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Title: Effects of KATP channel mutations on neurological function
Author: Gutiérrez, Caroline Lahmann
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Activating mutations in the ATP-sensitive potassium (KATP) channel cause neonatal diabetes mellitus (ND). In some patients, ND is accompanied by neurological symptoms including developmental delay, muscle hypotonia, balance and coordination problems, and hyperactivity- a condition known as iDEND syndrome. The majority of ND patients successfully manage their diabetes with sulphonylureas, which are selective blockers of the KATP channel. In the case of iDEND, it was hoped that sulphonylureas would also restore neurological function . However, the extent to which these drugs ameliorate these symptoms is not clear. In this thesis, I used mice hemizygously expressing the most common iDEND mutation (Kir6.2-V59M) selectively in neurones (nV59M mice) to assess the extent to which sulphonylureas modulate neuronal function in vivo. Interestingly, nV59M mice displayed reduced sensitivity to isoflurane anaesthesia, taking longer to lose their righting and withdrawal reflexes (LORR and LOWR, respectively). Systemic delivery of glibenclamide (a sulphonylurea) had no effect on the LORR (central nervous system mediated) although partially restored the LOWR (peripheral-reflex arc). Consistent with the idea that glibenclamide poorly modulates central nervous system activity in vivo, very low levels of glibenclamide were detected in the cerebrospinal fluid and brain of rats after systemic administration of the drug, despite high drug plasma levels. Furthermore, direct brain delivery of glibenclamide results in rapid transport out of the brain and into the blood . Taken together, the results presented in this thesis suggest that the inability of sulphonylureas to fully restore neurological function in iDEND patients is due to the failure of the drugs to accumulate in the brain at high enough concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available