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

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 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-B/c-Rel Ϫ/Ϫ mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel Ϫ/Ϫ 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 g/g) intraperitoneally at the onset of ischemia. Results-Leptin treatment activated the nuclear translocation of nuclear transcription factors 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 Ϫ/Ϫ 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 Ϫ/Ϫ mice. Conclusions-Leptin

NF-κB Activation in Hypothalamic Pro-opiomelanocortin Neurons Is Essential in Illness- and Leptin-induced Anorexia

“…4, I and J). Leptin Causes Hypothalamic NF-B Activation-Previous studies have shown that leptin, an important anorexigenic hormone, activates NF-B in cortical neurons, microglia, and astrocytes from the brain (32)(33)(34). Therefore, we investigated whether leptin also causes hypothalamic NF-B activation.…”

NF‐κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress

“…Further investigations confirmed that p50 and RelA subunit activation contributes to the apoptotic program in cells exposed to the β-amyloid peptide (Akama et al, 1998;Pizzi et al, 2005b;Valerio et al, 2006). In addition, the c-Rel-containing dimers p50/c-Rel and RelA/c-Rel are involved in neuroprotective effects elicited by S100B (Kögel et al, 2004), agonists at the metabotropic glutamate type 5 (mGlu5) receptors (Pizzi et al, 2005b;Sarnico et al, 2008b) or leptin (Valerio et al, 2009). Neuroprotection elicited by c-Rel against β-amyloid toxicity was associated with the expression of the antiapoptotic proteins B-cell lymphomaextra large (Bcl-x L ) and manganese superoxide dismutase (MnSOD) (Pizzi et al, 2005b) (Fig.…”

“…Furthermore, the adipocyte-derived hormone leptin, by activating c-Relcontaining dimers c-Rel/p50 and c-Rel/RelA, significantly increased Bcl-x L expression and reduced the infarct volume in mice exposed to permanent MCAO. As a confirmation of the pivotal role of c-Rel in limiting apoptosis, the protective effect of leptin in brain ischemia was suppressed in c-Rel deficient mice (Valerio et al, 2009). …”

Response to Letter by Tsuda

“…2 Accordingly, leptin treatment did not affect cerebral blood flow as assessed by laser Doppler analysis in our study. 3 As Dr Tsuda correctly mentioned, evidences indicate that NO has a role in neuroprotection. Compelling data from animal models demonstrate that NO generated by endothelial NO synthase (eNOS) plays a protective role against ischemic stroke.…”

“…7,8 Improved bioenergetics due to mitochondrial biogenesis augment tolerance to ischemic injury. 11 Thus, besides the NFB/c-Rel-mediated inhibition of neuronal apoptosis, 3 eNOS/PGC-1␣ mediated phenomena, including mitochondrial biogenesis, might take part to the protective effects of leptin against cerebral ischemia. The latter point is currently under investigation in our laboratories.…”