title: An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease.
abstract: The role that glia play in neurological disease is poorly understood but increasingly acknowledged to be critical in a diverse group of disorders. Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease caused by a primary astroglial abnormality, to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. We further demonstrate that muscarinic cholinergic signaling works through downstream Gαq to control oxidative stress and death of neurons and glia. Importantly, we document increased muscarinic cholinergic receptor expression in Alexander disease model mice and in postmortem brain tissue from Alexander disease patients, and that blocking muscarinic receptors in Alexander disease model mice reduces oxidative stress, emphasizing the translational significance of our findings. We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well.
  
  
  CONCLUSIONS
  Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles.
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Liqun
authors: L
authors: Wang
authors: Waisman Center, and Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705.
authors: Tracy L
authors: TL
authors: Hagemann
authors: Waisman Center, and Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705.
authors: Albee
authors: http://orcid.org/0000-0001-6049-0521
authors: A
authors: Messing
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and mel_feany@hms.harvard.edu.
authors: Mel B
authors: MB
authors: Feany
mesh_terms: D000293:Adolescent; D000328:Adult; D038261:Alexander Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D002648:Child; D002675:Child, Preschool; D018678:Cholinergic Agents / Q000008:administration & dosage; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004330:Drosophila; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D009422:Nervous System Diseases / Q000188:drug therapy / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology*; D055815:Young Adult
chemical_list: D018678:Cholinergic Agents; D018727:Muscarinic Antagonists
keywords: Alexander disease; Drosophila; chemical screen; cholinergic signaling; glia