- Author
-
A.A. Korotkov
- Title
- The role of microRNAs in epileptogenesis
- Subtitle
- Modulation of brain inflammation and the extracellular matrix
- Supervisors
- Co-supervisors
- Award date
- 7 May 2020
- Number of pages
- 258
- ISBN
- 9789082787177
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Epilepsy is a common chronic neurological disease of the brain, affecting more than 65 million people worldwide. Epileptogenesis is the process of the development and further progression of epilepsy. The current pharmacological treatments cannot adequately control seizure activity in about 30% of all epilepsy patients, therefore novel therapeutic approaches, directed at the prevention or modification of epileptogenesis are needed. MicroRNAs (miRNA, miRs) are a class of small non-coding RNAs that are able to control gene expression at the post-transcriptional level. In this thesis we aimed to investigate the involvement of miRNAs in the regulation of key epileptogenic processes in search for new therapeutic targets and miRNA-based approaches for the treatment of acquired epilepsy and associated co-morbidities. We identified the most commonly up-regulated miRNAs in epilepsy and studied their expression and cellular distribution in various epileptogenic pathologies, such as temporal lobe epilepsy (TLE), tuberous sclerosis complex (TSC) and traumatic brain injury (TBI). Furthermore, we investigated these miRNAs in experimental rat models of epileptogenesis and in vitro. The most commonly up-regulated miRNAs during epileptogenesis in the adult brain (miR132, miR142, miR146a and miR155) were found to be involved in the regulation of glial-mediated inflammation and ECM remodelling. In the developing brain miR34a was found to be involved in the regulation of corticogenesis. Our experiments as well as existing pre-clinical and clinical data indicate that miRNAs are able to regulate major processes associated with epileptogenesis. Therefore, modulating miRNAs could be a novel therapeutic approach in the treatment of epilepsy and associated co-morbidities.
- Persistent Identifier
- https://hdl.handle.net/11245.1/e7b07b98-c534-4b2e-98c9-72b40f23c591
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction & outline of the thesis
Chapter 2: Systematic review and meta-analysis of differentially expressed miRNAs in experimental and human temporal lobe epilepsy
Chapter 3: microRNA-132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro-epileptogenic factors in human cultured astrocytes
Chapter 4: Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
Chapter 5: Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation
Chapter 6: Increased miR34 expression in tuberous sclerosis complex during early development impairs corticogenesis and down-regulates cell-adhesion molecule contactin-3
Chapter 7: General discussion
Summary; Nederlandse samenvatting; List of publications; Portfolio; Curriculum vitae; Acknowledgements
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