Epidermal Overexpression of Stratum Corneum Chymotryptic Enzyme in Mice: A Model for Chronic Itchy Dermatitis

Identification of tissue-specific mechanisms involved in the pathophysiology of inflammatory skin diseases could offer new possibilities to develop effective therapies with fewer systemic effects. The serine protease stratum corneum chymotryptic enzyme is preferentially expressed in cornifying epithelia. We have previously reported on increased expression of the stratum corneum chymotryptic enzyme in psoriasis. Here is reported an increased epidermal expression of stratum corneum chymotryptic enzyme also found in chronic lesions of atopic dermatitis. Transgenic mice expressing human stratum corneum chymotryptic enzyme in suprabasal epidermal keratinocytes were found to develop pathologic skin changes with increased epidermal thickness, hyperkeratosis, dermal inflammation, and severe pruritus. The results suggest that stratum corneum chymotryptic enzyme may be involved in the pathogenesis of inflammatory skin diseases, and that stratum corneum chymotryptic enzyme and related enzymes should be evaluated as potential targets for new therapies

A New Mouse Model to Study Acquired Lymphedema

Schneider and colleagues say that the new model, published in PLoS Medicine, promises to increase our understanding of lymphedema and hopefully accelerate the development and testing of new treatments

A robust human norovirus replication model in zebrafish larvae.

Human noroviruses (HuNoVs) are the most common cause of foodborne illness, with a societal cost of $60 billion and 219,000 deaths/year. The lack of robust small animal models has significantly hindered the understanding of norovirus biology and the development of effective therapeutics. Here we report that HuNoV GI and GII replicate to high titers in zebrafish (Danio rerio) larvae; replication peaks at day 2 post infection and is detectable for at least 6 days. The virus (HuNoV GII.4) could be passaged from larva to larva two consecutive times. HuNoV is detected in cells of the hematopoietic lineage and the intestine, supporting the notion of a dual tropism. Antiviral treatment reduces HuNoV replication by >2 log10, showing that this model is suited for antiviral studies. Zebrafish larvae constitute a simple and robust replication model that will largely facilitate studies of HuNoV biology and the development of antiviral strategies

Nephrotoxic Effects in Zebrafish after Prolonged Exposure to Aristolochic Acid

With the aim to explore the possibility to generate a zebrafish model of renal fibrosis, in this study the fibrogenic renal effect of aristolochic acid I (AAI) after immersion was assessed. This compound is highly nephrotoxic able to elicit renal fibrosis after exposure of rats and humans. Our results reveal that larval zebrafish at 15 days dpf (days post-fertilization) exposed for 8 days to 0.5 µM AAI showed clear signs of AKI (acute kidney injury). The damage resulted in the relative loss of the functional glomerular filtration barrier. Conversely, we did not observe any deposition of collagen, nor could we immunodetect α-SMA, a hallmark of myofibroblasts, in the tubules. In addition, no increase in gene expression of fibrogenesis biomarkers after whole animal RNA extraction was found. As zebrafish have a high capability for tissue regeneration possibly impeding fibrogenic processes, we also used a tert-/- zebrafish line exhibiting telomerase deficiency and impaired tissue homeostasis. AAI-treated tert-/- larvae displayed an increased sensitivity towards 0.5 µM AAI. Importantly, after AAI treatment a mild collagen deposition could be found in the tubules. The outcome implies that sustained AKI induced by nephrotoxic compounds combined with defective tert-/- stem cells can produce a fibrotic response.status: publishe

Zebrafish-based identification of apicularen A as an anticonvulsant compound from myxobacteria

Purpose: Given the need for new and improved anti-epileptic drugs, this study focused on the identification of new anticonvulsant compounds from myxobacterial origin, using zebrafish larvae as the primary screening model. Methods: A library of 242 myxobacterial compounds from the Helmholtz Centre for Infection Research was screened for neuroactivity by the zebrafish photomotor response (PMR) assay. Next, neuroactive hits were screened for anticonvulsant activity by the zebrafish pentylenetetrazole (PTZ) seizure assay. Anticonvulsant activity was further investigated by local field potential (LFP) recordings of the zebrafish midbrain to evaluate the effect of a compound on PTZ-induced epileptiform discharges. Finally, anticonvulsant activity was investigated in the mouse timed i.v. PTZ assay to investigate activity in the mouse model. Results: 56 myxobacterial compounds were identified as neuroactive by the PMR assay. 24 selected neuroactive hits were screened for anticonvulsant activity by the zebrafish PTZ assay. 8 compounds were identified as anticonvulsant hits and confirmed for their activity. Among them, apicularen A significantly reduced PTZ-induced seizure behavior with high efficacy in a concentration-dependent manner and significantly reduced PTZ-induced epileptiform discharges. Moreover, apicularen A significantly increased the PTZ dose needed to trigger forelimb clonus in the mouse timed i.v. PTZ assay. Conclusions: Myxobacteria are increasingly recognized as producers of bioactive secondary metabolites and can be considered as a rich source for drug discovery. In this study, we identified for the first time anticonvulsant myxobacterial compounds using a zebrafish-based screening approach. The anticonvulsant activity of apicularen A was verified by LFP recordings of the zebrafish midbrain and confirmed in the mouse timed i.v. PTZ model. Our results not only support the potential of myxobacterial compounds, but expand their utility as an interesting source for anti-epileptic drug discovery.status: publishe

(EN) TREATMENT OF EPILEPSY (FR) TRAITEMENT DE L'ÉPILEPSIE

(EN) The present invention discloses pseurotins and azaspirofurans and their use in the treatment and prevention in epilepsy and other seizures. The present invention further discloses methods to screen pseurotin- and azaspirofuran- like molecules as pharmaceutically active compounds. (FR) La présente invention concerne des pseurotines et des azaspirofuranes et leur utilisation dans le traitement et la prévention de l'épilepsie et d'autres crises épileptiques. La présente invention concerne en outre des procédés pour cribler des molécules similaires à la pseurotine et à l’azaspirofurane en tant que composés pharmaceutiquement actifs

Cell Imaging Counting as a Novel Ex Vivo Approach for Investigating Drug-Induced Hepatotoxicity in Zebrafish Larvae

Drug-induced liver injury (DILI) is the most common reason for failures during the drug development process and for safety-related withdrawal of drugs from the pharmaceutical market. Therefore, having tools and techniques that can detect hepatotoxic properties in drug candidates at an early discovery stage is highly desirable. In this study, cell imaging counting was used to measure in a fast, straightforward, and unbiased way the effect of paracetamol and tetracycline, (compounds known to cause hepatotoxicity in humans) on the amount of DsRed-labeled hepatocytes recovered by protease digestion from Tg(fabp10a:DsRed) transgenic zebrafish. The outcome was in general comparable with the results obtained using two reference methods, i.e., visual analysis of liver morphology by fluorescence microscopy and size analysis of fluorescent 2D liver images. In addition, our study shows that administering compounds into the yolk is relevant in the framework of hepatotoxicity testing. Taken together, cell imaging counting provides a novel and rapid tool for screening hepatotoxicants in early stages of drug development. This method is also suitable for testing of other organ-related toxicities subject to the organs and tissues expressing fluorescent proteins in transgenic zebrafish lines.status: publishe