Neuroprotective effects of leptin on cerebral ischemia through JAK2/STAT3/PGC-1-mediated mitochondrial function modulation.
Neuroprotective effects of leptin have been shown in mouse model of cerebral ischemia/reperfusion injury and primary cortical neuronal culture with oxygen-glucose deprivation (OGD), while the underlying mechanisms are less understood. In the present study, we investigated whether leptin modulated mitochondrial function through JAK2/STAT3 in vivo mouse model of transient middle cerebral artery occlusion (MCAO) and in OGD-challenged primary neuronal cultures. JAK2/STAT3; mitochondrial biogenesis markers (PGC-1α); and apoptosis-associated proteins (caspase-3, BCL-2, BCL-XL, and cytochrome c) were detected by western blotting and reverse transcription-polymerase chain reaction at 1 h before and after ischemia/reperfusion. P-STAT3 and PGC-1α in neurons and astrocytes were detected. Moreover, mitochondrial morphology of the ischemic ipsilateral penumbra is examined using transmission electron microscopy. Primary cerebral cortical neurons were evaluated for viability, mitochondrial membrane potential (MMP), and apoptosis to assess whether dose-dependent neuroprotective effects of leptin during OGD were mitigated by the JAK2/STAT3 inhibitor AG490. Leptin activated JAK2/STAT3 signaling in neurons and astrocytes distributed in the ischemic ipsilateral penumbra, with peak p-STAT3 levels observed at 1 h after reperfusion. Leptin increased PGC-1α, BCL-2, and BCL-XL protein levels, cell viability, and MMP and decreased apoptosis both in vitro and in vivo; these effects were reversed by AG490 treatment. Our findings suggest that leptin-mediated neuroprotective effects in tMCAO may peak at 1 h to induce the transcription of its target gene PGC-1α, stabilization of MMP, inhibition of mitochondrial permeability transition pore opening, release of cytochrome c, and apoptosis.
['Zhang|Wenfang|W|', 'Jin|Yinchuan|Y|', 'Wang|Dong|D|', 'Cui|Jingjing|J|']
D000818:Animals D017209:Apoptosis D001921:Brain D002545:Brain Ischemia D020244:Infarction, Middle Cerebral Artery D053614:Janus Kinase 2 D020738:Leptin D008297:Male D053078:Membrane Potential, Mitochondrial D051379:Mice D008810:Mice, Inbred C57BL D008928:Mitochondria D009474:Neurons D018696:Neuroprotective Agents D019253:Proto-Oncogene Proteins c-bcl-2 D015427:Reperfusion Injury D050796:STAT3 Transcription Factor D015398:Signal Transduction D020521:Stroke D014157:Transcription Factors
Leptin PGC-1α Mitochondrial membrane potential (MMP) Brain Signaling pathway