title: Delayed leptin administration after stroke induces neurogenesis and angiogenesis.
abstract: 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.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Avraham
authors.forename: M
authors.initials: M
authors.lastname: Dayan
authors.forename: V
authors.initials: V
authors.lastname: Lassri
authors.forename: L
authors.initials: L
authors.lastname: Vorobiev
authors.forename: N
authors.initials: N
authors.lastname: Davidi
authors.forename: D
authors.initials: D
authors.lastname: Chernoguz
authors.forename: E
authors.initials: E
authors.lastname: Berry
authors.forename: R R
authors.initials: RR
authors.lastname: Leker
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D005904:Glial Fibrillary Acidic Protein; D020738:Leptin; D018696:Neuroprotective Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine