[P1-205]: TREATMENT WITH CALCIUM DOBESILATE REDUCES NEUROINFLAMMATION AND IMPROVES COGNITION IN A MOUSE MODEL OF ALZHEIMER's DISEASE

Calcium dobesilate (calcium 2,5-dihydroxybenzenesulfonate, CaD) is an oral drug currently used for the treatment of chronic venous insufficiency and microangiopathies such as diabetic retinopathy. Treatment with CaD prevents reactive gliosis and neuronal loss in animal models of diabetic retinopathy. Furthermore, CaD reduces reactive oxygen species production by neutrophils in vitro and lowers the production of pro-inflammatory cytokines in disease models. However, its effect on neuroinflammation and Alzheimer's disease (AD) is unknown and our goal was to determine the potential therapeutic effect of CaD in AD models. In vitro adhesion assays on integrin ligands were performed to analyze the effect of CaD on rapid adhesion under static conditions. Flow adhesion assays using Bioflux technology were performed to assess the effect of CaD under physiopathological conditions. Chemotaxis assays were performed using 3μm pore transwells and flow cytometry. 3xTg-AD mice, which present both amyloid and tau pathology were treated with CaD to determine the effect of this drug on memory decline and neuropathological changes. We recently demonstrated that neutrophils migrate into the brain and contribute to the induction of cognitive deficits in animal models of AD. Treatment of neutrophils with CaD reduced integrin-dependent rapid adhesion triggered by chemokines and TNF under static conditions. CaD also significantly inhibited neutrophil adhesion under flow conditions suggesting that this drug may interfere with neutrophil trafficking in vivo. Interestingly, CaD did not reduce chemotaxis and integrin expression, suggesting that it selectively interferes with signal transduction machinery controlling rapid adhesion and integrin activation. Notably, oral treatment for one month with CaD of 3xTg-AD mice led to a significant restoration of memory in Y maze and contextual fear conditioning behavioral tests when compared to control mice. Neuropathological studies showed that treatment with CaD reduced amyloid deposition mainly in the cortex and led to a drastic reduction of microglial activation in the hippocampus and cortex when compared to control animals. CaD has anti-inflammatory properties and can improve cognition in animal models of AD, suggesting that this drug may offer a new therapeutic strategy in AD with rapid translation into the clinic.