leptin and Brain-Infarction

Leptin is a potent AMP kinase (AMPK) inhibitor that induces neuroprotection, neurogenesis, and angiogenesis when administered immediately after stroke. To dissociate these effects, we explored the effects of delayed administration of leptin, at 10 days after stroke onset, on neurogenesis and angiogenesis after stroke. Sabra mice underwent photothrombotic stroke and were treated with vehicle or leptin given either as a single dose or in triple dosing, 10 days later. Newborn cells were labeled with bromodeoxyuridine. Functional outcome was studied with the neurological severity score for 90 days poststroke, and the brains were then evaluated via immunohistochemistry. Final infarct volumes did not differ between the groups. Exogenous leptin led to significant increments in the number of proliferating BrdU(+) cells in the subventricular zone and in the cortex abutting the lesion (2.5-fold and 1.4-fold, respectively). There were significant increments in the number of newborn neurons and glia (4- and 3.4-fold, respectively) in leptin-treated animals. Leptin also significantly increased the number of blood vessels in the perilesioned cortex. However, animals treated with leptin failed to demonstrate significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis even when given late after stroke but does not lead to better functional outcome in this delayed-treatment paradigm. These results suggest that the main beneficial effects of leptin after stroke are associated with its early neuroprotective role rather than with its proneurogenic or proangiogenic effects.

Topics: Animals; Blood Vessels; Brain Infarction; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Leptin; Male; Mice; Neovascularization, Physiologic; Neurogenesis; Neuroprotective Agents; Phosphopyruvate Hydratase; Platelet Endothelial Cell Adhesion Molecule-1; Stroke; Time Factors

The purpose of this study was to investigate the protective mechanism of leptin-mediated metabolic recovery against cerebral injury after ischemia and reperfusion. We determined the neurologic deficit score, extent of brain edema, and infarct volume after reperfusion. The histopathologic alterations and changes in glucose uptake in the brain were also observed. Moreover, the levels of lactate dehydrogenase (LDH), lactic acid, pyruvate, and ATP in brain tissue were detected. Leptin levels in serum were also detected. To further define leptin-induced neuroprotective signaling pathways, we examined the levels of phosphorylated Akt (p-Akt) in the brain and in cultured cells. After transient ischemia, leptin treatment markedly reduced the neurologic deficits, cerebral infarct volume, and brain edema. After leptin injection, ATP, leptin, and p-Akt levels were significantly increased, LDH levels and lactic acid/pyruvate ratio were noticeably reduced, and histopathologic injuries were alleviated, which were all reversed by the PI(3)K inhibitor LY294002. These data show that leptin ameliorates cerebral ischemia/reperfusion injury by enhancing p-Akt, which in turn improves the supply of energy. The PI(3)K/Akt pathway was found to be the critical pathway for the mediation of leptin-induced neuroprotection, a finding that may prove to be useful in the treatment of ischemic stroke.

Topics: Animals; Brain Edema; Brain Infarction; Chromones; Energy Metabolism; Enzyme Inhibitors; L-Lactate Dehydrogenase; Lactic Acid; Leptin; Male; Mice; Morpholines; Nerve Tissue Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyruvic Acid; Reperfusion Injury; Signal Transduction

Leptin is a potent AMP kinase (AMPK) inhibitor that is central to cell survival. Hence, we explored the effects of leptin on neurogenesis and angiogenesis after stroke. Neural stem cells (NSC) were grown as neurospheres in culture and treated with vehicle or leptin and neurosphere size and terminal differentiation were then determined. We then explored the effects of leptin on endogenous repair mechanisms in vivo. Sabra mice underwent photothrombotic stroke, were given vehicle or leptin and newborn cells were labeled with Bromo-deoxy-Uridine. Functional outcome was studied with the neurological severity score for 90 days post stroke and the brains were then evaluated with immunohistochemistry. In a subset of animals the brains were also evaluated for changes in the expression of leptin receptor and AMPK. In vitro, leptin led to a 2-fold increase in neurosphere size but did not change the differentiation of newborn cells. Following stroke, exogenous leptin led to a 4-fold increase in the number of NSC in the cortex abutting the lesion. There was a 1.5-fold increase in the number of newborn neurons and glia in leptin treated animals. Leptin also significantly increased the number of blood vessels in the peri-lesioned cortex. Leptin treated mice had increased expression of leptin receptor and increased phosphorylated AMPK concentration. Animals treated with leptin also had significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations. This may explain at least in part the better functional outcome observed in leptin treated animals after stroke.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Blood Vessels; Brain Infarction; Bromodeoxyuridine; CD3 Complex; Cell Count; Cell Differentiation; Cells, Cultured; Disability Evaluation; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Fibroblast Growth Factors; Glial Fibrillary Acidic Protein; Leptin; Mice; Neovascularization, Pathologic; Neural Stem Cells; Neurogenesis; Neuroprotective Agents; Protein Kinases; Receptors, Leptin; Stroke; Time Factors; TRPV Cation Channels; Tubulin

