VEGF treatment during status epilepticus attenuates long-term seizure-associated alterations in astrocyte morphology.

Vascular endothelial growth factor (VEGF) treatment during pilocarpine-induced status epilepticus (SE) causes sustained preservation of behavioral function in rats in the absence of enduring neuroprotection (Nicoletti et al., 2010), suggesting the possibility that other cells or mechanisms could be involved in the beneficial effects of VEGF during SE. Astrocytes have been reported to contribute to epileptiform discharges in the hippocampus (Tian et al., 2005; Kang et al., 1998) and to express VEGF receptors (Krum & Rosenstein, 2002). We report here that VEGF treatment significantly alters multiple astrocyte parameters. This study investigated astrocyte morphology one month after SE in animals treated with VEGF or inactivated VEGF control protein during SE. Individual GFAP-immunostained astrocytes from CA1 and dentate gyrus hilus were traced and morphologically quantified, and both somatic and process structures were analyzed. VEGF treatment during SE significantly prevented post-SE increases in number of branch intersections, process length, and node count. Furthermore, analysis of distance to nearest neighboring astrocytes revealed that VEGF treatment significantly increased inter-astrocyte distance. Overall, VEGF treatment during SE did not significantly alter the shape of the astrocytes, but did prevent SE-induced changes in branching complexity, size, and spatial patterning. Because astrocyte morphology may be related to astrocyte function, it is possible that VEGF's enduring effects on astrocyte morphology may impact the functioning of the post-seizure hippocampus.

Vascular endothelial growth factor attenuates status epilepticus-induced behavioral impairments in rats.

Vascular endothelial growth factor (VEGF) is a vascular growth factor more recently recognized as a neurotrophic factor (for review, see Storkebaum E, Lambrechts D, Carmeliet P. BioEssays 2004;26:943-54). We previously reported that endogenous VEGF protein is dramatically upregulated after pilocarpine-induced status epilepticus in the rat, and that intra-hippocampal infusions of recombinant human VEGF significantly protected against the loss of hippocampal CA1 neurons in this model (Nicoletti JN, Shah SK, McCloskey DP, et al. Neuroscience 2008;151:232-41). We hypothesized that we would see a preservation of cognitive and emotional functioning with VEGF treatment accompanying the neuroprotection previously observed in this paradigm. Using the Morris water maze to evaluate learning and memory, and the light-dark task to assess anxiety, we found a selective profile of preservation. Specifically, VEGF completely preserved normal anxiety functioning and partially but significantly protected learning and memory after status epilepticus. To determine whether the ability of VEGF to attenuate behavioral deficits was accompanied by sustained preservation of hippocampal neurons, we stereologically estimated CA1 pyramidal neuron densities 4 weeks after status epilepticus. At this time point, we found no significant difference in neuronal densities between VEGF- and control-treated status epilepticus animals, suggesting that VEGF could have protected hippocampal functioning independent of its neuroprotective effect.