Leptin is induced in the ischemic cerebral cortex and exerts neuroprotection through NF-κB/c-Rel-Dependent transcription

Alessandra Valeric, Marta Dossena, Paola Bertolotti, Flora Boroni, Ilenia Sarnico, Giuseppe Faraco, Alberto Chiarugi, Andrea Frontini, Antonio Giordano, Hsiou Chi Liou, Maria Grazia De Simoni, Pierfranco Spano, Michele O. Carruba, Marina Pizzi, Enzo Nisoli

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Purpose-Leptin is an adipose hormone endowed with angiopoietic, neurotrophic, and neuroprotective properties. We tested the hypothesis that leptin might act as an endogenous mediator of recovery after ischemic stroke and investigated whether nuclear transcription factors kB activation is involved in leptin-mediated neuroprotection. Methods-The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF-κB/c-Rel -/-mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel -/- and leptin-deficient ob/ob mice were subjected to permanent middle cerebral artery occlusion. Leptin production was measured in brains from wild-type mice with quantitative reverse transcriptase-polymerase chain reaction and immunostaining. Mice received a leptin bolus (20μg/g) intraperitoneally at the onset of ischemia. Results-Leptin treatment activated the nuclear translocation of nuclear transcription factors κB dimers containing the c-Rel subunit, induced the expression of the antiapoptotic c-Rel target gene Bcl-xL in both control and oxygen-glucose deprivation conditions, and counteracted the oxygen-glucose deprivation-mediated apoptotic death of cultured cortical neurons. Leptin-mediated Bcl-xL induction and neuroprotection against oxygen-glucose deprivation were hampered in cortical neurons from c-Rel -/- mice. Leptin mRNA was induced and the protein was detectable in microglia/macrophage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. Ob/ob mice were more susceptible than wild-type mice to the permanent middle cerebral artery occlusion injury. Leptin injection significantly reduced the permanent middle cerebral artery occlusion-mediated cortical damage in wild-type and ob/ob mice, but not in c-Rel -/- mice. Conclusions-Leptin acts as an endogenous mediator of neuroprotection during cerebral ischemia. Exogenous leptin administration protects against ischemic neuronal injury in vitro and in vivo in a c-Rel-dependent manner.

Original languageEnglish
Pages (from-to)610-617
Number of pages8
JournalStroke
Volume40
Issue number2
DOIs
Publication statusPublished - Feb 2009

Keywords

  • Animal models
  • Apoptosis
  • Brain ischemia
  • Leptin
  • NF-κb

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing
  • Medicine(all)

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