Abstract
Drug delivery to the central nervous system (CNS) by passing the blood-brain barrier (BBB) is limited to a small number of lipophilic and small molecule drugs. As a consequence, many brain-related conditions leading to neurodegeneration remain untreatable. This project investigates new modes of brain delivery, which improve the shortcomings of conventional dosage forms and avoid undesired side effects. Such is the case of the nasal route of administration, which is fast and non-invasive. It is proposed that small molecular weight drugs would reach the brain and avoid the BBB, by being transported through the olfactory and respiratory regions, in the upper part of the nasal cavity. Vaporised drugs could be transported intra or extracellularly through this pathway and address neurodegenerative diseases.The specific objectives of this study were to explore i) if Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) can be produced in vapour form by sublimation (the change from solid to gas without passing through the liquid phase) or vaporisation (the change from liquid to gas) using electronic cigarette technology, to potentially administer it to the CNS via the upper region of the nose, and ii) the effect of NSAIDs on microglial activation which can be used to measure neuroinflammation and potentially prevent neurodegeneration.
For the first objective, thermogravimetric and calorimetric analyses investigated if the test compounds (nambumetone, ibuprofen, indomethacin, and salicylic acid) could sublime. Microscopic observations of these compounds before, during, and after heating were recorded along with an evaluation of their crystallinity. Then, compound solubility in e-cigarette liquid was assessed by spectrophotometry.
For the second objective, the toxicity and inflammatory response of these NSAIDs and the endogenous prostaglandin (PGJ2) was assessed in N9 microglia mouse cultures. The toxicity of the proposed drugs and their concentrations were evaluated as cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT)-reduction assay. Then, the anti-inflammatory effect of NSAID treatment in response to lipopolysaccharide (LPS)-induced activation was investigated by quantifying the levels of the cytokines tumor necrosis factor alpha (TNF)-α and interleukin 1 beta (IL-1β ) with ELISA. Complementary to cytokine levels, NO production was assessed by measuring nitrite with the Griess reaction. Finally, the expression of inhibitor IkBα and transcription factor p65 (or nuclear factor NF-κB p65 subunit), by Western blot was semi-quantitatively analysed to determine if the nuclear factor kappa B (NF-κB) pathway was inhibited and therefore, causes the lower production of pro-inflammatory cytokines. To conclude, e-cigarette technology continues to have potential to deliver therapeutics to the CNS whilst avoiding side effects. Further studies are needed to develop a reliable tool to confirm efficacy of NSAIDs against microglia activation.
| Date of Award | 1 Oct 2019 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Sarah Thomas (Supervisor) & Gino Martini (Supervisor) |