Susan D. Croll, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) is a vascular growth factor recently shown to have neuroprotective effects both in vitro and in vivo. Preliminary data from our laboratories have shown that, in vitro, VEGF protects SK-N-SH cells from death following serum deprivation. VEGF's protective effects in this system are prevented by blocking the PKA-ERK1/2 and Akt (PKB) signaling pathways (unpublished data). Inhibiting VEGF receptor 2 (VEGFR2) activity with Sugen 1498 also blocks neuroprotection in these cells (unpublished data). Because VEGFR2 signals via these biochemical pathways, the most parsimonious explanation is that VEGF mediates in vitro neuroprotection via VEGFR2-mediated activation of ERK1/2 and Akt. VEGF also protects neurons in models of cell death in vivo. One such model is the pilocarpine-induced status epilepticus model, in which cell damage occurs within days after a single, prolonged status epilepticus event. While VEGF significantly protects neurons in this model (Croll et al., 2004, 2005), it is unknown whether protection in vivo uses the same biochemical pathways as protection in vitro. To test the hypothesis that VEGF uses the same pathways for neuroprotection in both systems, we have proposed a series of experiments to 1) better characterize the nature of the cell death which occurs after status epilepticus, 2) verify that treatment with VEGF induces the same signaling profile in adult rat hippocampus as in cell cultures, and 3) determine whether inhibition of PKA activation, Akt activation, and/or VEGFR2 activation prevents VEGF's neuroprotective effect. Because VEGF is a large protein which does not cross the blood-brain barrier, and has effects at multiple receptors, it is not, itself, an ideal therapeutic agent. However, by determining which receptors or signaling pathways mediate VEGF's protective effects in vivo, we can better design interventions with specific biochemical profiles. The results of the proposed experiments could guide future studies aimed at screening for small molecule reagents with high selectivity for the particular VEGF receptor systems and/or signaling pathways most likely to protect neurons from the damaging effects of status epilepticus or other neurological insults. Status epilepticus, a prolonged bout of generalized seizures, can lead to a loss of brain cells. We have recently shown that vascular endothelial growth factor protects neurons from cell death after status. The proposed studies seek to understand the signaling pathways underlying this protection so that new therapeutics can be developed to prevent this cell loss [unreadable] [unreadable]