perenne were grown under two contrasted N regimes. Defoliation intensity treatments consisted of a range of percentage leaf area removal (0, 25, 50, 75, or 100%). These treatments were applied in parallel to a set of plants previously undefoliated, and to a second set of plants which had been defoliated several times at a constant height. A (15)N tracer technique was used to quantify N uptake, mobilization, and allocation over a 7 d period. A significant reduction in plant N uptake was observed with the removal of more than 75% of lamina area, but only with high N supply. As defoliation intensity increased, the amount of N taken up and subsequently allocated to growing leaves during the labelling period was maintained at the expense of N allocation to roots and adult leaves. Increasing defoliation intensity increased the relative contribution of roots supplying mobilized N to growing leaves and decreased the relative contribution of adult leaves. Defoliation frequency did not substantially alter N uptake, mobilization, and allocation between roots, adult and growing leaves on a plant basis. However, tiller number per plant was largely increased under repeated defoliation, hence indicating that allocation and mobilization of N to growing leaves, on the basis of individual tillers, was decreased by defoliation frequency.

Exploration and motor activity in juvenile and adult rats exposed to hypergravity at 1.8 G during development: a preliminary report.

Pups from gestating rats exposed to hypergravity (1.8 G) or to normal gravity at the perinatal period were evaluated for motor activity, exploration and social interactions during juvenile and adult stages. By comparison to controls, the hypergravity group had shorter latencies before choosing a maze arm in a T-maze and a lower number of exploratory pokes in a hole board. During dyadic encounters, the hypergravity group had a lower number of self-grooming episodes and shorter latencies before crossing under the opposing rat. In contrast, no intergroup differences were observed during exploration of an elevated plus-maze and a light-dark box. These results indicate that exposure to 1.8 G during development appears to decrease exploratory tendencies in the hole board and fear-related responses in T-maze and social interaction tests.

Altered representation of peripersonal space in the elderly human subject: a sensorimotor approach.

The representation of the peripersonal space in humans and its modification with aging were studied by analyzing three-dimensional arm movements in healthy young and elderly adults. Participants drew ellipses in three reference planes (sagittal, frontal and horizontal), and errors in the orientation of ellipses with regard to the planes were measured. All subjects showed large disparities in the errors in different planes, errors were maximal in the horizontal plane. These findings imply that different planes are centrally represented with different errors and suggest that the mental representation of peripersonal space is anisotropic. Moreover, the elderly made larger errors than young subjects, regardless of the reference plane. Thus, the space representation is altered with aging. Compared with young adults, the elderly underestimate volume in space, a phenomenon that can be called the compression of space representation.

A study of mood changes and personality during a 31-day period of chronic hypoxia in a hypobaric chamber (Everest-Comex 97).

High altitudes of more than 3,000 meters produce physiological disorders and adverse changes in mood states. In the present study, we report analyses of mood states and personality traits in eight experienced climbers participating in a 31-day period of confinement in hypobaric chamber and gradual decompression from sea level to 8,848 m (Experiment 'Everest-Comex 97'). The subjects were tested at 5,500 m and 6,500 m on Day 13, 5,000 m and 6,500 m on Day 24, and 8,000 m and 8,848 m altitude on Days 27 and 31. Adverse changes in mood states, such as Vigor and Fatigue, occurred at 8,000 m and 8,848 m, which were significantly correlated with cerebral altitude symptomatology. In addition, a significant negative correlation was found between Fatigue and Factor C, which is a personality measure of emotional stability. We suggest that individuals with low emotional stability could be more sensitive to environmental stressors than more emotionally stable subjects who face reality.

Multi-muscle control of head movements in monkeys: the referent configuration hypothesis.

It is suggested that the nervous system may specify a referent configuration (R) of the body determined by the set of the threshold joint angles at which all skeletal muscles may be silent. At the same time, electromyographic (EMG) activity and forces are generated to resist deflections of the body from this configuration. The R configuration may thus be considered an internal geometric image with which the actual body configuration (Q) is compared. Thereby the difference between the R and Q is a major factor determining the recruitment and gradation of the activity of each skeletal muscle. Control systems may produce movements by changing the R configuration according to task demands. The referent hypothesis predicts that when the R and Q configurations match each other, a global minimum in the EMG activity of all muscles involved should occur, an event most likely observed in movements with reversal in direction. To test the validity of the R hypothesis for head movements, three-dimensional kinematics and EMG activity of 14 functionally diverse neck muscles were analysed in monkeys during head rotations to and from fruit targets placed beyond the oculomotor range. Despite the functional and anatomical diversity of the neck muscles, the activity of all muscles was minimised at a reversal point of the movement trajectory, as predicted by the R hypothesis. This study thus illustrates the notion that a change in the internal geometric image of a biomechanical system may underlie movement production.

