- Email: [email protected]
063 Repurposing of atypical antipsychotic with high affinity against 5-HT7 receptors as antipruritic agent
Clinical Outcomes | ABSTRACTS 061
062
Premature aging in Cockayne syndrome due to a failure in ribosomal biogenesis? M Alupei1, P esser2, K Scharffetter-Kochanek1 and S Iben1 1 University of Ulm, Ulm, Germany and 2 University of freiburg, Freiburg, Germany Cockayne syndrome (CS) is a progeroid disease characterized by growth failure, neurological degeneration, loss of subcutaneous fat and cachexia. The mutations of this polygenic disease inactivate a subbranch of the DNA-repair pathway nucleotide excision repair (NER), thus Cockayne syndrome is regarded as a DNA-repair disease. As the total loss of DNA repair by the NER in xeroderma pigmentosum does not lead to childhood degeneration, alternative functions of the CS proteins might account for the disease. One common alternative function of the Cockayne syndrome proteins is the key step in ribosomal biogenesis, transcription by RNA polymerase I in the nucleolus. We investigated the cellular consequences of a failure of RNA polymerase I transcription in CS-cells and discovered a circulus vitiosus repressing ribosomal biogenesis. A disturbed RNA polymerase I transcription gives rise to ribosomes with a low translational fidelity that produce misfolded proteins. Misfolded proteins provoke endoplasmic reticulum stress and an unfolded protein response that represses RNA polymerase I transcription. The oxidative hypersensitivity of Cockayne syndrome cells might be due to oxidation of misfolded proteins. The elevated apoptosis rate of CS cells after oxidative challenge can be overcome by pharmacological chaperones that dampen endoplasmic reticulum stress and the unfolded protein response. Pharmacological chaperones are restoring proper RNA polymerase I transcription by de-repression thus breaking the circulus vitiosus. This might be a treatment opportunity for children suffering from premature aging. Moreover, loss of proteostasis due to a reduced translational fidelity of ribosomes might be a mechanism contributing to aging and aging associated diseases in humans.
Stress perception impacts on clinical signs of skin ageing and modifies the epigenome R Pattinson1, C Bundy1, L Cordingley1, S Kyle1, W Yeung1, G Beauchef2, A Nkengne2, A O’Callaghan3, CE Griffiths1 and RE Watson1 1 University of Manchester, Manchester, United Kingdom, 2 Laboratoire CLARINS, Pontoise, France and 3 Fios Genomics Ltd., Edinburgh, United Kingdom In this study we tested the commonly held assumption that stress affects the appearance of skin through the premature occurrence of clinical features of skin ageing (lines, wrinkles and dark under-eye circles). We recruited 84 healthy adult female volunteers (age range, 24 e 40 years; mean 30.74.7 years); each volunteer completed a comprehensive battery of psychological and sleep questionnaires (State-Trait Anxiety Inventory, Perceived Stress Score, Hospital Anxiety and Depression Scale, Pittsburgh sleep quality index [PSQI], Ford insomnia response to stress test [FIRST] and consensus sleep diary), clinical photography (VISIA-CRÒ) and provided a sample of whole blood for epigenetic analysis. Image analysis of clinical photographs allowed the objective quantification of wrinkles around the eye (eye bag and crow’s feet), the nasolabial fold and deep mid-forehead frown lines. Initial analysis correlated perceived stress with worse sleep patterns; those volunteers who perceived stress more keenly had significantly disturbed sleep as measured by PSQI and FIRST with reduced sleep efficiency (r2¼-0.22; P<0.05) and increased wakefulness after sleep onset (r2¼0.32; P<0.01). In addition, sleep onset latency positively correlated with increased measures for nasolabial folds, frown lines and crow’s feet wrinkles (r2¼-0.47; p<0.01). We next stratified the volunteers on the basis of their stress perception response to identify extreme groups (high stress response, n¼12; low stress response, n¼12) for epigenetic analysis of whole blood. Using Infinium HumanMethylation450BeadChip, principal component analysis identified significant clustering of methylation signatures between the two groups, with 484 differentially methylated regions observed (P<0.001). Hence, how an individual perceives psychological stress appears to impact on physical signs of skin ageing although the precise mechanism remains unclear.
