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Sara Matos Santos Kyotorphin Derived Peptides in Pain and Alzheim

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Sara Matos Santos Kyotorphin Derived Peptides in Pain and Alzheim Universidade de Lisboa Faculdade de Medicina de Lisboa KYOTORPHIN DERIVED PEPTIDES IN THE RELATIONSHIP BETWEEN ANALGESIA AND ALZHEIMER’S DISEASE Sara Alexandra Matos dos Santos Doctorate in Biomedical Sciences Specialty in Medical Biochemistry 2014 Universidade de Lisboa Faculdade de Medicina de Lisboa KYOTORPHIN DERIVED PEPTIDES IN THE RELATIONSHIP BETWEEN ANALGESIA AND ALZHEIMER’S DISEASE Sara Alexandra Matos dos Santos Thesis supervised by Prof. Doctor Miguel Augusto Rico Botas Castanho Doctorate in Biomedical Sciences Specialty in Medical Biochemistry Todas as afirmações efectuadas no presente documento são da exclusiva responsabilidade do seu autor, não cabendo qualquer responsabilidade à Faculdade de Medicina de Lisboa pelos conteúdos nele apresentados. A impressão desta dissertação foi aprovada pelo Conselho Científico da Faculdade de Medicina de Lisboa em reunião de 22 de Abril de 2014. Acknowledgments During my PhD, I contacted and collaborated with many people that, in various ways, helped me to achieve my goals. I am thankful to all of them for their help and support. From these persons, I would like to highlight: Firstly, I am extremely grateful to Professor Miguel Castanho, my supervisor, for letting me join his group in the Institute of Molecular Medicine and for all the support and companionship he demonstrated during the development of my thesis. Without him and his critical and entrepreneurial spirit this work would have never been possible. I am honored to have worked under his supervision. The actual and past members of UBqF Unit (IMM, FMUL), for their support and friendship, and for receiving me so well. Specially to Marta Ribeiro for helping me to enter into a world far from my clinical day to day activities. To Sónia Sá Santos for all her help and the long hours working together in the pursuit of our projects. To Antónia Pinto for all her support and insight in the field of animal experimentation. The people of the Neurosciences Unit of the IMM for all the support and teaching in the field of animal behavior. The people from the Department of Experimental Biology in Oporto, Faculty of Medicine, formerly Institute of Histology and Embryology, especially Professor Isaura Tavares for all the collaboration. The people from the laboratory of metabolopathies of the Clinical Hospital of Santiago Compostela, especially Professors José Cocho and Laura Garcia-Nimo for all their willingness in helping with the development of mass spectrometry techniques to detect biomarkers in biological fluids. I thank the Instituto de Medicina Molecular and the Faculty of Medicine of the I University of Lisbon for providing all the facilities to perform my work and all people from there for the great atmosphere. I thank all my colleagues and staff who worked with me at the Hospital Prof Dr Fernando Fonseca, specially the Neurology and Anesthesiology services. I thank all the patients and their families for their willingness to participate, despite the difficult situations in which they find themselves. I thank them for keeping hope and the will to fight. I thank my friends Violeta and Baltazar for all the support and cherish during my long hours of work. Lastly, I want to thank my family for all their support, motivation and comprehension along this journey. To my grandmother Amélia, herself another victim of this terrible disease. To my parents, who always encouraged me to do my very best and to pursue my dreams. To Rui, for all his love, support and patience. And lastly, to the recently arrived baby Alice, an authentic revolution in our lives, for all the hope and joy she embodies. This thesis is dedicated to her, with all my love. II III Preface My PhD was devoted to the study of the possible relationship of pain and Alzheimer disease (AD) using the analgesic Kyotorphin as a bridge. I became very interested in the area of chronic pain still on the faculty of Medicine. Later, I started my hospital rotations and this area changed from a theoretical to a practical subject, since pain is one of the main complaints that drive patients to hospitals. The study and treatment of chronic pain were some of the reasons why I chose the residency in Anesthesiology. I always found laboratory work and basic research fascinating, so the possibility of working at the Institute of Molecular Medicine - Faculty of Medicine was a great opportunity to develop my PhD and link basic and clinical research. I was fortunate enough to know Professor Miguel Castanho and his group, who proposed me a translational project involving the study of the peptide kyotorphin in the relation between pain and neurodegeneration. This project conducted to pain evaluation in patients with the diagnosis of Alzheimer disease using validated scales. Later, the quantification of kyotorphin in the cerebro- spinal fluid of AD patients was determined. To achieve this, we collaborated with the laboratory of metabolopathies of the Hospital of Santiago Compostela, with the development of mass spectrometry techniques to detect