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Keywords:

  • angiogenesis;
  • cerebrovascular disease;
  • leptin;
  • neurogenesis;
  • neuroprotection;
  • stroke

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. © 2012 Wiley Periodicals, Inc.