Leptin Induces Neuroprotection Neurogenesis and Angiogenesis after Stroke

Y.      Avraham; N.      Davidi; V.      Lassri; L.      Vorobiev; M.      Kabesa; M.      Dayan; D.      Chernoguz; E.      Berry; R.      R. Leker

Abstract

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.

Keywords: Angiogenesis, cerebrovascular disease, leptin, neurogenesis, neuroprotection, stroke, cerebral vessels., Growth of Mouse Neurospheres, Trypsin-EDTA, Immunohistochemistry, Gliogenesis, Protein Expression, hemispheric volume, cardiovascular diseases, myocardial infarction