- Author
- Title
- The epileptogenic trinity
- Subtitle
- Oxidative stress, brain inflammation and iron in epilepsy
- Supervisors
- Co-supervisors
- Award date
- 4 May 2021
- Number of pages
- 300
- ISBN
- 9789082787184
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Epilepsy is a neurological disease, characterized by an enduring predisposition to generate epileptic seizures, that affects approximately 65 million people worldwide. While anti-epileptic drugs can suppress seizures, approximately 30 % of patients present with drug-resistant epilepsy, requiring alternative treatments. The etiology of epilepsy is diverse, ranging from genetic mutations, such as in mTORopathies due to mutations in the mammalian target of rapamycin (mTOR) signaling pathway, to acquired epilepsy in response to i.a. acute brain injuries. In recent years, overproduction of seizure-mediated reactive oxygen species and oxidative stress (OS) have been appreciated as important contributers to epilepsy. Therefore, we aimed to investigate OS, its relation to inflammation and iron metabolism, and its contribution to cellular damage and altered neuronal circuitry in epileptogenesis and epilepsy.. In cortical brain tissue from the mTORopathies focal cortical dysplasia type 2 and tuberous sclerosis complex we identified a strong interconnection between OS and neuroinflammation, which was mediated by the ROS-sensitive transcription factor SPI1/PU.1 in cells with mTOR activation. Moreover, we discovered that pro-inflammatory factors produced by cells with mTOR activation may attract peripheral immune cells to the brain, exacerbating neuroinflammation. Additionally, we found chronic activation of the antioxidant transcription factor NRF2 via the inflammation-induced transcriptional modulator microRNA 155 which promotes release of pro-oxidant iron. Altered iron metabolism was also identified in the hippocampus of patients with temporal lobe epilepsy and accompanied by oxidative damage and overexpression of neuroinflammatory factors. We conclude that therapies targeting OS, neuroinflammation and/or iron metabolism warrant further exploration as novel epilepsy treatments.
- Persistent Identifier
- https://hdl.handle.net/11245.1/7268a2d5-f525-43bc-84f5-f85e4e72e45c
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: Molecular insights into their interdependence
Chapter 3: Balloon cells promote immune system activation in focal cortical dysplasia 2b
Chapter 4: Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress
Chapter 5: Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations
Chapter 6: Iron accumulation and dysregulated iron metabolism after status epilepticus and temporal lobe epilepsy
Chapter 7: General discussion
Chapter 8: English summary
Chapter 9: Nederlandse samenvatting
List of publications; Portfolio; Curriculum vitae; Acknowledgements
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