Leptin reduces infarct size in association with enhanced expression of CB2, TRPV1, SIRT-1 and leptin receptor.
Brain ischemia is associated with detrimental changes in energy production and utilization. Therefore, we hypothesized that leptin, an adipokynin hormone protecting against severe energy depletion, would reduce infarct volume and improve functional outcome after stroke. Male Sabra mice underwent permanent middle cerebral artery occlusion (PMCAO) by photothrombosis. Following initial dose-response and time-window experiments animals were treated with vehicle or leptin, were examined daily by a neurological severity score (NSS) and were sacrificed 72 hours after stroke. Infarct volume was determined and the expression of key genes involved in neuroprotection and survival including the cannabinoid receptors CB1, CB2 and TRPV1, SIRT-1, leptin receptor and Bcl-2 was quantified in the cortex. A separate group of mice were examined with the neurological severity scale 1, 24 and 48 hours and 1, 2 and 3 weeks after stroke, and were killed 3 weeks post stroke to examine metabolic status in the peri-infarct area. Leptin given at a dose of 1mg/kg intra-peritoneally 30 minutes after PMCAO significantly improved neurological disability and reduced infarct volume. Leptin treatment led to increased expression of CB2 receptor, TRPV1, SIRT-1 and leptin receptor and reduced expression of CB1 receptor. There was also a non-significant increase in Bcl-2 gene expression following leptin administration. These results suggest that leptin may be used for attenuating ischemic injury after stroke via induction of an anti-apoptotic state.
Avraham
Yosefa
Y
Department of Human Nutrition and Metabolism, Braun School of Public Health, Hebrew University-Hadassah Medical School, Jerusalem, Israel. yosefa@md.huji.ac.il
Davidi
Neta
N
Porat
Moran
M
Chernoguz
David
D
Magen
Iddo
I
Vorobeiv
Lia
L
Berry
Elliot M
EM
Leker
Ronen R
RR
D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology; D004185:Disability Evaluation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000209:etiology; D020738:Leptin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D020738:Leptin; D043885:Receptor, Cannabinoid, CB2; D054411:Receptors, Leptin; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1