063
064
Repurposing of atypical antipsychotic with high affinity against 5-HT7 receptors as antipruritic agent A Dogrul, M Seyrek, O Yesilyurt and M Deveci Pathology, Gulhane Academy of Medicine, Ankara, Turkey Atypical antipsychotic drugs have also been used off-label for the treatment of psychogenic pruritus. In addition to dopamine D2 receptors and serotonin 5-HT2A receptor blocking action, some second generation antipsychotics such as risperidone, olanzapine and paliperidone have a high affinity against serotonin 5-HT7 receptors. The involvement of 5-HT2A and 5-HT7 receptors have been shown in itch. Thus, in this study we examined the antipruritic action of risperidone, olanzapine and paliperidone. Adult male Balb-C mice (23-28 g) were used. The intradermal (i.d.) injection of 5-HT (25 mg), selective 5-HT7 receptor agonist LP 44 (100 mg), compound 48 80 (100 mg), Mrgpr A3 agonist chloroquine (150 mg) and PAR-2 activating peptide SLIGRL-NH2 (100 mg) induced scratches were counted for 30 min. The hapten-induced murine model with multiple features of atopic dermatitis and chronic allergic dermatitis was established using repeated oxazolone (0.5%) challenges into the nape of neck. Risperidone, olanzapine and paliperidone were given intraperitoneally (i.p.) 30 min prior to i.d. injection of pruritogen or the last oxazolone challenges and the scratches we counted for 30 min observation period. Risperidone, olanzapine and paliperidone (0.005, 0,01, 0.1, 0.2, 0.5 and 1 mg/kg) potently and dose dependently blocked i.d. injected 5-HT, LP 44, compound 48 80, chloroquine, SLIGRL-NH2-induced scratches and chronic oxazolone induced scratching behaviour. Our data provide evidence that atypical antipsychotic with a high affinity against 5-HT7 receptors elicit very potent antipruritic action: repurposing the some atypical antipsychotic seems a new strategy in the treatment of pruritus in somatic origin
The building of the bavarian electronic pollen information network - ePIN J Oteros1, M Sofiev2, M Smith3, C Traidl-Hoffmann4, A Menzel4, C Bergmann5, R Wachter6, B Clot7, C Schmidt-Weber1 and JT Buters1 1 Zentrum Allergie und Umwelt (ZAUM), Techical University Munich, Munich, Germany, 2 Finnish Meteorological Institute, Helsinki, Finland, 3 University of Worcester, Worcester, United Kingdom, 4 Techical University Munich, Augsburg, Germany, 5 Charite´, Berlin, Germany, 6 Polleninformationsdienst (PID), Ganderkesee, Germany and 7 Meteoswiss, Payerne, Switzerland Pollen monitoring is mostly performed manually. There is, however, a need for rapid reporting of pollen counts in addition to the alleviation of the workload of manual operation. We investigated the different steps needed for building an automatic pollen monitoring network in Bavaria, Germany. First, we tested the performance of the automatic pollen monitor BAA500, by comparing its data with data from a Hirst-type pollen trap at the same location. Next, during 2015, we built a new manual Bavarian pollen monitoring network with 27 Hirsttype pollen traps, including all closed but reopened operating traps from the German Polleninformation Network (PID). The selection of monitoring locations was based on: 1. Coverage of Bavarian land surface and population, but also 2. trying to represent the different environmental and climatic areas and 3. selecting the best positions to increase the predictability of pollen amounts based on forecasting models. Traps were located under optimal local monitoring conditions. The most informative locations were selected by applying redundancy and clustering analysis. Only 8 pollen traps are needed to cover most of variability in pollen dynamics. We found that three large groups of stations could be differentiated: 1. An extensive central cluster agglomerating most of the stations 2. a cluster agglomerating the stations located at the coldest areas of Bavaria and 3. a cluster of the Northern part of Bavaria. At the same time, we found the existence of eight sub-clusters related with different environmental conditions. We are now replacing these 8 manual stations by automatic pollen monitors and incorporating our network into local law to guarantee continuity.
