title: 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.
authors: Département de Biologie Cellulaire et de Morphologie, University of Lausanne, Lausanne, Switzerland. anne.vaslin@hotmail.com
authors: Anne
authors: A
authors: Vaslin
authors: Sonia
authors: S
authors: Naegele-Tollardo
authors: Julien
authors: J
authors: Puyal
authors: Peter G H
authors: PG
authors: Clarke
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D010455:Peptides; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase; C478085:D-JNKI-1