Ischemia And Neuroprotection

Ischemia

Fig. 1: Three-dimensional re-construction showing examples of lesion in control rat (left) and D-JNKI-1 treated rat 6 hours after permanent ischemia (right). The areas of the ischemic lesion and of the whole brain were traced using the Neurolucida software program for computer-aided microscopy.

In our prevoius study, (Borsello et al, 2003) D-JNKI1 revealed a great neuroprotective effect when administered 6h after the ischemic insult, offering a window of clinically relevance. Our second aim has been to understand the cerebral ischemic cascade activation and the powerful D-JNKI1 neuroprotection. We established that JNK activation peak is at 6h after ischemia and correlates well with P-c-jun peak.

Regarding the D-JNKI1 neuroprotective treatment we found that it diminishes the increase of P-c-Jun in both core and penumbra and it powerfully inhibits the caspase-3 activation in the core. Taken together these results indicate that targeting the JNK cascade in a very specific way provides a promising therapeutic approach for ischemia (Repici et al., 2007).

Fig. 2: D-JNKI1 interferes with protein-protein interaction along signaling event by preventing JNK action.

Traumatic brain injury

In collaboration with Dott.ssa Grazia De Simoni

Controlled cortical impact model of cerebral contusion model

Neurological outcome following traumatic brain injury (TBI) is the result of the extent of the primary brain insult caused by the mechanical disruption of brain tissue and of the secondary neurochemical and molecular changes, occurring as a consequence of the mechanical injury, progressing over minutes to months after the initial traumatic event. Despite significant research effort the molecular alterations related to brain damage following TBI is still unclear.

While a number of studies have demonstrated direct evidence for the activation of apoptotic cascades in TBI, the precise pathway by which these cascades are initiated remains a subject of intense investigation. The initiation and execution of apoptosis depend on activation of the extrinsic and/or intrinsic death pathways. In any case the apoptotic process is finely regulated by many intracellular signaling pathways among these the Mitogen Activated Protein Kinases (MAPK)10 play an important role, including c-Jun N-terminal Kinase (JNK)’s pathway.

We tested the hypothesis that c-Jun N-terminal kinase (JNK) plays a role in traumatic brain injury.

Time course of JNK activation in cortex and hippocampus after controlled cortical impact brain injury. JNK activation is expressed as the ratio between P-JNK/JNK in the area ipsilateral to trauma versus the contralateral one.

 

 

Research Participants:
Tiziana Borsello
Xenia Antoniou, PhD
Federica Morelli
Paola Roderi
Agata Camassa

 

More Research Interests:
The Cargo Strategy As A Key Tool In Neuroprotection
Synaptic Dysfunction
Signalling Pathways In Alzheimer Disease
Signalling Pathways And Neuroprotection

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