scholarly journals Evaluation of Indolocarbazoles from Streptomyces sanyensis as a Novel Source of Therapeutic Agents against the Brain-Eating Amoeba Naegleria fowleri

2020 ◽  
Vol 8 (5) ◽  
pp. 789
Author(s):  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
Luis Cartuche ◽  
Iñigo Arberas-Jiménez ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Ros Generation ◽  
Naegleria Fowleri ◽  
Lethal Infection ◽  
The Central Nervous System ◽  
Cell Membrane Disruption ◽  
Nægleria Fowleri ◽  
Opportunistic Pathogenic ◽  
Amoebic Meningoencephalitis ◽  
The Brain

Naegleria fowleri is an opportunistic pathogenic free-living amoeba which is able to rapidly colonize the central nervous system (CNS) and causes a lethal infection known as primary amoebic meningoencephalitis (PAM). Furthermore, more than 98% of the known cases of PAM are fatal and affect mainly children under 12 and young adults. Until now, no fully effective therapeutic agents against N. fowleri are available and hence the urgent need to find novel agents to treat PAM. At present, PAM therapy is based on the combination of amphotericin B, miltefosine, among others, with unwanted toxic effects. Recently, our team isolated various indolocarbazoles (ICZs) from the culture of a mangrove strain of Streptomyces sanyensis which showed activity against kinetoplastids and the Acanthamoeba genus. Hence, in this study, the activity of the previously isolated ICZs, staurosporine (STS), 7-oxostaurosporine (7OSTS), 4′-demethylamino-4′-oxostaurosporine, and streptocarbazole B, was evaluated against two type strains of N. fowleri. Furthermore, the performed activity assays revealed that STS was the most active ICZ presenting an inhibitory concentration 50 (IC50) of 0.08 ± 0.02 µM (SI 109.3). Moreover, STS induced programmed cell death (PCD) in the treated amoebae by triggering DNA condensation, mitochondrial disfunction, cell membrane disruption, and reactive oxygen species (ROS) generation. Therefore, STS could be a promising therapeutic agent against PAM.

scholarly journals Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1320 ◽  
Author(s):  
Andrea Güémez ◽  
Elisa García
Keyword(s):  
Molecular Mechanisms ◽  
Case Reports ◽  
Naegleria Fowleri ◽  
Initial Exposure ◽  
Immunomodulatory Agents ◽  
Primary Amoebic Meningoencephalitis ◽  
The Central Nervous System ◽  
Nægleria Fowleri ◽  
Amoebic Meningoencephalitis ◽  
The Brain

Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the “brain-eating amoeba.” This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low morbidity, it has shown a mortality rate of 98%, usually causing death in less than two weeks after the initial exposure. This review summarizes the most recent information about N. fowleri, its pathogenic molecular mechanisms, and the neuropathological processes implicated. Additionally, this review includes the main therapeutic strategies described in case reports and preclinical studies, including the possible use of immunomodulatory agents to decrease neurological damage.

scholarly journals Intranasal Coadministration of the Cry1Ac Protoxin with Amoebal Lysates Increases Protection against Naegleria fowleri Meningoencephalitis

2004 ◽  
Vol 72 (8) ◽  
pp. 4368-4375 ◽  
Author(s):  
Saúl Rojas-Hernández ◽  
Marco A. Rodríguez-Monroy ◽  
Rubén López-Revilla ◽  
Aldo A. Reséndiz-Albor ◽  
Leticia Moreno-Fierros
Keyword(s):  
Cholera Toxin ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Protective Effects ◽  
Naegleria Fowleri ◽  
Lethal Challenge ◽  
Mucosal Vaccines ◽  
Nægleria Fowleri ◽  
Adjuvant Effects ◽  
Amoebic Meningoencephalitis

ABSTRACT Cry1Ac protoxin has potent mucosal and systemic adjuvant effects on antibody responses to proteins or polysaccharides. In this work, we examined whether Cry1Ac increased protective immunity against fatal Naegleria fowleri infection in mice, which resembles human primary amoebic meningoencephalitis. Higher immunoglobulin G (IgG) than IgA anti-N. fowleri responses were elicited in the serum and tracheopulmonary fluids of mice immunized by the intranasal or intraperitoneal route with N. fowleri lysates either alone or with Cry1Ac or cholera toxin. Superior protection against a lethal challenge with 5 × 104 live N. fowleri trophozoites was achieved for immunization by the intranasal route. Intranasal immunization of N. fowleri lysates coadministered with Cry1Ac increased survival to 100%; interestingly, immunization with Cry1Ac alone conferred similar protection to that achieved with amoebal lysates alone (60%). When mice intranasally immunized with Cry1Ac plus lysates were challenged with amoebae, both IgG and IgA mucosal responses were rapidly increased, but only the increased IgG response persisted until day 60 in surviving mice. The brief rise in the level of specific mucosal IgA does not exclude the role that this isotype may play in the early defense against this parasite, since higher IgA responses were detected in nasal fluids of mice intranasally immunized with lysates plus either Cry1Ac or cholera toxin, which, indeed, were the treatments that provided the major protection levels. In contrast, serum antibody responses do not seem to be related to the protection level achieved. Both acquired and innate immune systems seem to play a role in host defense against N. fowleri infection, but further studies are required to elucidate the mechanisms involved in protective effects conferred by Cry1Ac, which may be a valuable tool to improve mucosal vaccines.

