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.

Research highlights
► VEGF protects neurons from status epilepticus-induced death 24 hours after the acute seizure event. To test whether this protection is accompanied by preservation of function, we infused VEGF during status epilepticus and then evaluated learning and memory in the Morris water maze and anxiety in the light-dark exploration apparatus.
► Animals treated with VEGF showed statistically significant preservation of behavioral function, suggesting a protective role for VEGF against seizure-induced behavioral impairments.
► Surprisingly, cell counts conducted one month after status epilepticus showed that the protective effects of VEGF against neuronal loss were transient, suggesting that other factors contributed to the behavioral preservation.