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Astrocytes and inflammation
Astrocytes (astro from the Greek Astron which means star, due to their star-like mor- phology) are abundantly present in the brain in various structurally and functionally distinct appearances. Astrocytes can be roughly divided into protoplasmic astrocytes and fibrous astrocytes, where the first type is mostly present in the grey matter of the brain and in the spinal cord, where they have highly branched processes with which they envelop neuronal synapses and blood vessels 109. Fibrous astrocytes are mostly found in the white matter of the brain, exhibit long unbranched processes with perivascular or subpial endfeet 109. Additionally, radial glia are elongated astroglia that are abundantly present during development. The processes of radial glia span from the ventricular to the outer cortex surface which plays a crucial role during neuronal migration 110. Additionally to the increased complexity and size of mammalian brain, human astro- cytes are approximately 2.2-2.5 times larger than in rodent brain and have about 10-fold more primary processes and even more fine processes than rodent astrocytes, enabling contact with approximately 20 times more synapses 111. Taken together with functional experiments that indicate a relationship between astrocyte complexity and cognitive performance 112, these numbers emphasize the importance of astrocytes in the human brain. Astrocytes serve critical roles in many key physiological processes like CNS devel- opment, barrier function, metabolic support, synaptic transmission, regulation of blood flow, higher and integrative brain functions, neuroprotection and response to injury 113.
In the epileptogenic brain, astrocytes are considered one of the most import- ant types of glial cells contributing to the neuroinflammatory response 94, 108, 114. CNS inflammation is accompanied by astrocytic cytokine release like interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα) or interleukin-6 (IL-6). These cytokines in turn induce other inflammatory factors like cyclooxygenase-2 (COX-2) via nuclear factor kappa-light- chain-enhancer of activated B cells (NF-κB)-mediated transcription, leading to increased excitability, excitotoxicity, epileptic seizures and general neurological dysfunction 108. In resected brain tissue from patients with epilepsy, increased expression of several inflam- matory factors was found, however, most prominent changes were evident in astrocytes, in which the expression of IL-1β, its receptor IL-1 type 1 receptor (IL-1R1), and NF-κB was most obvious 105, 106. Altogether, these data suggest an important role for astrocyte-medi- ated inflammation in epilepsy. Therefore, we will focus in this thesis specifically on astro- cytes and study their role in inflammatory processes related to epilepsy, in order to find interesting targets for manipulating inflammatory pathways as treatment for epilepsy.
Targeting inflammation: microRNAs?
Until now, many anti-inflammatory approaches have been tested in various experimental epilepsy models, but only a few anti-inflammatory drugs have been tested in clinical trials 95. Promising results have been shown in targeting the IL-1R pathway in experimental models of epilepsy and in several proof-of-concept clinical studies using various specific anti-inflammatory agents, but further research is needed before these pharmaceutical therapies can be used for patients 95. Since inflammatory pathways play a critical role in the generation of seizures and epileptic pathology, research is needed to find new approaches for specific modulation of these pathways. A promising new therapeutic