NEUROPROTECTION BY LEPTIN AGAINST PERMANENT FOCAL ISCHEMIC DAMAGE INVOLVES ENHANCEMENT OF STAT3 PHOSPHORYLATION IN DISCRETE BRAIN CELLS

Leptin is an adipose hormone whose neurotrophic effects have recently been described. Here, we investigate its neuroprotective potential in an experimental model of focal brain ischemia induced in rats by permanent occlusion of the middle cerebral artery (pMCAo). A single, subcutaneous (s.c.) administration of leptin (1 mg/kg, 3 h before pMCAo) significantly reduces brain infarct volume and neurological deficit measured up to 7 days after pMCAo. Western blot analysis combined with immunohistofluorescence show that the ischemic insult significantly increases STAT3 phosphorylation in both the cytosolic and nuclear fractions of the ipsilateral, ischemic cortex 3 h after pMCAo and this further increases in the nuclear but not in the cytosolic fraction of the ischemic cortex 24 h after occlusion. In comparison to vehicle-treated animals, 3h after pMCAo, leptin further increases STAT3 phosphorylation in the nuclear fraction of the astrocytes populating the penumbra. By contrast, after 24 h of ischemia, leptin further increases STAT3 phosphorylation in the cytosolic fraction of neurons and this is associated with increased expression of TIMP-1. Thus, the early activation of astrocytes, together with the late elevation of TIMP-1 in neurons, may represent crucial mechanisms by which STAT3 mediates neuroprotection afforded by leptin in focal ischemia.