Abstract T P234: Cell Cycle Inhibition via Blocking Src Family Kinases Promotes Hippocampal Neuron Survival and Improves Cognitive Function after Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) is one of the most serious hemorrhagic brain diseases being associated with blood brain barrier (BBB) disruption, brain edema, neuron loss, cognitive impairment and high mortality in humans. Increasing evidence suggests that neuronal cell death ensues when neurons attempt to re-enter the cell cycle. Our previous study has demonstrated that cell cycle inhibition via blocking Src family kinases (SFKs) prevents neuronal cell death. However, one of the concerns with cell cycle therapy might be that it would inhibit proliferation of neural progenitor cells (NPCs) and that inhibiting neurogenesis would produce cognitive effects related to the therapy itself. Using the rodent in vivo IVH model we show that i.p. injection of SFK inhibitor (PP2) prevents IVH-induced death of hippocampal neurons and cognitive deficits assessed on the Morris Water Maze. Moreover, PP2 (i.p.) alone did not affect proliferation of NPCs and did not affect cognition. Since there are several SFK gene family members in brain, we targeted specific SFK subtypes (e.g. Fyn, Lck and c-Src) using a newly developed in vivo nanoparticle-based siRNA transfection system. We show that nanoparticle-siRNA-Fyn plus nanoparticle-siRNA-Src attenuate IVH-induced neuron loss and cognitive deficits. Nanoparticle-siRNA-Fyn nor nanoparticle-siRNA-Src had no significant affects on population of NPCs or cognitive side effects, possibly because the nanoparticle-based siRNA transfection system only produces transient knockdown of the gene targets. This could provide a novel therapy for treating IVH patients as the nanoparticle-based siRNA approach provides heightened specificity for specific SFK gene(s) with less off target effects and this approach has been used in humans. Acknowledgements: This study was supported by AHA Beginning Grant-in-Aid 12BGIA12060381 (DZL) and NIH grant NS054652 (FRS). There were no conflicts of interest.