Effects of dopaminergic agents and of an NMDA receptor antagonist on motor coordination in Lurcher mutant mice.

Lurcher mutant mice, characterized by an ataxic gait and olivocerebellar degeneration, were evaluated for motor coordination in the coat-hanger test after peripheral injections of two doses of dextromethorphan, a noncompetitive N-methyl-D-aspartate receptor antagonist, L-dopa/carbidopa, and SKF 77434, a dopamine D1 receptor agonist. There was an improvement in the distance traveled on the suspended horizontal string after 25 and 50 mg/kg of dextromethorphan and 37.5 mg/kg of L-dopa/carbidopa, but not after SKF 77434. None of the drugs reduced movement times or increased latencies before falling. These results indicate that NMDA receptor antagonism or stimulation of some dopaminergic mechanisms partially improve genetically determined cerebellar ataxia in mice.

An anxiety, personality and altitude symptomatology study during a 31-day period of hypoxia in a hypobaric chamber (experiment 'Everest-Comex 1997').

Extreme environmental situations are useful tools for the investigation of the general processes of adaptation. Among such situations, high altitude of more than 3000 m produces a set of pathological disorders that includes both cerebral (cAS) and respiratory (RAS) altitude symptoms. High altitude exposure further induces anxiety responses and behavioural disturbances. The authors report an investigation on anxiety responses, personality traits, and altitude symptoms (AS) in climbers participating in a 31-day period of confinement and gradual decompression in a hypobaric chamber equivalent to a climb from sea-level to Mount Everest (8848 m altitude). Personality traits, state-trait anxiety, and AS were assessed, using the Cattell 16 Personality Factor questionnaire (16PF), the Spielberger's State-Trait Anxiety Inventory (STAI), and the Lake Louise concensus questionnaire. Results show significant group effect for state-anxiety and AS; state-anxiety and AS increased as altitude increased. They also show that state-type anxiety shows a similar time-course to cAS, but not RAS. Alternatively, our results demonstrate a significant negative correlation between Factor M of the 16PF questionnaire, which is a personality trait that ranges from praxernia to autia. In contrast, no significant correlation was found between personality traits and AS. This suggests that AS could not be predicted using personality traits and further support that personality traits, such as praxernia (happening sensitivity), could play a major role in the occurrence of state-type anxiety responses in extreme environments. In addition, the general processes of coping and adaptation in individuals participating in extreme environmental experiments are discussed.

Performance of visually triggered wrist movements task in monkey: an application of information theory to evaluate deficits following unilateral substantia nigra pars reticulata lesion.

On the basis of an information theory approach, visual-motor efficiency (VME) was analyzed during pointing movement tasks in rhesus monkeys. This application was used to evaluate deficits in the ability to perform pointing movements as well as to chart the progress of the monkey during the chronic stage recovery period following unilateral lesion of the medial part of the substantia nigra pars reticulata. This unilateral lesion produced slight but significant chronic contralateral head roll tilt associated with body turning and induced profound modification of the VME at the beginning of the chronic stage of the symptomatology. Recovery developed in the following weeks, leading to a 3-fold increase in VME. However, at the end of the test (4 weeks postoperative), performance remained sub-normal: a decrease of 20-30% when compared to the control.

Muscular after-contraction and ongoing postural reactions in standing and sitting humans.

Muscular after-contraction (MA-C) and the ongoing postural reaction of the body was studied in standing and sitting subjects in two visual situations: eyes open or closed. EMG of trapezius and latissimus dorsalis and 3D kinematic recordings of the left scapula were analysed. The release of the long-lasting sustained isometric contraction at the level of the scapula produced a muscular after-contraction consisting of involuntary muscular contraction associated with a trunk movement similar to the unroll of a spiral. The unroll of the spiral is in the opposite direction when we compare the standing and sitting situations. We suppose that the muscular after-contraction reveals the activity of central tonigenic structures in evoking involuntary trunk movements in humans and stresses the importance of the initial postural situation (standing or sitting) and the visual condition in the characteristics of these involuntary movements.