KTP in biological fluids. The results were promising enough to advance further to the testing of kyotorphin derived peptides in an animal model of Alzheimer disease. During this path I worked with people specialized in the various fields the work involved, namely pain, neurosciences and biochemistry, which was a very enriching experience. My PhD work originated the following papers, most of them already published: I. Biomedical applications of di- and tri-peptides Santos SM, Torcato I, Castanho M Biopolymeres Peptide Science (2012) Volume 98, Issue 4, pages 288–293 (DOI: 10.1002/bip.22067) IV II. The use of visual analogue scales to compare pain between patients with Alzheimer’ disease and patients without any known neurodegenerative disease and their caregivers. Santos SM, Castanho M Am J Alzheimer’s Dis and Other Demen (2013) (DOI: 10.1177/1533317513517046) [Epub ahead of print] III. Neuropeptide kyotorphin (tyrosyl-arginine) has decreased levels in the cerebro- spinal fluid of Alzheimer’s disease patients: potential diagnostic and pharmacological implications. Santos SM; Garcia-Nimo L, Sá Santos S, Tavares I, Cocho JA, Castanho MARB. Frontiers in Aging Neuroscience (2013) Volume 5, Article 68 (DOI: 10.3389/fnagi.2013.00068) IV. Amidated and ibuprofen conjugated kyotorphins are neuroprotective in the hippocampus and improve spatial working memory after bilateral carotid occlusion in female rats In preparation V. Side effects of analgesic Kyotorphin derivatives: advantages over clinical opioid drugs Ribeiro MM, Santos SS, Sousa DS, Oliveira M, Santos SM, Heras M, Bardaji E, Tavares I, Castanho M Amino Acids (2013) Volume 45, Issue 1, pages 171-178 (DOI: 10.1007/s00726-013- 1484-2) This dissertation is divided into 5 sections. In the first section the reader can find an introduction to the complexity of pain physiological pathways and to the complexity of endogenous opioid peptides as well as the potential of peptides to treat pain conditions, with a particular focus on kyotorphin. In this chapter the reader can also V find a brief approach to the pathophysiology and actual therapeutic options for Alzheimer´s disease. In sections 2 and 3 different studies carried out within the context of this thesis are presented, in the form of scientific papers. A general conclusion of all results is presented in Chapter 4. There were two key papers seminal to this work: the first (Ribeiro, 2011a) is a paper on the subject of the inhibition of nociceptive responses after systemic administration of amidated kyotorphin and the second (Ribeiro, 2011b) is a paper showing that the chemical conjugation of Kyotorphin and Ibuprofen enhances brain targeting and analgesia. Both papers originated from the same investigation group and support the later work, condensed in this dissertation. In this dissertation, two distinct referencing methods were followed. The References cited along the thesis (excluding articles) are listed in section 5, sorted alphabetically by first author’s last name. Within each paper published, the format of the References cited comply with the guidelines defined by the respective journal and are listed at the end of the articles. VI Abbreviations and Symbols -OR – delta opioid receptor -OR – kappa opioid receptor µ-OR – mu opioid receptor BBB – blood-brain barrier CNS – central nervous system i.c.v. - intracerebroventricular i.p. – intra-peritoneal IASP – International Association for the Study of Pain Ib – ibuprofen IbKTP – kyotorphin linked to ibuprofen IbKTP-NH2 – kyotorphin-amide linked to ibuprofen KTP – kyotorphin KTP-NH2 – kyotorphin amide KTPr – kyotorphin specific receptor NO – nitric oxide NOP – nociceptin/orphanin receptor NSAIDs – non-steroidal anti-inflammatory drugs DRG - dorsal root ganglia AD – Alzheimer´s Disease Ach – Acetylcholine MCI - mild cognitive impairment CSF - cerebrospinal fluid VII Resumo O aumento da esperança média de vida tem provocado um aumento na incidência de doenças relacionadas com o processo de envelhecimento. Entre estas, destacam-se as doenças neurodegenerativas, nomeadamente a Doença de Alzheimer (DA), e outras entidades associadas a fenómenos de dor crónica. A possível correlação entre duas entidades – dor e doença de Alzheimer - com uma carga epidemiológica tão grande afigura-se um passo relevante. A dor, hoje considerada como 5º sinal vital e presente numa larga camada da população, encontra-se ainda de grande modo sub-tratada, sendo necessários novos fármacos que actuem em alvos diferentes e que, ao mesmo tempo, tenham uma menor panóplia de efeitos adversos. Por outro lado, a doença de Alzheimer é uma patologia largamente disseminada na nossa população, afectando primariamente as camadas idosas mas também e cada vez mais uma população mais jovem. O desconhecimento, a complexidade dos processos bioquímicos e fisiológicos envolvidos e a progressiva perda cognitiva dos pacientes resultam em terapêuticas ainda pouco eficazes. O aumento do conhecimento científico sobre a doença aos vários níveis é a via obrigatória para assegurar uma melhoria na prestação de cuidados de Saúde apropriados e aumentar a possibilidade de intervir em estadios precoces da doença, inclusivamente ao nível da prevenção e diagnóstico.
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