LA NEURODEGENERAZIONE E LA NEUROPLASTICITÀ NEI DIVERSI FENOTIPI DELLA SCLEROSI MULTIPLA

Diego Centonze

GRAY MATTER DEGENERATION IN MULTIPLE SCLEROSIS: A MATTER OF DENDRITES AND SYNAPSES?

What’s lost in the atrophic cortex and deep nuclei of MS brain?

Glia (astroglia, microglia)?

Neurons (somata, axons, dendrites)?

Kettenmann H et al., 2013 Neuron

Centonze D et al., 2009 J Neurosci

CHRONIC INFLAMMATION CAUSES SYNAPTIC DAMAGE AND DENDRITIC LOSS IN THE GRAY MATTER OF EAE MICE

THE INFLAMMATORY MILIEU DIFFERS IN RELAPSING AND PROGRESSIVE MS PATIENTS

Rossi S et al., 2011, Ann Neurol

Rossi S et al., 2014, Mult Scler

A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?

A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?

A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?

A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?

“Recent evidence implicates molecules classically associated with the peripheral immune system in the modulation of homeostatic synaptic plasticity. In particular, the pro-inflammatory cytokine TNFa, class I major histocompatibility complex, and neuronal pentraxin 2 are essential in the regulation of the compensatory synaptic response that occurs in response to prolonged neuronal inactivity.”

Wang G et al., Neural Plasticity 2012

TNFa ACTIVITY AND THE DOWNREGULATION OF ARC ARE KEY STEPS IN SYNAPTIC UP-SCALING

SYNAPTIC UP-SCALING IS MASSIVELY INDUCED IN A MOUSE MODEL OF PROGRESSIVE MS

Centonze D et al., J Neurosci 2009 Haji N et al., Exp Neurol 2012

EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS

Rossi S et al., 2014 Mult Scler

EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS

Rossi S et al., 2014 Mult Scler

EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS

Studer V et al., 2014 J Neuroimmunol

A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?

A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?

CSF FROM ACTIVE RMS PATIENTS ENHANCES THE FREQUENCY OF GLUTAMATERGIC SYNAPTIC CURRENTS IN BRAIN SLICES

Stimulating electrode

Recording electrode

Rossi S et al., 2011, Ann Neurol

CSF FROM ACTIVE RMS PATIENTS CAUSES NEURONAL SWELLING

Rossi S et al., 2011, Ann Neurol

IL-1b IS RESPONSIBLE FOR SYNAPTIC ALTERATIONS INDUCED BY CSF OF ACTIVE RMS PATIENTS

Rossi S et al., 2011, Ann Neurol

IL-1b/IL-1ra RATIO CORRELATES WITH INTRACORTICAL FACILITATION EXPLORED BY MEANS OF pp-TMS IN RMS PATIENTS

Rossi S et al., 2011, Ann Neurol

TO SUMMARIZE…

Musella A et al., 2015 Mult Scler

SUMMARY & CONCLUSIONS

The neurodegenerative process typical of MS seems to be mediated, at least in part, by excitotoxic mechanisms causing severe dendritic and synaptic loss in the gray matter.

Pro-inflammatory cytokines, such as TNF (in PMS) and IL-1 b (in RMS), mediate the abnormalities of excitatory synaptic transmission through post- (TNF) and pre-synaptic (IL-1 )b effects.

Understanding the specific mechanisms of inflammatory neurodegeneration in PMS and in RMS is crucial to develop treatments able to halt disease worsening and progression.

FREEDOMS: reduction in the rate of brain atrophyversus placebo over time

Chin P et al. Poster P350 presented at ENS 2012

Ch

an

ge in

mean

BV

fr

om

baselin

e (

%)

Placebo (n = 329)

Fingolimod 0.5 mg (n = 356)

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

0.00 24126

–0.2

−35% vs placebop=0.006

-0.84p<0.001

-0.22

-0.34

-0.50p=0.026

-0.65

-1.31

ITT population without multiplicity adjustments; p-values are for comparisons over Months 0-6, 0-12 and 0-24

FINGOLIMOD NORMALIZES ABNORMAL GLUTAMATERGIC TRANSMISSION IN EAE

Rossi S et al., 2012 Br J Pharmacol

FINGOLIMOD IS NEUROPROTECTIVE IN EAE BY PREVENTING GLUTAMATE-MEDIATED SYNAPTOPATHY

Rossi S et al., 2012 Br J Pharmacol