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Comparative neurotoxicities of amphotericin B and amphotericin B methyl ester in mice and on oligodendrocytes in culture
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Nnodi, Oluchukwu U.. Comparative neurotoxicities of amphotericin B and amphotericin B methyl ester in mice and on oligodendrocytes in culture. Retrieved from https://doi.org/doi:10.7282/T3N015SR

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TitleComparative neurotoxicities of amphotericin B and amphotericin B methyl ester in mice and on oligodendrocytes in culture
NameNnodi, Oluchukwu U. (author); Reuhl, Reuhl R (chair); Robson, Mark G (internal member); Cooper, Keith R (internal member); Richardson, Jason (internal member); Borders, Donald B (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2014
Other Date2014-10 (degree)
SubjectToxicology, Amphotericin B, Neurotoxicology
Extent1 online resource (xv, 190 p. : ill.)
DescriptionAmphotericin B methyl ester (AME) similar to Amphotericin B (AMB), is a macrolide antibiotic highly effective against complex systemic fungal infections. Clinical data suggested AME was neurotoxic, but subsequent analysis of lots used in its only clinical-trial revealed contamination with AMB and multi-methylated AMB-derivatives. Accruing evidence suggests AMB not highly-purified AME causes neurotoxicity, thus, it is likely that AMB contributed to neurotoxicity observed during the AME trials. Preliminary assessment of adult Balb/c mice given alternate day intraperitoneal (i.p) AME to mimic the human dose used (5 mg/kg of body weight [b.w]) compared with similarly treated AMB mice was carried out after 1-month and 2-months of injections. Light microscopy of cerebral white matter stained with hematoxylin/eosin and luxol fast blue suggested AME caused less demyelination than AMB. AMB induced CNS demyelination persisted after 3-months of drug-cessation following 2-months of injections. The nuclear area factor (NAF) analysis of AMB-brains provides preliminary data that AMB may cause apoptotic change in cerebral white matter of mice. Myelin lesions were absent in AME-brains, and even after 5-months of day i.p treatment of adult mice with 7-mg/kg b.w of AME alone, ultrastructural myelin changes were minimal. Differentiated human oligodendrocyte cell line (MO3.13) exposed to 0.5-30µg/ml AMB or AME for 24 hours demonstrated a progressive increase in cytotoxicity as determined by dye exclusion. The lowest concentration of AMB to induce cell injury was 1µg/ml, whereas injury first appeared in AME-exposed cells at10 µg/ml, a concentration far exceeding those expected in clinical use. AMB at1µg/ml showed apoptotic nuclear change in cells colocalizing for propidium iodide and fluorescein diacetate. Confirmation with Hoechst and fluorescent inhibition of caspases labeling revealed a significant decrease in the NAF and an increase in caspase-3 and -9 activity, suggesting induction of the intrinsic mitochondrial apoptotic pathway. AMB also caused increased cytochrome c release with a significant loss of mitochondrial membrane potential (ΔΨΜ) that was refractory to rescue with Trolox as determined with JC-1 dye. Cytotoxicity was not observed in similarly treated AME-cells. Our data suggests that AMB, but not AME may induce oligodendrocytes cytotoxicity and mitochondrial damage, eventually diminishing ΔΨΜ with consequent apoptosis.
NotePh.D.
NoteIncludes bibliographical references
Noteby Oluchukwu U. Nnodi
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3N015SR
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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