Excitotoxicity-induced endocytosis mediates neuroprotection by TAT-peptide-linked JNK inhibitor.

ABSTRACT: Excitotoxicity and cerebral ischemia induce strong endocytosis in neurons, and we here investigate its functional role in neuroprotection by a functional transactivator of transcription (TAT)-peptide, the c-Jun N-terminal kinase (JNK) inhibitor D-JNKI1, against NMDA-excitotoxicity in vitro and neonatal ischemic stroke in P12 Sprague-Dawley rats. In both situations, the neuroprotective efficacy of D-JNKI1 was confirmed, but excessively high doses were counterproductive. Importantly, the induced endocytosis was necessary for neuroprotection, which required that the TAT-peptide be administered at a time when induced endocytosis was occurring. Uptake by other routes failed to protect, and even promoted cell death at high doses. Blocking the induced endocytosis of D-JNKI1 with heparin or with an excess of D-TAT-peptide eliminated the neuroprotection. We conclude that excitotoxicity-induced endocytosis is a basic property of stressed neurons that can target neuroprotective TAT-peptides into the neurons that need protection. Furthermore, it is the main mediator of neuroprotection by D-JNKI1. This may explain promising reports of strong neuroprotection by TAT-peptides without apparent side effects, and warns that the timing of peptide administration is crucial.

[Voyage en Italie : 1824-1830]. , Monument découvert près de Chiusi autrefois Clusium. La hauteur totale serait de 6,500 : état actuel ; fragment trouvé dans la fouille : [coupe et plan, détail, élévation du monument] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 80

[Voyage en Italie : 1824-1830]. , Monastère du Mont-Cassin à S. Germano (royaume de Naples). Bâti par Fonzago architecte 1649 : [plan moderne] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 65