Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment. A difficulty in synthesising an effective treatment for ALS stems from its heterogenous nature and that there are numerous pathological processes involved in progression. Therefore, the need for a therapy which can effectively target multiple pathways, thus being effective in treating numerous forms of the disease, is imperative.Ghrelin is an endogenous growth hormone that enhances appetite. ALS patients show reduced ghrelin, whilst having a lower body mass index, suggesting impaired ghrelin signalling contributes to disease progression, with ghrelin having been found to exert neuroprotective effects on primary murine motor neurons.
In chapter 2, to investigate the neuroprotective capabilities of ghrelin against the reactive oxygen species (ROS) hydrogen peroxide (H₂O₂), SH-SY5Y human neuroblastoma cells were utilised. In these experiments, treatment with ghrelin led to an increase in cell viability when cells were faced with H₂O₂ insult.
Chapter 3 utilised NSC-34 murine motor neuron-like cells to assess the effects of ghrelin on The cytokine TNF-α was utilised to mimic pro-inflammatory conditions observed in ALS patients. Ghrelin provided significant protection against cell death and improvements to cell viability. Subsequent experiments found that ghrelin treatment reduced caspase 3 activation, suggesting that ghrelin prevents apoptosis via inhibition of the caspase pathway.
In chapter 4, in order to further understanding of ghrelin’s ability to attenuate the immune response, BV-2 microglial cells, alone and in co-culture with NSC-34 cells were utilised. It was found that treatment with ghrelin led to a decrease in microglial CD68 expression, a proxy for lysosomal activity following LPS inducement. Pilot qPCR data (n=1) also suggests in addition to a reduction in proinflammatory cytokines, ghrelin treatment leads to an upregulation of anti-inflammatory cytokines. Therefore, future experiments should focus on understanding how ghrelin may modulate microglia from their active to tissue repair state.
The pathology of ALS and effects of ghrelin both involve a wide range of molecular pathways the data presented in this study highlight areas of interest for subsequent experiments involving shared aspects of ALS pathology and ghrelin, namely anti-inflammatory, mitochondrial and metabolic function.
Date of Award | 4 Dec 2024 |
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Original language | English |
Awarding Institution |
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Supervisor | Gayle Helane Doherty (Supervisor) |
Keywords
- ALS
- Motor neuron disease
- Ghrelin
- Leptin
- Metabolism
- Neuroendocrinology
Access Status
- Full text open