www.jidonline.org S171
062
Premature aging in Cockayne syndrome due to a failure in ribosomal biogenesis? M Alupei1, P esser2, K Scharffetter-Kochanek1 and S Iben1 1 University of Ulm, Ulm, Germany and 2 University of freiburg, Freiburg, Germany Cockayne syndrome (CS) is a progeroid disease characterized by growth failure, neurological degeneration, loss of subcutaneous fat and cachexia. The mutations of this polygenic disease inactivate a subbranch of the DNA-repair pathway nucleotide excision repair (NER), thus Cockayne syndrome is regarded as a DNA-repair disease. As the total loss of DNA repair by the NER in xeroderma pigmentosum does not lead to childhood degeneration, alternative functions of the CS proteins might account for the disease. One common alternative function of the Cockayne syndrome proteins is the key step in ribosomal biogenesis, transcription by RNA polymerase I in the nucleolus. We investigated the cellular consequences of a failure of RNA polymerase I transcription in CS-cells and discovered a circulus vitiosus repressing ribosomal biogenesis. A disturbed RNA polymerase I transcription gives rise to ribosomes with a low translational fidelity that produce misfolded proteins. Misfolded proteins provoke endoplasmic reticulum stress and an unfolded protein response that represses RNA polymerase I transcription. The oxidative hypersensitivity of Cockayne syndrome cells might be due to oxidation of misfolded proteins. The elevated apoptosis rate of CS cells after oxidative challenge can be overcome by pharmacological chaperones that dampen endoplasmic reticulum stress and the unfolded protein response. Pharmacological chaperones are restoring proper RNA polymerase I transcription by de-repression thus breaking the circulus vitiosus. This might be a treatment opportunity for children suffering from premature aging. Moreover, loss of proteostasis due to a reduced translational fidelity of ribosomes might be a mechanism contributing to aging and aging associated diseases in humans.
Stress perception impacts on clinical signs of skin ageing and modifies the epigenome R Pattinson1, C Bundy1, L Cordingley1, S Kyle1, W Yeung1, G Beauchef2, A Nkengne2, A O’Callaghan3, CE Griffiths1 and RE Watson1 1 University of Manchester, Manchester, United Kingdom, 2 Laboratoire CLARINS, Pontoise, France and 3 Fios Genomics Ltd., Edinburgh, United Kingdom In this study we tested the commonly held assumption that stress affects the appearance of skin through the premature occurrence of clinical features of skin ageing (lines, wrinkles and dark under-eye circles). We recruited 84 healthy adult female volunteers (age range, 24 e 40 years; mean 30.74.7 years); each volunteer completed a comprehensive battery of psychological and sleep questionnaires (State-Trait Anxiety Inventory, Perceived Stress Score, Hospital Anxiety and Depression Scale, Pittsburgh sleep quality index [PSQI], Ford insomnia response to stress test [FIRST] and consensus sleep diary), clinical photography (VISIA-CRÒ) and provided a sample of whole blood for epigenetic analysis. Image analysis of clinical photographs allowed the objective quantification of wrinkles around the eye (eye bag and crow’s feet), the nasolabial fold and deep mid-forehead frown lines. Initial analysis correlated perceived stress with worse sleep patterns; those volunteers who perceived stress more keenly had significantly disturbed sleep as measured by PSQI and FIRST with reduced sleep efficiency (r2¼-0.22; P<0.05) and increased wakefulness after sleep onset (r2¼0.32; P<0.01). In addition, sleep onset latency positively correlated with increased measures for nasolabial folds, frown lines and crow’s feet wrinkles (r2¼-0.47; p<0.01). We next stratified the volunteers on the basis of their stress perception response to identify extreme groups (high stress response, n¼12; low stress response, n¼12) for epigenetic analysis of whole blood. Using Infinium HumanMethylation450BeadChip, principal component analysis identified significant clustering of methylation signatures between the two groups, with 484 differentially methylated regions observed (P<0.001). Hence, how an individual perceives psychological stress appears to impact on physical signs of skin ageing although the precise mechanism remains unclear.
