microrna-146a has therapeutic effects in seizure and ... filethe transient blockade of the...
TRANSCRIPT
microRNA-146a has therapeutic effects in seizure
and epilepsy models by reducing the IL-1R1/TLR4
signaling activation in neurons and glia
Valentina Iori
Lab. Experimental Neurology, Mario Negri Institute for Pharmacological Research,
Milan, Italy
MORE THAN NEURONS: toward a less neuronocentric view of brain disordersTorino, December 1-3, 2016
Epilepsy
About 30% of people with epilepsy have seizures poorly
or not controlled by the available AEDs
Epilepsy is a disorder of the brain characterized by an enduring predisposition
to generate epileptic seizures, and by the neurobiologic, cognitive, psychological
and social consequences of this condition (ILAE 2005, 2014)
There is an urgent need to develop novel treatments
affecting the key mechanisms involved in seizure pathogenesis
for either preventing the disease onset or ameliorating its course
Neuroinflammation in epilepsy
Clinical studies
ACTH, steroids, Ig, PEX, immunosuppressants
Increased inflammatory mediators inepileptogenic tissue
Therapeutic effects of large spectrumand specific anti-inflammatory treatments
Cytokines, Danger signals, Complement, COX-2, etc
Experimental studies
Anti-cytokines, COX inhibitors, oxidative stress
Epigenetic controlmiR-146a
Combinatorial anti-inflammatory treatmentVX-765 (IL-1) + Cyanobacterial LPS (TLR4)
Neuroinflammation Activation of the IL-1β/IL-1R1 & HMGB1/TLR4 system in epilepsy
X
Reviewed in Vezzani et al., BBI, 2011
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IL-1R1 or TLR4 antagonists, IL-1b synthesis inhibitors reduce seizure recurrence
Activated by brain injury/seizures in experimental and human epilepsy
Strategies to target neuroinflammation:
VX-765+CyP
miR-146a
VX-765
Pralnacasan
LPS-RS
BoxAAnakinraIfenprodil
MicroRNAs are small non-coding RNAs, which post-transcriptionally regulate gene expression by base-pairing totheir target mRNAs, mediating mRNA cleavage or translationalrepression
microRNAs in epilepsy
Changes in miRNAs expression occur both in experimental andhuman epileptic tissue(Nudelman et al, 2010; Jimenez-Mateos et al, 2011; Song et al, 2011; Hu et al, 2011 and 2012;Aronica et al, 2010 and 2012; Kanet al, 2012; Mc Kiernan et al, 2012; Omran et al, 2012; Sanoet al, 2012; see review Jimenez-Mateos & Henshall 2013; Alsharafi et al, 2015)
MicroRNAs are small non-coding RNAs, which post-transcriptionally regulate gene expression by base-pairing totheir target mRNAs, mediating mRNA cleavage or translationalrepression
microRNAs in epilepsy
Changes in miRNAs expression occur both in experimental andhuman epileptic tissue(Nudelman et al, 2010; Jimenez-Mateos et al, 2011; Song et al, 2011; Hu et al, 2011 and 2012;Aronica et al, 2010 and 2012; Kanet al, 2012; Mc Kiernan et al, 2012; Omran et al, 2012; Sanoet al, 2012; see review Jimenez-Mateos & Henshall 2013; Alsharafi et al, 2015)
Control TLE/FCD Epileptic rat
miR-146a is induced in glia and neurons in human and experimental epileptogenic foci, and it provides a feed-back inhibitory control of the activation of the IL-1R1/TLR4 axis in astrocytes (Aronica et al., 2010; Iyer et al., 2012)
Aim of the study
We studied whether epilepsy progression is inhibited
by increasing miR-146a level in seizure-generating brain areas
miR-146a up-regulation in epilepsy is an homeostatic inhibitory control mechanism of neuroinflammation, but its endogenous induction is not sufficient
to promote efficient control of IL-1R/TLR activation
Hypothesis
Using a synthetic miR-146a analog (Mimic), we studied the effects of miR-146a over-expression on seizure generation in experimental models
This inefficient control of neuroinflammation will, in turn,
contribute to seizure generation in epilepsy
The transient blockade of the IL-1R1/TLR4 pathway after
epilepsy onset using two complemetary treatment approaches
significantly improves the clinical course of the disease
Acknowledgements
Academisch Medisch Centrum:E. AronicaA. M Iyer
Mario Negri Insitute for Pharmacological Research:A. VezzaniT. RavizzaS. Marchini, L. Paracchini, L. Beltrame, M. D’IncalciM. Zucchetti, M. FerrariM. Cerovic, R. Brambilla
Thank you for your attention
Insubria University:M. Molteni, C. Rossetti
University of Washington:C. Hill, S. White