Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 8, Number 5, 2008
Contents
Recent Advances in the Biochemistry and
Treatment of Cysticercosis
Guest Editor: Marta C. Romano
Editorial Pp. 366-367
Cysticercosis in the Pig
Pp. 368-374
Aline S. de Aluja
[Abstract]
Morphology and Biochemistry of the Pork Tapeworm,
Taenia Solium Pp. 375-382
Kaethe Willms
[Abstract]
The Complex Role of Pro- and Anti-Inflammatory
Cytokines in Cysticercosis: Immunological Lessons fro Experimental
and Natural Hosts Pp. 383-392
Luis I. Terrazas
[Abstract]
Taenia solium: Antioxidant Metabolism Enzymes
as Targets for Cestocidal Drugs and Vaccines Pp.
393-399
F. Vaca-Paniagua, A. Torres-Rivera, R. Parra-Unda and
A Landa
[Abstract]
The Neuroimmunoendocrine Network in the Complex
Host-Parasite Relationship During Murine Cysticercosis
Pp. 400-407
J. Morales-Montor, G.Escobedo, J.A. Vargas-Villavicencio
and C. Larralde
[Abstract]
Are Hormones Relevant for the Search and Design
of Anti Parasitic Drugs? Pp. 408-414
Marta C. Romano, Ricardo A. Valdez, Lorena Hinojosa, Yolanda
Gómez and Pedro Jiménez
[Abstract]
Vaccines Against Cysticercosis Pp. 415-423
Edda Sciutto, Gladis Fragoso, Marisela Hernández,
Gabriela Rosas and Carlos Larralde
[Abstract]
Medical Treatment for Neurocysticercosis: Drugs,
Indications and Perspectives Pp. 424-433
Helgi Jung, Graciela Cárdenas, Edda Sciutto and
Agnes Fleury
[Abstract]
Molecule of Month Pp. 434
Abstracts
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Editorial
Parasite infections are common in many developing countries
and constitute a public health problem. Taenia solium
cysticercosis is still an important parasitosis in rural pigs
in many developing countries and affects millions of humans
in Asia, Africa and Latin America. The tapeworms produce thousand
of embryos in eggs that are infective for humans, causing
the human disease neurocysticercosis, and porcine cysticercosis
in the natural intermediate host, the pig. Recent reports
describe the appearance of neurocysticercosis cases in industrialized
countries where the disease has been eradicated.
The clinical and radiologic presentation of the disease is
highly heterogeneous because of diversity in parasite number,
localization, size and stage and intensity of nervous system
inflammation. Factors determining this diversity need to be
studied. Although the use of cysticidal drugs and a better
understanding of the host immune response have had important
advances in the last years, neurocysticercosis treatment is
not ideal because of adverse drug effects. The inflammation
triggered by the parasite can complicate the disease and be
the cause of severe sequelae, and the administration of cysticidal
drugs frequently increases local inflammation, which can increase
the severity of the disease. Hence, research on the biology
of the parasite, and search for new treatments, or improvement
of the traditional ones continue.
The purpose of the current issue of “Current Topics
in Medicinal Chemistry” is to review recent developments
in cysticercosis. This issue presents review articles from
eight groups of researchers who are involved in the investigation
of the physio-pathology and treatment of cysticercosis.
Aline Aluja opens the issue with a revision on aspects of
the swine disease. As stated above the pork is the intermediate
host of the parasite, and the ingestion of the undercooked
or raw infected meat by humans spreads the parasite. The ingestion
of the tapeworm eggs by the pig or humans cause cysticercosis
and neurocysticercosis. The chapter reviews the diagnostic
procedures in the pig and the macro and microscopic characteristics
of the developmental stages of cysticerci.
The second review by Kaethe Willms describes the ultrastructure
of the Taenia solium tapeworm and metacestode (cysticerci)
with special emphasis on the reproductive units of the adult
tapeworm called proglottids. The chapter reviews work on the
surface characteristics of the larval stage as well as the
experimental models developed to study morphological and physiological
traits of the adult tapeworm which include descriptions of
the tissue localization of glycogen deposits, calcium binding
proteins, myosin isoforms and gap junctions and steroid producing
enzymes.
The next review presented by Luis Terrazas, describes the
role of pro- and antinflammatory cytokines in cysticercosis
and the host-parasite interactions. The review also emphasizes
the importance of STAT-6 mediated signaling. It also describes
the dual role of macrophages in the pathology of the infection
and the immunomodulatory effect of glucocorticoids in the
treatment of cysticercosis.
The fourth review presented by Vaca-Paniagua, Torres-Rivera,
Parra-Unda and Abraham Landa focused on the role of three
antioxidant enzymes in different aspects of the disease. Oxidative
damage produced by reactive oxygen species (ROS) such as superoxide
anion (O2.-), hydrogen peroxide
(H2O2)
and hydroxyl radical are some of the major challenges that
the parasite must confront. Some of these enzymes are targets
for cestocidal drugs.