063
064
Repurposing of atypical antipsychotic with high affinity against 5-HT7 receptors as antipruritic agent A Dogrul, M Seyrek, O Yesilyurt and M Deveci Pathology, Gulhane Academy of Medicine, Ankara, Turkey Atypical antipsychotic drugs have also been used off-label for the treatment of psychogenic pruritus. In addition to dopamine D2 receptors and serotonin 5-HT2A receptor blocking action, some second generation antipsychotics such as risperidone, olanzapine and paliperidone have a high affinity against serotonin 5-HT7 receptors. The involvement of 5-HT2A and 5-HT7 receptors have been shown in itch. Thus, in this study we examined the antipruritic action of risperidone, olanzapine and paliperidone. Adult male Balb-C mice (23-28 g) were used. The intradermal (i.d.) injection of 5-HT (25 mg), selective 5-HT7 receptor agonist LP 44 (100 mg), compound 48 80 (100 mg), Mrgpr A3 agonist chloroquine (150 mg) and PAR-2 activating peptide SLIGRL-NH2 (100 mg) induced scratches were counted for 30 min. The hapten-induced murine model with multiple features of atopic dermatitis and chronic allergic dermatitis was established using repeated oxazolone (0.5%) challenges into the nape of neck. Risperidone, olanzapine and paliperidone were given intraperitoneally (i.p.) 30 min prior to i.d. injection of pruritogen or the last oxazolone challenges and the scratches we counted for 30 min observation period. Risperidone, olanzapine and paliperidone (0.005, 0,01, 0.1, 0.2, 0.5 and 1 mg/kg) potently and dose dependently blocked i.d. injected 5-HT, LP 44, compound 48 80, chloroquine, SLIGRL-NH2-induced scratches and chronic oxazolone induced scratching behaviour. Our data provide evidence that atypical antipsychotic with a high affinity against 5-HT7 receptors elicit very potent antipruritic action: repurposing the some atypical antipsychotic seems a new strategy in the treatment of pruritus in somatic origin
The building of the bavarian electronic pollen information network - ePIN J Oteros1, M Sofiev2, M Smith3, C Traidl-Hoffmann4, A Menzel4, C Bergmann5, R Wachter6, B Clot7, C Schmidt-Weber1 and JT Buters1 1 Zentrum Allergie und Umwelt (ZAUM), Techical University Munich, Munich, Germany, 2 Finnish Meteorological Institute, Helsinki, Finland, 3 University of Worcester, Worcester, United Kingdom, 4 Techical University Munich, Augsburg, Germany, 5 Charite´, Berlin, Germany, 6 Polleninformationsdienst (PID), Ganderkesee, Germany and 7 Meteoswiss, Payerne, Switzerland Pollen monitoring is mostly performed manually. There is, however, a need for rapid reporting of pollen counts in addition to the alleviation of the workload of manual operation. We investigated the different steps needed for building an automatic pollen monitoring network in Bavaria, Germany. First, we tested the performance of the automatic pollen monitor BAA500, by comparing its data with data from a Hirst-type pollen trap at the same location. Next, during 2015, we built a new manual Bavarian pollen monitoring network with 27 Hirsttype pollen traps, including all closed but reopened operating traps from the German Polleninformation Network (PID). The selection of monitoring locations was based on: 1. Coverage of Bavarian land surface and population, but also 2. trying to represent the different environmental and climatic areas and 3. selecting the best positions to increase the predictability of pollen amounts based on forecasting models. Traps were located under optimal local monitoring conditions. The most informative locations were selected by applying redundancy and clustering analysis. Only 8 pollen traps are needed to cover most of variability in pollen dynamics. We found that three large groups of stations could be differentiated: 1. An extensive central cluster agglomerating most of the stations 2. a cluster agglomerating the stations located at the coldest areas of Bavaria and 3. a cluster of the Northern part of Bavaria. At the same time, we found the existence of eight sub-clusters related with different environmental conditions. We are now replacing these 8 manual stations by automatic pollen monitors and incorporating our network into local law to guarantee continuity.
www.jidonline.org S171