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Neuroscience

Laboratory of Acute Brain Injury and Therapeutic Strategies

Head
Elisa
R. Zanier
Head of Laboratory
Neuroscience
elisa.zanier@marionegri.it
Senior Advisor
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Acute brain injury has often severe and long-lasting consequences. Pharmacological neuro-protection, both for traumatic brain injury (TBI) or hemorrhagic lesions, is not available. There is a gap from successful experimental interventions in experimental models and failures in clinical applications. Essential for our research, therefore, is a lively connection/interplay between the laboratory and the clinical work. Parallel exploration of mechanisms in the clinical setting (through invasive monitoring and neuro-imaging, for instance) and in the laboratory aim at:

  • refining experimental models;
  • discovering biomarkers of injury progression/resolution;
  • identifying molecular targets;
  • developing therapeutic approaches.
RESEARCH AREAS

TBI and Neurodegeneration

Survivors of traumatic brain injury (TBI) are at risk of late neurodegeneration (including chronic traumatic encephalopathy; CTE) and dementia (Alzheimer’s disease). The cellular drivers and molecular mechanisms of such progressive cognitive deterioration syndromes are unclear. Together with the Laboratory of Prion Disease we recently provided first evidence that a single TBI can generate an abnormal form of the dementia associated protein tau (tauTBI) that can slowly spread through the brain, resulting in memory deficits and neuronal damage. The observation that a single brain trauma is associated with widespread tau deposition in humans and with the formation of a self-propagating form of tau in a relevant animal model provides first evidence for how a mechanical brain injury might evolve into chronic degenerative brain disease, including CTE. More recently, with the Laboratory of Human Pathology in Model Organism, we employed the nematode C. elegans as a biosensor and established the pathogenic role of TBI generated tau in the long-term consequences of TBI. This work also sets the ground for the development of a C. elegans-based platform for screening anti-tau compounds. Ongoing studies are focused on the development of therapeutic strategies able to interfere with tau propagation.

Traumatic brain injury: cell therapy for brain protection

We aim at assessing neurorestorative strategies with a specific focus on mesenchymal stromal cells (MSCs) and their derivatives. We have shown that MSC improve outcome fostering protective and restorative processes after experimental acute brain injury. We have found that MSCs protect the brain through the release of bioactive factors (secretome) mediating plasticity and restorative events. Ongoing studies aim at: 1) testing novel biomaterial in order to improve MSC survival after transplant in order to boost the secretome release overtime, 2) capturing the MSC-derived key effectors that induce protection after acute brain injury; 3) providing mechanistic insight onto how MSC-secretome affect systemic and brain cell populations; 4) thoroughly characterizing the therapeutic potential of the secretome by defining a preclinical protocol and by evaluating critical issues related to patients’ selection (i.e. gender issue, aging and TBI heterogeneity); 5) to evaluate MSC-secretome immunomodulatory potential on immune cells obtained from TBI patients in relation to age and injury severity.

Biomarkers of acute brain injury and post traumatic epilepsy

Predicting long-term outcome in TBI is extremely challenging. This reflects our incomplete understanding of how traumatic lesions influence neural networks and brain functions. Direct longitudinal brain monitoring of pathophysiological processes would be helpful to understand mechanisms and timing of disease progression. We aim at developing a multimodal device where diagnostic capabilities are integrated. We will combine an electric, fluidic and optical component thus allowing the online investigation of energy derangements, neuronal activity, and molecular events. Together with the Laboratory of Experimental Neurology, we aim at identifying a combination of blood, imaging (MRI) and EcoG biosignature for spontaneous post-traumatic epilepsy (PTE, a condition that represents 10% of all epilepsies) in the mouse model; key drivers identified in the preclinical model will be subjected to clinical validation using archived serum samples from TBI patients with/without PTE. Clinically validated PTE biosignatures could ultimately serve as risk and diagnostic biomarkers as well as lead candidates for novel therapeutic targets.

Sport-related TBI

Repeated exposure to low energy TBI, as in contact sports, increases the risk of developing neurodegenerative diseases and dementia later in life. At present specific treatments able to prevent long-term consequences of sport-related TBI are lacking. Moreover, we need to improve diagnostic tools able to monitor microstructural changes taking place after mild TBI. We have developed a mouse model of repeated mild TBI capable of capturing key features of the human pathology such as the development of chronic cognitive deficits associated with neuroinflammation. In this study, we have identified plasmatic biomarkers of axonal injury well before the onset of chronic cognitive impairment. The identification of new circulating biomarkers of axonal injury might be of great impact to evaluate the long term consequences of sport-related TBI and to evaluate the efficacy of new therapeutic strategies.

Argon’s therapeutic potential in TBI

Supportive treatment for the management of TBI has progressed over the past 20 years, but specific neuroprotective strategies are still lacking. Recently it has been shown that noble gases may have promising neuroprotective properties. Argon has numerous advantages such as having no significative side effects, being very cheap and not having anesthetic properties at normobaric condition. In collaboration with the laboratory of Laboratory of Cardiopulmonary Pathophysiology we have recently demonstrated that in our murine model of TBI, Argon is effective in accelerating the recovery of sensorimotor and cognitive functions by reducing the area of vasogenic edema- and microglial- (brain resident immune cells) mediated neuroinflammation. Future studies will investigate 1) the therapeutic window, 2) the efficacy of lower doses of Argon and 3) the mechanisms involved in the observed protection by combining MRI, blood biomarker analysis and histopathology.

Development of in vitro preclinical models as a screening platform for terapeutic strategies

The use of animals in medical research is essential to understand pathologic mechanisms induced after TBI and to test novel therapeutic strategies. However, simplified in vitro preclinical models are needed to minimize the use of animals and to carry out a rapid screening of candidate with the identification of lead compounds for in vivo tests. We therefore developed a new in vitro model of TBI, using organotypic cortical brain slices subjected to controlled impact. This model effectively reproduces key aspects of traumatic pathology: we observed a focal tissue damage that spreads to surrounding areas, and increases over time, with a massive impact on the neuronal population and an induction of glial activation. Treatment with MSC-secretome led to a reduction in brain death and neuronal damage, demonstrating the responsiveness of this model to effective therapeutic treatments.

Head Unit
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Staff
Noemi
Di Marzo
Researcher
noemi.di_marzo@guest.marionegri.it
Gloria
Vegliante
Researcher
gloria.vegliante@marionegri.it
Francesca
Pischiutta
Researcher
francesca.pischiutta@marionegri.it
Rosaria
Pascente
Researcher
rosaria.pascente@marionegri.it
Federico
Moro
Researcher
federico.moro@marionegri.it
Enrico
Caruso
Researcher
enrico.caruso@marionegri.it
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Codice:

International Consensus on Cardiopulmonary Resuscitation.

1205
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Head
Elisa
R. Zanier
Head of Laboratory
Neuroscience
elisa.zanier@marionegri.it
Senior Advisor
No items found.

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