1. LA NEURODEGENERAZIONE E LA NEUROPLASTICITÀ NEI DIVERSI FENOTIPI DELLA SCLEROSI MULTIPLA Diego Centonze

4. 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

5. Centonze D et al., 2009 J Neurosci CHRONIC INFLAMMATION CAUSES SYNAPTIC DAMAGE AND DENDRITIC LOSS IN THE GRAY MATTER OF EAE MICE

6. THE INFLAMMATORY MILIEU DIFFERS IN RELAPSING AND PROGRESSIVE MS PATIENTS Rossi S et al., 2011, Ann Neurol Rossi S et al., 2014, Mult Scler

7. A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS? A PREFERENTIAL ROLE FOR IL-1  IN THE NEURODEGENERATIVE PROCESS OF RMS?

8. A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS? A PREFERENTIAL ROLE FOR IL-1  IN THE NEURODEGENERATIVE PROCESS OF RMS?

9. “Recent evidence implicates molecules classically associated with the peripheral immune system in the modulation of homeostatic synaptic plasticity. In particular, the pro- inflammatory cytokine TNF , 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.”

10. Wang G et al., Neural Plasticity 2012 TNF  ACTIVITY AND THE DOWNREGULATION OF ARC ARE KEY STEPS IN SYNAPTIC UP-SCALING

11. 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

12. EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS Rossi S et al., 2014 Mult Scler

13. EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS Rossi S et al., 2014 Mult Scler

14. EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS Studer V et al., 2014 J Neuroimmunol

15. A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS? A PREFERENTIAL ROLE FOR IL-1  IN THE NEURODEGENERATIVE PROCESS OF RMS?

16. 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

17. CSF FROM ACTIVE RMS PATIENTS CAUSES NEURONAL SWELLING Rossi S et al., 2011, Ann Neurol

18. IL-1  IS RESPONSIBLE FOR SYNAPTIC ALTERATIONS INDUCED BY CSF OF ACTIVE RMS PATIENTS Rossi S et al., 2011, Ann Neurol

19. IL-1  /IL-1ra RATIO CORRELATES WITH INTRACORTICAL FACILITATION EXPLORED BY MEANS OF pp-TMS IN RMS PATIENTS Rossi S et al., 2011, Ann Neurol

20. TO SUMMARIZE… Musella A et al., 2015 Mult Scler

21. 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  (in RMS)  mediate the abnormalities of excitatory synaptic transmission through post- (TNF) and pre-synaptic (IL-1  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.

22. FREEDOMS: reduction in the rate of brain atrophy versus placebo over time Chin P et al. Poster P350 presented at ENS 2012 Change in mean BV from baseline (%) Placebo (n = 329) Fingolimod 0.5 mg (n = 356) –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 0.0 024126 –0.2 −35% vs placebo p=0.006 -0.84 p<0.001 -0.22 -0.34 -0.50 p=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

25. FINGOLIMOD NORMALIZES ABNORMAL GLUTAMATERGIC TRANSMISSION IN EAE Rossi S et al., 2012 Br J Pharmacol

26. FINGOLIMOD IS NEUROPROTECTIVE IN EAE BY PREVENTING GLUTAMATE-MEDIATED SYNAPTOPATHY Rossi S et al., 2012 Br J Pharmacol