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Inhibition of stress activated protein kinase signalling as a therapeutic strategy against excitotoxicity

Final Report Summary - STRESSPROTECT (Inhibition of stress activated protein kinase signalling as a therapeutic strategy against excitotoxicity)

STRESSPROTECT was created to elucidate the intraneuronal mechanisms underlying excitotoxicity on several levels of physiological, molecular-genetic and biochemical analysis. At the end of the funding period, STRESSPROTECT has contributed to our current knowledge of excitotoxicity and treatment of neurological disorders at several levels.

In the area of characterisation of the use of the TAT-fused JNK inhibitor D-JNKI1 (XG-102), the project reports that:
- detailed characterisation of its pharmacokinetic and pharmacodynamic properties;
- demonstration that D-JNKI1 is targeted selectively into the neurons that need it by an endocytic mechanism;
- Significant protective and beneficial neuroprotection in various in vitro and in vivo models including excitotoxicity models such as ischemia (neonatal and adult) and seizures; apoptosis following axotomy and trophic deprivation; Alzheimer, traumatic hearing loss;
- elucidation of novel death-mediating mechanisms downstream of JNK inhibition including autophagy;
- combination of D-JNKI1 and Hyperbaric oxygenation (HBO) several hours after transient cerebral ischemia reduced the infarct area by 83 % and 62 % in the cortical areas of the penumbra and in the ischemic core, respectively;
post-ischemic application of D-JNKI1 resulted in a lasting improvement of neurological scores and behaviour in an adult stroke model.

These achievements have been published in internationally respected journals including Nature Neuroscience, Journal of Cell Biology, Journal of Neuroscience, Molecular and Cellular Neuroscience and have been reviewed in Nature Neuroscience Reviews and in Trends in Pharmacological Sciences. Moreover, STRESSPROTECT presented data and strategies during several international conferences including FENS (lectures and symposia). This scientific success could only be achieved by intense collaboration and frank exchange of information within the STRESSPROTECT network funded by the European Commission (EC).

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