Epilepsy Flashcards
epilepsy defintion
enduring predisposition so seizures
biol., cog., psych. and social consequences
two unprovoked seizures at least 24 hours apart
epilepsy syndrome definition
one unprovoked seizure and probability of >60% of reoccurence
based on family history, ruling out other conditions
status epileptica
seizures lasting hours to days to months
SUDEP
sudden unexplained death in epilepsy
probably something with brain stem
proportion pharmacoresistant epileptics
one third
epilepsy brain consequences
neuronal loss
unwanted neurogenesis
axonal and glial changes
BBB changes
animal epilepsy models
pharmacological by chemokines -> inflammation
electrode implantation -> status epileptica
epilepsy phases
acute phase
latent phase
chronic phase
microRNA
small
around 22 nucleotides
non-coding
binds to messenger RNA
fine-tune protein output
can stabilize and destabilise
silencing genes
by binding to mRNA
miRNA location
produced in nucleus
transported by exporting 5
cleaved into single strand by dicer
swimming around in cytoplasm
miRNA in epilepsy
affecting immune and inflammatory responses
sterile damage
damage originating from the brain itself
inflammatory responses in the brain
leaky BBB
glial activation
mitochondrial dysfunction
demyeliniation
astrocytes as epilepsy model
tissue from surgery
induction of inflammation through IL-1 beta
binding to astrocytes
producing IL-1beta and COX-2
upregulates miRNA146a
miRNA146a
mimics cell’s own miRNA
decreases IL-beta and Cox-2 secretion
-> anti-inflammatory
miRNA21
no effect
control miRNA
miRNA155
increases IL-1beta and Cox-2
-> inflammatory
miRNA147b
decreases IL-1beta
-> anti-inflammatory
anti-inflammatory miRNA as treatment
miRNA146a and 147b
reduces astrocyte proliferation
promotes neuronal differentiation
-> stem cells develop into neurons, not glia
-> less gloss
146a affects gene transcription through AP-1 and NFkB
miRNA in epilepsy phases
miRNA21 unregulated in all phases
miRNA146a, 147b and 155 highest in acute, lowest in latent
-> latent might be the window of opportunity
first animal model success in epilepsy
blockage of IL1R / TLR4 pathway
suppressing disease progress
miRNA134
regulates dendritic spine volume
via Plum2
-> influencing network excitability
miRNA135a
regulates excitatory synapse density
via Mef2 pathway
reduces seizures in chronic trials
delivery systems for miRNA
liposome
dendrimers
PEI particles
-> all have to be tested in animals again
Miravirsen
first miRNA drug
for hepatitis
in the liver
targeting miRNA122
proving the principle of miRNA drugs
antisense oligonucleotide therapy
works for Dravet syndrome
caused by SCN1 mutation
reduces seizures and SUDEP in mice
miRNA145a
biomarker candidate for epilepsy
leak out of dead cells
in acute phase
there might be different biomarkers for each phase
ROC
receiver operation characteristic curve
important in biomarker finding
area under the curve of true positive / false positive
0.5 is random
closer to 1 is better
isomiRNAs
variations on miRNAs
nucleotide additions
truncations
elongations
