la neurodegenerazione e la neuroplasticitÀ nei diversi fenotipi della sclerosi multipla diego...
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LA NEURODEGENERAZIONE E LA NEUROPLASTICITÀ NEI DIVERSI FENOTIPI DELLA SCLEROSI MULTIPLA
Diego Centonze
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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
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Centonze D et al., 2009 J Neurosci
CHRONIC INFLAMMATION CAUSES SYNAPTIC DAMAGE AND DENDRITIC LOSS IN THE GRAY MATTER OF EAE MICE
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THE INFLAMMATORY MILIEU DIFFERS IN RELAPSING AND PROGRESSIVE MS PATIENTS
Rossi S et al., 2011, Ann Neurol
Rossi S et al., 2014, Mult Scler
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A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?
A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?
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A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?
A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?
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“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.”
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Wang G et al., Neural Plasticity 2012
TNFa ACTIVITY AND THE DOWNREGULATION OF ARC ARE KEY STEPS IN SYNAPTIC UP-SCALING
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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
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EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS
Rossi S et al., 2014 Mult Scler
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EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS
Rossi S et al., 2014 Mult Scler
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EVIDENCE OF SYNAPTIC UP-SCALING AND TNF-MEDIATED NEURODEGENERATION IN PROGRESSIVE MULTIPLE SCLEROSIS
Studer V et al., 2014 J Neuroimmunol
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A PREFERENTIAL ROLE FOR TNF IN THE NEURODEGENERATIVE PROCESS OF PMS?
A PREFERENTIAL ROLE FOR IL-1b IN THE NEURODEGENERATIVE PROCESS OF RMS?
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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
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CSF FROM ACTIVE RMS PATIENTS CAUSES NEURONAL SWELLING
Rossi S et al., 2011, Ann Neurol
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IL-1b IS RESPONSIBLE FOR SYNAPTIC ALTERATIONS INDUCED BY CSF OF ACTIVE RMS PATIENTS
Rossi S et al., 2011, Ann Neurol
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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
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TO SUMMARIZE…
Musella A et al., 2015 Mult Scler
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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.
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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
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FINGOLIMOD NORMALIZES ABNORMAL GLUTAMATERGIC TRANSMISSION IN EAE
Rossi S et al., 2012 Br J Pharmacol
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FINGOLIMOD IS NEUROPROTECTIVE IN EAE BY PREVENTING GLUTAMATE-MEDIATED SYNAPTOPATHY
Rossi S et al., 2012 Br J Pharmacol