Exploring the Anti-Infective Value of Inuloxin A Isolated from Inula viscosa against the Brain-Eating Amoeba (Naegleria fowleri) by Activation of Programmed Cell Death

2020 ◽  
Vol 12 (1) ◽  
pp. 195-202
Author(s):  
Ikrame Zeouk ◽  
Ines Sifaoui ◽  
Aitor Rizo-Liendo ◽  
Iñigo Arberas-Jiménez ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Naegleria Fowleri ◽  
Nægleria Fowleri ◽  
The Brain

Primary amoebic meningoencephalitis with Naegleria fowleri: Clinical review

1996 ◽  
Vol 15 (3) ◽  
pp. 230-234 ◽  
Author(s):  
Nancy D.P. Barnett ◽  
Allen M. Kaplan ◽  
Robert J. Hopkin ◽  
Michael A. Saubolle ◽  
Mark F. Rudinsky
Keyword(s):  
Clinical Review ◽  
Naegleria Fowleri ◽  
Primary Amoebic Meningoencephalitis ◽  
Nægleria Fowleri ◽  
Amoebic Meningoencephalitis

iPS models of Parkin and PINK1

2015 ◽  
Vol 43 (2) ◽  
pp. 302-307 ◽  
Author(s):  
Aleksandar Rakovic ◽  
Philip Seibler ◽  
Christine Klein
Keyword(s):  
Dopaminergic Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Agents ◽  
Axonal Outgrowth ◽  
Disease Mechanisms ◽  
The Central Nervous System ◽  
Degenerative Disorder ◽  
Induced Pluripotent ◽  
Druggable Targets ◽  
The Brain

Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the unique possibility of studying disease mechanisms in human tissue that was otherwise not accessible, such as the brain. Of particular interest are the monogenetic forms of PD as they closely resemble the more common ‘idiopathic’ PD and, through the mutated protein, provide a clear research target in iPSC-derived neurons. Recessively inherited Parkin and PTEN-induced putative kinase 1 (PINK1) mutations have been investigated in this context and the present review describes the first insights gained from studies in iPSC-derived dopaminergic neurons, which comprise abnormalities in mitochondrial and dopamine homoeostasis, microtubular stability and axonal outgrowth. These new models of PD have a high translational potential that includes the identification of druggable targets, testing of known and novel therapeutic agents in the disease-relevant tissue using well-defined read-outs and potential regenerative approaches.

Naegleria fowleri Hemorrhagic Meningoencephalitis: Report of Two Fatalities in Children

2004 ◽  
Vol 19 (3) ◽  
pp. 231-233 ◽  
Author(s):  
Darin T. Okuda ◽  
Hank J. Hanna ◽  
Stephen W. Coons ◽  
John B. Bodenstelner
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Stem ◽  
Mass Effect ◽  
Severe Headache ◽  
Neurologic Examination ◽  
Naegleria Fowleri ◽  
Neck Stiffness ◽  
Nuchal Rigidity ◽  
Nægleria Fowleri ◽  
The Brain

Two cases of hemorrhagic meningoencephalitis secondary to Naegleria fowleri infection confirmed by postmortem analysis are described. The first patient is a 5-year-old boy who presented with a severe headache, neck stiffness, and lethargy. His neurologic examination was significant for somnolence and nuchal rigidity. Cerebrospinal fluid studies and structural neuroimaging were consistent with hemorrhagic meningoencephalitis. Another 5-year-old boy presented to a different institution 2 miles away in the same week with similar complaints. Both patients declined rapidly and expired within 48 hours of admission secondary to transtentorial herniation caused by the mass effect of inflammation, edema, and hemorrhage with displacement of the brain stem. Histopathologic and immunochemistry analysis of brain tissue revealed the presence of Naegleria trophozoites in both cases.

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