Leptin Is Induced in the Ischemic Cerebral Cortex and Exerts Neuroprotection Through NF-κB/c-Rel–Dependent Transcription

• Published in: Stroke (1970) Vol. 40; no. 2; pp. 610 - 617
• Main Authors: Valerio, Alessandra, Dossena, Marta, Bertolotti, Paola, Boroni, Flora, Sarnico, Ilenia, Faraco, Giuseppe, Chiarugi, Alberto, Frontini, Andrea, Giordano, Antonio, Liou, Hsiou-Chi, De Simoni, Maria Grazia, Spano, PierFranco, Carruba, Michele O, Pizzi, Marina, Nisoli, Enzo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-02-2009; Lippincott Williams & Wilkins
• Subjects: Biological and medical sciences; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Fundamental and applied biological sciences. Psychology; Medical sciences; Neurology; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; Animal model; Stroke; Cerebral cortex; Nervous system diseases; animal models; Cardiovascular disease; Cerebral disorder; Vascular disease; NF-κB; Leptin; Central nervous system disease; Brain ischemia; Cerebrovascular disease; Apoptosis
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.108.528588

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 κB 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 (20 μg/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.