Neuroprotective effects of leptin in vivo and in vitro.
The present study explored the efficacy of leptin in protecting against in vivo induction of excitotoxic lesions by the glutamatergic analogue ibotenate injected into the developing mouse brain and against in vitro NMDA-induced cell death in primary neuronal cultures. Ibotenate injected intracerebrally (i.c.) to mice on postnatal day 5 produced transcortical necrosis and white matter cysts. Co-treatment with leptin administered i.c. or i.p. reduced ibotenate-induced cortical lesions and white matter cysts by 50%. in vitro, leptin afforded significant neuroprotection of mouse cortical neurons against NMDA cytotoxicity. The neuroprotective effect of leptin was antagonized both in vivo and in vitro by the Jak2 inhibitor AG490, indicating that it was mediated via the leptin receptor and Jak2 activation. These findings are the first evidence for a role of leptin in neuroprotection.
Dicou
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E
INSERM E9935, Hôpital Robert-Debré, 48 Bvd Sérurier, F-75019 Paris, France.
Attoub
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Gressens
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P
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D007051:Ibotenic Acid / Q000633:toxicity; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D053614:Janus Kinase 2; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D020738:Leptin; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2