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Pluchino S.,San Raffaele Scientific Institute | Pluchino S.,University of Cambridge | Cusimano M.,San Raffaele Scientific Institute | Bacigaluppi M.,Institute of Experimental Neurology INSpe | Martino G.,Institute of Experimental Neurology INSpe
Archives Italiennes de Biologie | Year: 2010

Compelling evidence exists that somatic neural stem/precursor cell (NPC)-based therapies protect the central nervous system (CNS) from chronic inflammation-driven degeneration, such as that occurring in experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), cerebral ischemic/hemorrhagic stroke and spinal cord injury (SCI). However, while it was first assumed that NPC transplants may act through direct replacement of lost/damaged cells, it has now become clear that they are able to protect the damaged nervous system through a number of 'bystander' mechanisms other than the expected cell replacement. In immune-mediated experimental demyelination - both in rodents and non-human primates - others and we have shown that transplanted NPC possess a constitutive and inducible ability to mediate efficient 'bystander' myelin repair and axonal rescue. This novel mechanism(s), which may improve the success of transplantation procedures, is likely to be exerted by undifferentiated NPCs whose functional characteristics are regulated by both CNS-resident and blood-borne inflammatory cells releasing in situ major stem cell regulators. Here, we discuss some of these alternative 'bystander' mechanisms, while pointing at the formation of the atypical ectopic perivascular niches, as the most challenging example of reciprocal biologically sound cross talk between the inflamed microenvironment(s) and transplanted therapeutic NPCs. Source

Cerami C.,Vita-Salute San Raffaele University | Crespi C.,Vita-Salute San Raffaele University | Della Rosa P.A.,Vita-Salute San Raffaele University | Della Rosa P.A.,CNR Institute of Molecular Bioimaging and Physiology | And 8 more authors.
Journal of Alzheimer's Disease | Year: 2015

Posterior cortical atrophy (PCA) is characterized by basic visual and high order visual-spatial dysfunctions. In this study, we investigated long-distance deafferentation processes within the frontal-parietal-occipital network in ten PCA patients using a MRI-PET combined approach. Objective voxel-based [18F]FDG-PET imaging measured metabolic changes in single patients. Comprehensive investigation of diffusion tensor imaging (DTI) metrics and grey-matter density with voxel-based morphometry were obtained in a subgroup of 6 patients. Fractional anisotropy in the superior longitudinal fasciculus correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. [18F]FDG-PET analysis showed in each PCA case the typical bilateral hypometabolic pattern, involving posterior temporal, parietal, and occipital cortex, with additional hypometabolic foci in the frontal eye fields. Voxel-based morphometry showed right-sided atrophy in the parieto-occipital cortex, as well as a limited temporal involvement. DTI revealed extensive degeneration of the major anterior-posterior connecting fiber bundles and of commissural frontal lobe tracts. Microstructural measures in the superior longitudinal fasciculus were correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. Our results confirmed the predominant occipital-temporal and occipital-parietal degeneration in PCA patients. [18F]FDG-PET and DTI-MRI combined approaches revealed neurodegeneration effects well beyond the classical posterior cortical involvement, most likely as a consequence of deafferentation processes within the occipital-parietal-frontal network that could be at the basis of visuo-perceptual, visuo-spatial integration and attention deficits in PCA. © 2015 IOS Press and the authors. All rights reserved. Source

Martino G.,Institute of Experimental Neurology INSpe | Butti E.,Institute of Experimental Neurology INSpe | Bacigaluppi M.,Institute of Experimental Neurology INSpe
Journal of Clinical Investigation | Year: 2014

Neural stem/precursor cells (NPCs) that reside within germinal niches of the adult CNS have more complex roles than previously expected. In addition to their well-documented neurogenic functions, emerging evidence indicates that NPCs exert non-neurogenic functions that contribute to the regulation and preservation of tissue homeostasis under both physiological and pathological conditions. In this issue of the JCI, Mohammad et al. found that DCs efficiently patrol the CNS only when the germinal niche of the subventricular zone functions properly. Indeed, DCs traveled from the ventricles along the rostral migratory stream to the olfactory bulb (a cervical lymph node access point) to dampen anti-CNS immune responses. The authors' findings further support a non-neurogenic role for NPCs in maintaining tissue homeostasis and promoting tissue protection in the adult brain. Source

Ruffini F.,Institute of Experimental Neurology INSpe | Rossi S.,NeuroLogica | Bergamaschi A.,Institute of Experimental Neurology INSpe | Brambilla E.,Institute of Experimental Neurology INSpe | And 9 more authors.
Multiple Sclerosis Journal | Year: 2013

Background: There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage. Objective: Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear. Methods: C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 μM). Results: Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents. Conclusions: Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination. © The Author(s) 2012. Source

Cambiaghi M.,San Raffaele Scientific Institute | Cambiaghi M.,Institute of Experimental Neurology INSpe | Cursi M.,San Raffaele Scientific Institute | Cursi M.,Institute of Experimental Neurology INSpe | And 10 more authors.
Epilepsy Research | Year: 2013

Deletion of one or more synapsin genes in mice results in a spontaneous epilepsy. In these animals, seizures can be evoked by opening or moving the cage. Aim of the present study was to characterize the evolution of the epileptic phenotype by neurophysiological examination and behavioral observation in synapsin triple knock-out (Syn-TKO) mice. Syn-TKO mice were studied from 20 postnatal days (PND) up to 6. months of age by video-EEG recording and behavioral observation. Background EEG spectral analysis was performed and data were compared to WT animals. Syn-TKO revealed rare spontaneous seizures and increased susceptibility to evoked seizures in mice from 60 to 100 PND. Spontaneous and evoked seizures presented similar duration and morphology. At times, seizures were followed by a post-ictal phase characterized by a 4. Hz rhythmic activity and immobility of the animal. Spectral analysis of background EEG evidenced a slowing of the theta-alpha peak in Syn-TKO mice compared to WT mice within the period from PND 40 to 100. These data indicate that Syn-TKO mice do not exhibit a linear progression of the epileptic phenotype, with the period corresponding to a higher susceptibility to evoked seizures characterized by background EEG slowing. This aspect might be connected to brain dysfunction often associated to epilepsy in the interictal period. © 2012 Elsevier B.V. Source

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