0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
RATIONALE
The classical divide between inflammatory and degenerative disorders of
the central nervous system (CNS) is vanishing, as our understanding on the
intimate nature of several disease conditions is improving. Inflammatory
processes play an important role in the pathophysiology of primarily degenerative
disorders, and neurodegeneration complicates primarily inflammatory
diseases of the brain and spinal cord such as multiple sclerosis (MS). In this
respect, it is increasingly clear that alterations of the neuronal compartment
of the CNS occur early and are largely independent of demyelination in MS.
MS-associated neurodegenerative damage is ultimately responsible for the
primary and secondary progressive phases of MS, as well as for cognitive
impairment seen in MS patients, and it is still debated whether the currently
approved immunomudulatory or immunosuppressant agents can interfere
with the pathological process at the basis of this process. It is conversely likely
that corticosteroids, which are commonly used to treat MS-related relapses,
negatively impact neurodegenerative damage in this pathological condition,
since it is well established that they induce neuronal death [Jacobs et al. 2006;
Tata et al. 2006; Lee et al. 2008; Noguchi et al. 2008], and exacerbates cognitive
deficits [Yao et al. 2007].
Very little is known about the cellular and molecular determinants of neurodegenerative
damage in MS, but recent evidence from our laboratory
showed that, in an experimental model of MS (the mouse with experimental
autoimmune encephalomyelitis, EAE), CNS invasion by myelin-specific
blood-borne immune cells triggers a chain of events involving activation of
resident microglia in the gray matter, release of TNF-a, downregulation of the
early gene Arc/Arg3.1, and abnormal expression, phosphorylation and function
of glutamate AMPA receptors in neurons, which finally undergo a dramatic
loss of dendritic spines and neurodegenerative damage [Centonze et al.
2009]. Pharmacological compounds able to interfere with this chain of events
are likely to exert neuroprotective effects in MW patients.
Glutamate-mediated excitotoxicity is emerging as a crucial determinant
of neuronal injury in MS. Accordingly, glutamate levels have been found to be
significantly higher in the cerebrospinal fluid and in the the brains of MS
patients. Furthermore, glutamate clearance and receptor expression are
impaired in MS brains and in animal models of the disease, while glutamate
receptor antagonists exert beneficial effects in EAE [Centonze et al. 2009] and
in MS by limiting not only oligodendrocyte but also neuronal damage. These
findings, therefore, suggest that glutamate-mediated excitotoxicity may play a
role in the pathogenesis of MS, as proposed in primarily neurodegenerative
disorders.
AIM OF THE STUDY
Thus, aim of the present project is to investigate whether interferon b-1a
and cladribine are able to mitigate, and possibly to block, EAE-associated
synaptic alteration and degeneration in both early (inflammatory) and late
650 2009