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.

Topics: Analysis of Variance; Animals; Brain Infarction; Disability Evaluation; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Leptin; Male; Mice; Receptor, Cannabinoid, CB2; Receptors, Leptin; Sirtuin 1; Time Factors; TRPV Cation Channels; Up-Regulation

Metabolic syndrome and abdominal obesity are the risk factors for cardiovascular diseases. The greater amount of adipose tissue the higher level of leptin, adipocytocin with potential proatherogenic properties.. was to evaluate the leptin level in patients with acute ischemic stroke and leptin's role in the pathogenesis of cerebrovascular diseases.. We examined 45 patients with acute ischemic stroke and 17 cases without CNS diseases, matched with age and gender. In all subjects we examined lipid pattern (cholesterol, HDL-cholesterol, LDL-cholesterol, triglicerydes), blood glucose level, blood pressure, BMI (body mass index) and central fat--measured by WC (waist circumference) and W/HR (waist to hip ratio). On the basis of these parameters we diagnosed the presence of metabolic syndrome, according to American Heart Association 2005. Leptin level was measured by an enzyme linked immunosorbent assay. Ultrasonographic scanning of the carotid artery was performed in every patient to evaluate the CIMT and arteriosclerosis.. Hyperleptiemia is more often present in patient with abdominal obesity (p < 0.001) and in subjects with metabolic syndrome (p < 0.01)--the constellation of risk factors predisposing to ischemic stroke. There is no independent association between increased leptin concentrations and glucose levels and presence of hypertension (p > 0.05). Hyperleptynemia is associated with CIMT--an early marker of asymptomatic atherosclerosis.. Leptin can be the stroke manifestation of obesity. There is necessary to further evaluation of leptin's role in the pathogenesis of cerebrovascular diseases and its potential role in prophylaxis of ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Brain Infarction; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal

Leptin is the major adipose hormone that regulates body weight and energy expenditure by activating leptin receptors in the hypothalamus. Leptin receptors are also present in other cell types, and a potent antiapoptotic effect for leptin has recently been reported. We investigated whether leptin was neuroprotective against ischemic brain injury.. In vitro ischemic injury was induced in rat primary neuronal culture by oxygen-glucose deprivation for 90 minutes. In vivo ischemic brain injury was induced by middle cerebral artery occlusion in mice for 60 minutes.. Leptin receptors were detected in cultured rat cortical neurons, as well as in the mouse cortex, striatum, and hippocampus. In vitro results showed that leptin, 50 to 100 mug/mL, protected primary cortical neurons against death induced by oxygen-glucose deprivation in a concentration-dependent manner. In vivo studies in the mouse brain demonstrated that the intraperitoneal administration of leptin, 2 to 8 mg/kg, dose-dependently reduced infarct volume induced by middle cerebral artery occlusion. Leptin was effective when injected 5 minutes before or 30 to 90 minutes after reperfusion, but not 2 hours after reperfusion. Leptin improved animal body weight recovery and behavioral parameters after cerebral ischemia. Leptin enhanced the phosphorylation of extracellular signal-related kinase 1/2. Both extracellular signal-related kinase 1/2 activation and neuroprotection were abolished by the administration of PD98059 in vitro and in vivo.. Leptin is neuroprotective against ischemic neuronal injury. Our findings suggest that leptin is a legitimate candidate for the treatment of ischemic stroke.

Topics: Animals; Apoptosis; Body Weight; Brain; Brain Infarction; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Glucose; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Leptin; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Phosphorylation; Rats; Receptors, Cell Surface; Receptors, Leptin; Recovery of Function; Reperfusion Injury; Treatment Outcome