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Neuroprotective effects of leptin on cerebral ischemia through JAK2/STAT3/PGC-1-mediated mitochondrial function modulation.

07:00 EST 11th January 2020 | BioPortfolio

Summary of "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.

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This article was published in the following journal.

Name: Brain research bulletin
ISSN: 1873-2747
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Medical and Biotech [MESH] Definitions

Cell surface receptors for obesity factor (LEPTIN), a hormone secreted by the WHITE ADIPOCYTES. Upon leptin-receptor interaction, the signal is mediated through the JAK2/STAT3 pathway to regulate food intake, energy balance and fat storage.

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Softening or loss of brain tissue following CEREBRAL INFARCTION; cerebral ischemia (see BRAIN ISCHEMIA), infection, CRANIOCEREBRAL TRAUMA, or other injury. The term is often used during gross pathologic inspection to describe blurred cortical margins and decreased consistency of brain tissue following infarction. Multicystic encephalomalacia refers to the formation of multiple cystic cavities of various sizes in the cerebral cortex of neonates and infants following injury, most notably perinatal hypoxia-ischemic events. (From Davis et al., Textbook of Neuropathology, 2nd ed, p665; J Neuropathol Exp Neurol, 1995 Mar;54(2):268-75)

A 16-kDa peptide hormone secreted from WHITE ADIPOCYTES. Leptin serves as a feedback signal from fat cells to the CENTRAL NERVOUS SYSTEM in regulation of food intake, energy balance, and fat storage.

A disorder characterized by a reduction of oxygen in the blood combined with reduced blood flow (ISCHEMIA) to the brain from a localized obstruction of a cerebral artery or from systemic hypoperfusion. Prolonged hypoxia-ischemia is associated with ISCHEMIC ATTACK, TRANSIENT; BRAIN INFARCTION; BRAIN EDEMA; COMA; and other conditions.

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