Leptin Is Induced in the Ischemic Cerebral Cortex and Exerts Neuroprotection Through NF- (cid:1) B/c-Rel–Dependent Transcription

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 (cid:1) B 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- (cid:1) B/c-Rel (cid:1) / (cid:1) mice exposed to oxygen–glucose deprivation. Wild-type, c-Rel (cid:1) / (cid:1) 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 (cid:2) g/g) intraperitoneally at the onset of ischemia. Results —Leptin treatment activated the nuclear translocation of nuclear transcription factors (cid:1) B 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 (cid:1) / (cid:1) mice. Leptin mRNA was induced and the protein was detectable in microglia/macro-phage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. O b/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 (cid:1) / (cid:1) 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. ( Stroke . 2009;40:00-00.) after ischemia. Mortality was below 3% without differences among groups. Laser Doppler (PF2B; Perimed) analysis carried out for 30 minutes after ischemia revealed that drug treatment did not affect basal cerebral blood flow and drop on artery cauterization. Mice were euthanized 24 hours after pMCAO unless otherwise specified and brains snap-frozen in nitrogen vapor. For infarct determination, toluidine blue-stained coronal sections were imaged using the Image-Pro Plus 3.0 analysis software (Media Cybernetics). Infarct insen-sitive to the effects of leptin on pMCAO, the present study demonstrates that c-Rel is necessary to the neuroprotective effect of leptin in vivo. Leptin is efficacious and well tolerated in the treatment of rare human conditions. 32 We suggest that leptin administration, by targeting NF- (cid:1) B/c-Rel– mediated transcription, may have the potential as a safe therapeutic approach to enhance endogenous repair mecha-nisms in focal ischemic stroke.