The review by Morales-Montor, Escobedo, Vargas-Villavicencio
and Larralde described the complex neuroimmunoen-docrine relationship
which develops in the course of the Taenia crassiceps
experimental cysticercosis. The role of sex-steroid hormones
in the immune profile, changes of c-fos expression in different
areas of the nervous system, are relevant points described
in the article.
The chapter by Romano, Valdez, Hinojosa, Gómez and
Jiménez focused on the endocrine capacity of parasites
and in the consequences on their own development. It also
discusses the result of blocking hormone effects or inhibiting
the enzymes involved in sterol synthesis in different parasites
and their relevance in the design of antiparasitic drugs.
The last two articles are related to the medical treatment
and prevention of cysticercosis. “Vaccines against cysticercosis”
by Sciutto, Fragoso, Hernández, Rosas and Larralde
reviews the current knowledge on vaccines against porcine
cysticercosis. It highlights new developments designed to
increase effectiveness by novel routes and delivery systems.
Finally, Jung, Cárdenas, Sciutto and Fleury revised
critical aspects of human cysticidal treatments used today,
discussing pharmacological aspects, therapy for the different
types of neurocysticercosis, control of associated inflammation,
as well as the side effects of medication.
I would like to offer my thanks to all the authors of this
special issue; this collection could not have been created
without their essential input. I also wish to thank Dr. A.B.
Reitz and E. Juaristi for the invitation to be the Guest Editor
of this special issue.
Marta C. Romano
Center for Research and Advanced Studies (CINVESTAV)
Dept. of Physiology, Biophysics and Neuroscience
Av. I.P.N. # 2508
Mexico, D.F., Mexico
E-mail: mromano@fisio.cinvestav.mx
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Cysticercosis in the Pig
Aline S. de Aluja
Taenia solium cysticercosis is still an important parasitosis
in rural pigs in many developing countries, México
among them. The main causes for the persistence of this condition
are lack of hygiene in the rural communities, lack of education
of the animal owners, lack of control in the trade of pigs
and their meat and lack of conscientious meat inspection.
The pig production systems in the marginated areas of Mexico
are briefly mentioned and it is stressed that among the important
reasons for the persistence of the reproductive cycle of Taenia
solium is the fact that appropriate toilet facilities
in village dwellings are not mandatory. The diagnostic methods
of cysticercosis in the living pigs and in their meat are
discussed and the degenerative stages of the larvae as well
as methods to test their viability are explained. The treatment
of infected pigs and their meat is discussed. Recommendations
for control programmes are given.
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Morphology and Biochemistry of the Pork Tapeworm, Taenia
Solium
Kaethe Willms
This chapter describes the life cycle, general morphology
and ultrastructure of the larval and adult stages of Taenia
solium, a parasitic flatworm of humans found in underdeveloped
countries. Experimental results describing the role of proteins
and glycoproteins in the host-parasite relationship, as well
as the various strategies the larval stage has developed to
evade the host immune responses are analyzed. Characteristics
of the tapeworm attachment site in the hamster intestine and
the host inflammatory reaction are reviewed. The general morphology
and ultrastructure of the experimental tapeworm is described,
with emphasis on muscle fiber distribution, the abundance
of cytoplasmic glycogen and its association with gap junctions,
the development of testis, structure of mature spermatids
and vas efferens. Recent descriptions of T. solium
actin, myosin and calreticulin components, metabolic
steroid pathways, apoptosis and glucose uptake of tapeworms
in the hamster model are reviewed.
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The Complex Role of Pro- and Anti-Inflammatory Cytokines in
Cysticercosis: Immunological Lessons from Experimental and
Natural Hosts
Luis I. Terrazas
Parasitic helminthes have developed complex mechanisms to
evade or modulate hosts responses. Studies on cysticercosis
are solid, but scarce. The most studied immunological models
of cysticercosis are Taenia crassiceps infecting
mice and T. solium infecting pigs. These parasites,
despite being widely exposed to the host, are able to modulate
the host immune system. Taenia metacestodes, much
like other helminthes parasites, have developed complicated
strategies in order to infect and successfully colonize their
hosts. We focus here on the accumulated evidence from experimental
models that have been helpful in analyzing and characterizing
the host immune response to cysticercosis. Moreover, the mouse
model has been used to design rationale vaccine strategies,
some of them with promising results. We also discuss recent
advances in understanding immune-regulation of cysticercosis.
The parasite is able to manipulate the host immune system
into supporting its survival by keeping a low inflammatory
profile by causing the production of some cysticerci-released
products that have immunomodulatory activities, as well as
promoting the raise of alternatively activated macrophages.
Finally, we delineate, according to recent literature, the
likely pathway involved in protection and susceptibility against
cysticercosis. As more aspects of the role of different immune
and parasite-derived molecules are elucidated, better therapeutic
targets may be identified to help treat cysticercosis.
