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Activity of Essential Oils and Coumarins Against the Nematodes Caenorhabditis Elegans and Anisakis Simplex

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Activity of Essential Oils and Coumarins Against the Nematodes Caenorhabditis Elegans and Anisakis Simplex ACTIVITY OF ESSENTIAL OILS AND COUMARINS AGAINST THE NEMATODES CAENORHABDITIS ELEGANS AND ANISAKIS SIMPLEX Kristiina Tukiainen University of Helsinki Faculty of Pharmacy Division of Pharmaceutical Biosciences November 2018 Tiedekunta/Osasto Fakultet/Sektion – Faculty Osasto/Sektion– Department Faculty of Pharmacy Division of Pharmaceutical Biosciences Tekijä/Författare – Author Kristiina Tukiainen Työn nimi / Arbetets titel – Title Activity of essential oils and coumarins against the nematodes Caenorhabditis elegans and Anisakis simplex Oppiaine /Läroämne – Subject Pharmaceutical Biology Työn laji/Arbetets art – Level Aika/Datum – Month and year Sivumäärä/ Sidoantal – Number of pages Master’s Thesis November 2018 60 Tiivistelmä/Referat – Abstract Anisakiasis is a parasitic disease caused by larval nematodes of the genus Anisakis. Humans become infected by consuming contaminated raw or undercooked seafood products. Most human infections are caused by Anisakis simplex (A. simplex) complex. Currently there is no effective drug for this global emerging disease. Novel active compounds against the nematode are needed for drug development purposes. The research with A. simplex requires the isolation of the larvae from fish, which is time-consuming, unecological and uneconomical. Thus, the utilization of the model nematode Caenorhabditis elegans (C. elegans) in the research of A. simplex is considered in this study. Activities of Tea tree, Java citronella and Ho wood essential oils against C. elegans were studied. Aim of the assays was to examine whether C. elegans could be used as a model for A. simplex. Observed effects on C. elegans were compared to the previously reported effects on A. simplex. Activity of Tea tree and Java citronella essential oils against A. simplex was also examined to confirm previously reported activity. In addition, activity of six coumarins against A. simplex was investigated. The aim of the assays was to discover novel active compounds against the pathogenic nematode. Four coumarins were tested against C. elegans to examine possible comparable effects. Toxicity studies were performed in aquatic medium in a 6 well plate format (A. simplex) and in a 96 well plate format or in 1.5 mL Eppendorf tubes (C. elegans). Tea tree essential oil showed dose dependent activity against C. elegans, producing 100% mortality with the concentration 20 µL/mL after 24 hours exposure. Compared to A. simplex, two to three times higher doses were required to produce same degree of mortality in C. elegans. By contrast, Java citronella and Ho wood essential oils showed no significant activity against C. elegans. The activity of Tea tree and Java citronella essential oils against A. simplex was confirmed. The tested coumarins displayed no significant activity against the nematodes. Due to the contradictory results, further investigation about the suitability of C. elegans as a model for A. simplex is needed. Differences between the effective concentrations are probably caused by the differences in the biology of the nematodes, which result from the phylogenetic distance. Based on current results, the tested coumarins were excluded as potential antinematodal compounds against A. simplex, due to the lack of any significant activity on this model. Avainsanat – Nyckelord – Keywords Anisakis simplex, Caenorhabditis elegans, coumarins, essential oils, toxicity studies, model nematode, anisakiasis Säilytyspaikka – Förvaringställe – Where deposited Division of Pharmaceutical Biosciences Muita tietoja – Övriga uppgifter – Additional information Supervisors: Adjunct Professor Adyary Fallarero and Doctor Carlota Gómez-Rincón Tiedekunta/Osasto Fakultet/Sektion – Faculty Osasto/Sektion– Department Farmasian tiedekunta Farmaseuttisten biotieteiden osasto Tekijä/Författare – Author Kristiina Tukiainen Työn nimi / Arbetets titel – Title Eteeristen öljyjen ja kumariinien aktiivisuus Caenorhabditis elegans ja Anisakis simplex - sukkulamatoja vastaan Oppiaine /Läroämne – Subject Farmaseuttinen biologia Työn laji/Arbetets art – Level Aika/Datum – Month and year Sivumäärä/ Sidoantal – Number of pages Pro gradu -tutkielma Marraskuu 2018 60 Tiivistelmä/Referat – Abstract Anisakiaasi on Anisakis-sukuun kuuluvien sukkulamatojen toukkien aiheuttama loistauti. Ihmiset saavat tartunnan syömällä kontaminoituneita raakoja tai huonosti kypsennettyjä mereneläviä. Useimmat ihmisen infektiot ovat Anisakis simplex (A. simplex) -kompleksin aiheuttamia. Tällä hetkellä tähän maailmanlaajuiseen lisääntyvään tautiin ei ole tehokasta lääkettä. Tätä sukkulamatoa vastaan tarvitaan uusia aktiivisia yhdisteitä lääkekehitystarkoituksiin. A. simplex -tutkimus edellyttää