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

X

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