[Back to top]
Taenia solium: Antioxidant Metabolism Enzymes as
Targets
for Cestocidal Drugs and Vaccines
F. Vaca-Paniagua, A. Torres-Rivera, R. Parra-Unda and
A. Landa
This review focuses in the role that antioxidant enzymes
play in protection and other important physiological functions
such as signal transduction, cell differentiation, growth
and apoptosis. Parasites use these enzymes to evade ROS produced
by the host immune response and for development inside the
host. In the cestoda Taenia solium, three antioxidant
enzymes have been studied: a cystosolic Cu,Zn superoxide dismutase
that is a target of cestocidal drugs (bencimidazoles); a 2-Cys
peroxiredoxin that is a regulatory enzyme of H2O2,
molecule essential for several physiological functions; and
two isoforms of glutathione transferases that are immunological
targets, since they protect immunized mice against cysticercosis.
Moreover, all these enzymes are present in all stages of the
parasite. These findings suggest that antioxidant enzymes
have an important role in T.solium physiology and
infection, therefore they might represent the Achilles’
heel of the parasite.
[Back to top]
The Neuroimmunoendocrine Network in the Complex Host-Parasite
Relationship During Murine Cysticercosis
J. Morales-Montor, G.Escobedo, J.A. Vargas-Villavicencio
and C. Larralde
SUMMARY We review here the role that sex steroids play
in experimental intraperitoneal Taenia crassiceps
cysticercosis of male and female BalbC/AnN mice. Briefly,
estrogens favour and androgens hinder the reproduction of
cysticerci by at least two main mechanisms: 1) through estradiol
tilting the TH2/TH1 immune system balance towards parasite-permissive
TH2 response,s accomplished by way of TH2which is IL-6 dependent
IL-6 mediating P450-aromatase over expression, shunting testosterone
towards estradiol and thus creating a positive feedback loop
which progressively favours TH2 response, blockings in turns
TH1 responses and furthers parasite growth; and 2) in vitro
estrogens and androgens acting directly upon the cysticercus
reproductive system, favoring or hindering, respectively,
its asexual reproduction. Later in infection, when parasite
loads are for milliarsimmense, male mice become estrogenized,
deandrogenized and diminish their copulative, aggressive and
social behaviors in association with P450-aromatase testis
overexpression. Changes in c-fos expression in different
areas of the infected mice brain of the infected mice point
to the additional connection of the central nervous systembrain
with the infection driven events, which senses and perhaps
reacts to infection with behavioral changes. This complex
immuneo-neuro-endocrine network management of parasite loads
in murine cysticercosis, and its physiological and behavioral
consequences upon the host, may be operative in other infections
of mammals. Such complexity may also help to explain the often
conflicting results, observed between infections with respect
to the role of the hosts sex, and hints to other avenues of
research and strategies for their treatment and control.
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Are Hormones Relevant for the Search and Design of Anti-Parasitic
Drugs?
Marta C. Romano, Ricardo A. Valdez, Lorena Hinojosa, Yolanda
Gómez and Pedro Jiménez
Over the last years the biology of many parasites that
infect humans and domestic animals has been intensively studied.
Considerable efforts were addressed to obtain information
on the parasite-host immune relationship. However, the knowledge
of the endocrine physiology of parasites and the consequences
of the local hormone production on the host tissues needs
further investigation. We review here literature and our own
studies on endocrine parasite capacities with special emphasis
on cysticercosis. Besides the biological interest, these investigations
may contribute to identify in the future alternative treatments
for the disease.
[Back to top]
Vaccines Against Cysticercosis
Edda Sciutto, Gladis Fragoso, Marisela Hernández,
Gabriela Rosas and Carlos Larralde
Taenia solium cysticercosis is a major parasitic disease
that seriously and frequently affects human health and economy
in undeveloped countries. Since pigs are an indispensable
intermediate host, it is conceivable to curb transmission
by reducing pig cysticercosis through their effective vaccination.
This article reviews current knowledge on the development
vaccines against porcine cysticercosis. It highlights the
development of several versions of S3Pvac aimed to increase
effectiveness, reduce costs and increase feasibility by novel
delivery systems and alternative routes of administration.
[Back to top]
Medical Treatment for Neurocysticercosis: Drugs, Indications
and Perspectives
Helgi Jung, Graciela Cárdenas, Edda Sciutto and
Agnes Fleury
Neurocysticercosis is one of the most frequent parasitic
diseases affecting the central nervous system. The introduction
of anticysticidal therapy in the early 80’s and the
concomitant improvement of the radiological techniques have
lead to apparently significant progress in patient prognosis.
However, due to the specificity of the disease, a great debate
has been generated on the real usefulness of cysticidal drugs.
This article revises and discusses the pharmacological aspects
of cysticidal treatment and summarizes current indications
for the different types of the disease.
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