Treatment of Hydrocephalus by Decreasing Inflammatory Cytokine Response Using GIT 27

BackgroundSurgical insertion of a ventricular shunt initiates a cytokine response shown to play a role in shunt failure caused by obstruction. These pro-inflammatory and anti-inflammatory cytokines cause astrocytes, amongst others, to enter an activated state which causes an increase in attachment. 4,5-Dihydro-3-phenyl-5-isoxazoleacetic acid (GIT 27) is a reagent with immunomodulatory properties which acts by blocking the main signaling protein on astrocytes and microglia called toll-like receptor 4 (TLR-4). MethodsIn this experiment, we tested the effect of GIT 27 on astrocytes when used as a pre-treatment, simultaneous treatment, and post-treatment relative to shunt insertion represented by the introduction of IL-1{beta} or IL-10. Control, DMSO vehicle control, and GIT 27 treated sample groups were assayed for cell counts and cytokine concentration data. ResultsExposure of astrocytes to suspended GIT 27 in a DMSO vehicle caused a decrease in cell attachment and a significant decrease in the concentration of the majority of cytokines. Comparisons of GIT 27 exposure times, represented by pre-, simultaneous, and post-treatment groups, showed that pre-treatment with GIT 27 is most effective at decreasing cellular attachment where post-treatment was generally the most effective at decreasing pro-inflammatory cytokine concentrations. In future practice, this could be embodied by pharmacologic dosing prior to shunting and/or slow release from the shunt surface. ConclusionsGIT 27 is most effective at decreasing cell counts and cytokines when in-suspension compared to when attached to the shunt surface. Our data show that GIT 27 has the potential to be used as an effective way to modulate the cytokine response associated with shunt insertion.