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Title: Hearing loss induced by bacterial meningitis : investigations into the possible involvement of : i) bacterial ototoxins ii) nitric oxide, excitotoxicity, and reactive oxygen species
Author: Drew, Shelley Jean
ISNI:       0000 0001 3432 8272
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 1999
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Background: At the commencement of this work there was evidence to suggest that a bacterial ototoxin, pneumolysin, was at least partly responsible for meningitis-induced hearing losses caused by Streptococcus pneumoniae type II; preliminary evidence existed for an ototoxin produced by Haemophilus influenzae type b (Hib). There was also evidence to suggest that: (i) excitatory amino acids (EAAs), nitric oxide (NO) and reactive oxygen species (ROSs) may also be involved in hearing losses induced by meningitis; (ii) N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors are involved in excitatory damage produced by EAAs in the cochlea, with non-NMDA receptors playing a predominant role; (iii) NO and ROSs mediated the ototoxic effects which ensue from activation of NMDA receptors in the cochlea. There were no reports concerning the possible involvement of NO and ROSs in the ototoxic effects which ensue from activation of non-NMDA receptors. Summary of this work: All bacterial extracts and other chemicals were perfused into the cochlea of anaesthetised guinea pigs and the level of ototoxicity of each extract/chemical was determined by recording auditory evoked potentials. 1. Attempts were made to demonstrate/identify ototoxins in cytoplasmic contents of -S'. pneumoniae type ITT, Hib and Neisseria meningitidis. Ototoxic activity was demonstrated in extracts of Hib, N. meningitidis and wild type S. pneumoniae type III. Tentative evidence was adduced to demonstrate the presence of a 'pneumolysin-like' protein in extracts of Hib and N. meningitidis. The amounts of this proteinpresent, estimated by inspection of SDS gel analyses of comparable gel loadings, reflected the ototoxic potency of these meningitogenic bacteria: S. pneumoniae > Hib > N. meningitidis (trace). In addition, extracts from a pneumolysin-deficient mutant of £ pneumoniae type III were ototoxic as were preparations of wild type extracts immunopurified with anti-pneumolysin immunosorbents; this suggests the possibility of another ototoxin in S. pneumoniae. 2. Evidence points to the possibility that excitotoxicity in the cochlea during meningitis contributes to some (particularly transient) hearing losses probably involving activation of non-NMDA, as well as NMDA receptors. If the non-NMDA receptors were definitively shown to be involved in the induction of deafness, it is unlikely that such effects would be mediated by NO, and ROSs, for the following reasons. NO synthase inhibitors (L-nitro arginine methyl ester (L-NAME) and L- methyl arginine (L-MA)) and ROS scavengers (Superoxide dismutase (SOD) and deferoxamine (DEF)) afforded no protection on cochleae from the excitotoxic actions of kainate and quisqualate - known agonists of non-NMDA receptors - as judged by electrophysiological and morphological criteria.
Supervisor: Not available Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)