toukkien eristämistä kaloista, mikä on aikaa vievää, epäekologista ja epätaloudellista. Täten tässä työssä tarkastellaan Caenorhabditis elegans (C. elegans) -sukkulamatomallin hyödyntämistä A. simplex -tutkimuksessa. Teepuun, Java sitronellan ja Ho-puun eteeristen öljyjen aktiivisuuksia tutkittiin C. elegans - matoa vastaan. Kokeiden tarkoituksena oli selvittää, voitaisiinko C. elegans -matoa käyttää A. simplex -madon mallina. C. elegans -madossa havaittuja vaikutuksia verrattiin aiemmin raportoituihin vaikutuksiin A. simplex -madossa. Myös Teepuun ja Java sitronellan eteeristen öljyjen aktiivisuutta A. simplex -matoa vastaan tutkittiin aiemmin raportoitujen vaikutusten varmistamiseksi. Lisäksi kuuden kumariinin aktiivisuutta A. simplex -matoa vastaan tutkittiin. Kokeiden tarkoituksena oli löytää uusia aktiivisia yhdisteitä patogeenistä sukkulamatoa vastaan. Neljää kumariinia testattiin C. elegans -matoa vastaan mahdollisten vertailukelpoisten vaikutusten tarkastelemiseksi. Toksisuustutkimukset suoritettiin vesiviljelyaineessa 6- kuoppalevyillä (A. simplex) ja 96-kuoppalevyillä tai 1,5 ml:n Eppendorf-putkissa (C. elegans). Teepuun eteerinen öljy osoitti annoksesta riippuvaa aktiivisuutta C. elegans -matoa vastaan, aiheuttaen 100 % kuolleisuuden pitoisuudella 20 µl/ml 24 tunnin altistuksen jälkeen. Verrattuna A. simplex -matoihin, kahdesta kolmeen kertaa suurempia annoksia tarvittiin tuottamaan samanasteinen kuolleisuus C. elegans -madoissa. Sitä vastoin Java sitronellan ja Ho-puun eteeriset öljyt eivät osoittaneet merkittävää aktiivisuutta C. elegans -matoa vastaan. Teepuun ja Java sitronellan eteeristen öljyjen aktiivisuus A. simplex -matoa vastaan vahvistettiin. Testatut kumariinit eivät osoittaneet merkittävää aktiivisuutta sukkulamatoja vastaan. Ristiriitaisista tuloksista johtuen lisätutkimuksia tarvitaan C. elegans -madon sopivuudesta A. simplex -madon malliksi. Erot vaikuttavien pitoisuuksien välillä aiheutuvat todennäköisesti sukkulamatojen biologisista eroista, jotka johtuvat fylogeneettisestä etäisyydestä. Tämänhetkisten tulosten perusteella testatut kumariinit hylättiin potentiaalisina A. simplex -sukkulamatoon tehoavina yhdisteinä, koska merkittävää aktiivisuutta ei havaittu tässä mallissa. Avainsanat – Nyckelord – Keywords Anisakis simplex, Caenorhabditis elegans, kumariinit, eteeriset öljyt, toksisuustutkimukset, sukkulamatomalli, anisakiaasi Säilytyspaikka – Förvaringställe – Where deposited Farmaseuttisten biotieteiden osasto Muita tietoja – Övriga uppgifter – Additional information Ohjaajat: Dosentti Adyary Fallarero ja Tohtori Carlota Gómez-Rincón ACKNOWLEDGEMENTS The experimental part of this thesis was performed in the Faculty of Health Sciences, San Jorge University, Spain. First, I would like to express my gratitude to late Professor Pia Vuorela, who encouraged and supported me to study abroad. I would like to thank Doctor Carlota Gómez-Rincón for the opportunity to work in her research group and for the guidance during the laboratory work. I would also like to thank Adjunct Professor Adyary Fallarero for the valuable and encouraging feedback during the writing process. I am grateful to Inés Reigada Ocaña and Cristina Moliner for their friendship, help and guidance in the laboratory. I would like to thank the staff and students of the San Jorge University, who were friendly and helpful during my stay in Spain. I am also grateful to my fellow exchange students for their friendship and support during this experience. I would like to acknowledge The Jubilee Fund, University of Helsinki and The Finnish Pharmacists' Society for the financial support. Finally, I would like to thank Markus Rudanko for the precious support during my studies. Espoo, November 19th 2018 Kristiina Tukiainen TABLE OF CONTENTS 1 INTRODUCTION...........................................................................................1 2 LITERATURE REVIEW................................................................................3 2.1 Anisakiasis....................................................................................................3 2.1.1 Epidemiology.............................................................................................3 2.1.2 Clinical features.........................................................................................4 2.1.3 Diagnosis, treatment and prevention.........................................................6 2.2 Nematodes....................................................................................................8 2.2.1 Phylogeny..................................................................................................9 2.2.2 Life cycle of Anisakis simplex and Caenorhabditis elegans...................10 2.2.3 Anthelmintic drugs..................................................................................15 2.3 Essential oils...............................................................................................16
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