General recommendations.

NASA: Recommendations from a workshop on Space Neuroscience Research held in Paris on April 22-24, 1997 are summarized. Research areas include the autonomic nervous system, development and neurobiology, posture and movement, visual perception, vestibular function, cognition, and human factors. Long-term neuroscience research studies are being planned for the International Space Station. Experiments in microgravity should be accompanied by appropriate, ground-based research on the effects of gravity.^ieng

Neurobehavioral evaluation of lurcher mutant mice during ontogeny.

Lurcher mutant mice were compared to normal littermate controls for body weight, body righting, negative geotropism, sensorimotor coordination (rotating grid, wire suspension, rotorod), and visuomotor coordination requiring swimming toward a pole during postnatal (P) days 0-30. Lurcher mutants had a lower body weight on P20-P30 and were slower before performing the complete body righting response on P13-P30. Because of postural instability during the negative geotropism test, lurcher mutants turned quicker up the slope than normal mice. The mutants fell sooner from the rotating grid on P11-P14, from the horizontal wire on P15-P16, and from the rotorod on P14-P30. Lurcher mutants were also slower before swimming to the pole or climbing to the top of the pole and were inferior in pole climbing height on P22-P30. These results indicate test-selective and time-selective neurobehavioral deficits during ontogeny in a spontaneous cerebellar mutant.

Sensorimotor learning in three cerebellar mutant mice.

Cerebellar damage occurs during developmental stages in three mutant mice (staggerer, hot-foot, and lurcher), causing disturbances in posture and equilibrium. During three tests of motor coordination, the performances of staggerer mutants was inferior to that of normal mice and did not improve with extended practice for up to 7 days of training. The sensorimotor performance of hot-foot mutants and of lurcher mutants was also lower than that of normal mice. Nevertheless, hot-foot mutants showed evidence of learning in two of the three tests and lurcher mutants in all three tests. Cerebellar atrophy in the latter two mutants did not prevent sensorimotor learning, but instead impaired their ability to reach the same level of performance as that of normal mice.

Spontaneous alternation, motor activity, and spatial learning in hot-foot mutant mice.

Hot-foot mutant mice, characterized by defective innervation of Purkinje cells and an ataxic gait, were less active than normal mice in a T-maze. In spontaneous alternation testing with either single or multiple trials, hot-foot mutants, contrary to normal mice, did not alternate above chance. Moreover, the mutants had a higher number of errors and higher escape latencies in a water-filled Z-maze. These results indicate that in addition to motor coordination deficits, these cerebellar mutants have deficits in spatial learning and perseverate choices of maze arms.

Dorsal striatal lesions in rats. 1: Effects on exploration and motor coordination.

Rats with small dorsal striatal lesions were compared to sham-operated controls in a series of test measuring their exploratory behavior in a T-maze, a hole-board, and an elevated plus-maze. Motor coordination was evaluated in the inclined grid and in the square bridge tests and grip strength in the wire suspension test. The rats with dorsal striatal lesions were not impaired in the motor coordination tests, the grip strength test, nor in spontaneous alternation. By contrast, an increase of emergence latencies in the elevated plus-maze and a reduction of motor activity in the hole-board confined space during the early part of testing were observed in rats with dorsal striatal lesions. These results are ascribed to a lesion-induced situation-specific increase in inhibition.

Dorsal striatal lesions in rats. 2: Effects on spatial and non-spatial learning.

Rats with small electrolytic lesions of the dorsal striatum were evaluated in acquisition of spatial learning, sensorimotor learning, and a straight runway food approach response and its extinction. No differences were detected between rats with dorsal striatal lesions and sham-operated controls during acquisition of hidden and visible trials in the Morris water maze. Neither was an intergroup difference observed during acquisition of the rotorod test of motor coordination. Lesioned rats were not impaired in running for a food reward, but their running latencies on day 2 of extinction were lower than those of controls, an indication of perseveration. These results indicate that perseverative responding may occur in dorsal striatal lesioned rats in the absence of spatial or sensorimotor defects.