Inproceedings: an article in a conference proceedings.
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Role of the JNK pathway in a rat neonatal cerebral hypoxia/ischemia model
Title of the conference
48th Annual Meeting of the European Society for Paediatric Research, Prague, Czech Republic : 6-8 October, 2007
Background and aims: Perinatal asphyxia is an important cause of neurological morbidities and no effective drug treatment is yet available. The c-Jun NH2-terminal kinase (JNK) pathway has been shown to be involved in several models of excitotoxicity such as hypoxic-ischemic (HI) brain damage. Because D-JNKI1, a JNK inhibitor, has been shown to be strongly neuroprotective in a cerebral focal ischemia, we hypothe- tized that D-JNKI1 is neuroprotective in a severe rat model of perinatal asphyxia. Methods: Using the Vannucci-Rice model of P7 rats we investigated the JNK pathway and the effects of D-JNKI1 administration performing Nissl-stained sections, Western blot analysis and immunohistochemistry. Results: We demonstrated that neonatal cerebral HI strongly decreased the activation level of total JNK (P < 0.05, n = 5 each). In the cortex, the levels of phospho- JNK had decreased 3x by 30 min and 2x at 24 h after HI, compared to sham animals (n = 5). No effect of D-JNKI1 was shown on the extent and size of the lesion despite different administration regimens. We showed an activa- tion of c-jun, 24 h after HI, conﬁrmed by immunohisto- chemistry. While caspase 3 expression was unchanged, calpain expression was signiﬁcantly reduced in injected animals. Calpain is involved in the necrotic and autophagic pathways.We are now investigating possible differences in the speciﬁc activation of the JNK isotypes and the effects of repeated DJNKI1 injections. Conclusions: We conclude that JNK pathway is involved in a severe neonatal HI model and modulates the necrotic and autophagic pathways. We speculate that repeated DJNKI1 injections after the insult will have an effect on the size of the lesion.
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