title: Quantitative screening for anticestode drugs based on changes in baseline enzyme secretion by Taenia crassiceps.
abstract: Neurocysticercosis (NCC), an infection of the brain with the larval stage of the Taenia solium tapeworm, is responsible for an estimated one-third of adult-onset epilepsy cases in regions of the world where it is endemic. Currently, anthelmintic drugs used for treatment of NCC are only partially effective, and there is, therefore, a pressing need for new therapeutic agents. Discovery of new anthelmintics with activity against T. solium has been limited by the lack of suitable sensitive assays that allow high-throughput screening. Using an in vitro culture system with Taenia crassiceps metacestodes, we demonstrate that changes in secretion of parasite-associated alkaline phosphatase (AP) and phosphoglucose isomerase (PGI) can be used to detect and quantify anthelmintic effects of praziquantel (PZQ), a drug with activity against T. solium. We applied two enzyme release assays to screen for anti-T. crassiceps activity in nonconventional antiparasitic drugs and demonstrate that nitazoxanide and artesunate induced release of both AP and PGI in differing time- and dose-related patterns. Furthermore, imatinib, a tyrosine kinase inhibitor previously reported to have parasiticidal activity against Schistosoma mansoni, also induced release of both AP and PGI in a dose-dependent manner, similar in pattern to that observed with the other anthelmintics. We also evaluated release of ATP into cyst supernatants as an indicator of drug effects but did not see any differences between treated and untreated cysts. These data provide the basis for rapid and quantitative screening assays for testing for anthelmintic activity in candidate anticestode agents.
authors.affiliation: Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. smahanty@niaid.nih.gov
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mahanty
authors.forename: Elise M
authors.initials: EM
authors.lastname: Madrid
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Nash
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism*; D000818:Animals; D000923:Anticestodal Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D001549:Benzamides / Q000494:pharmacology; D004827:Epilepsy / Q000469:parasitology; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020019:Neurocysticercosis / Q000188:drug therapy / Q000469:parasitology; D009574:Nitro Compounds; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000494:pharmacology; D011223:Praziquantel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013621:Taenia / Q000187:drug effects* / Q000201:enzymology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000923:Anticestodal Agents; D037621:Artemisinins; D001549:Benzamides; D009574:Nitro Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000077332:Artesunate; D011223:Praziquantel; D000068877:Imatinib Mesylate; D000469:Alkaline Phosphatase; D005956:Glucose-6-Phosphate Isomerase; C041747:nitazoxanide