by in-vitro dissolution, permeability study (everted intestine sac method), and in-vivo oral pharmacokinetic study using rats. Also, its safety and efficacy were evaluated after 3 months of treatment by oral administration. Results: The soluplus based NEF displayed dramatic improvement in aqueous solubility (17.53-fold) and sta- bility due to amorphization, hydrogen bonding interaction and mi- cellization. Moreover, the NEF demonstrated significant improvement in intestinal permeability and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2, 16.1 and 14.8-fold enhancement compared to EDR suspension at 46, 138 and 414 mM/kg dose. Besides, our data confirms non-toxicity up to 414 mM/kg dose after 3 months and its potential to reverse AD-like cognitive deficits of APP/PS1 mice in dose dependent manner. Conclusions: NEF has great potential to mitigate the limita- tion associated with EDR and can pave the way for its clinical development for the treatment of AD. P4-587 SUPPRESSION OF CNS INFLAMMATION BY PHOSPHODIESTERASE-1 (PDE1) INHIBITORS: TOWARD NEW TREATMENTS FOR NEURODEGENERATIVE DISEASES Gretchen L. Snyder, Sophie Dutheil, Jennifer L. O’Brien, Stephanie Cruz, Yuan Tian, Joseph P. Hendrick, Lawrence P. Wennogle, Robert E. Davis, Intra-Cellular Therapies Inc., New York, NY, USA. Contact e-mail: gsnyder@intracellulartherapies.com Background: Neuroinflammatory processes are implicated in the cause and progression of neurodegenerative disorders, like Alz- heimer’s disease. Elevated intracellular cyclic nucleotide levels suppress neuroinflammatory responses by controlling microglial activation. The second messenger cyclic adenosine monophosphate (cAMP) is a negative modulator of inflammatory cell responses, including cytokine secretion and leukocyte recruitment. Similarly, increasing intracellular cyclic guanosine monophosphate (cGMP) attenuates lipopolysaccharide (LPS)-induced responses in micro- glia. Hence, increasing intracellular cAMP or cGMP using analogs or phosphodiesterase (PDE) inhibitors, antagonizes changes in mi- croglial cell morphology and production of proinflammatory cyto- kines in the context of inflammation. Intra-Cellular Therapies, Inc. has developed ITI-214, a potent, specific, and clinically-safe inhib- itor of PDE1, a dual-specificity (cAMP/cGMP) PDE, and tested its ability to control neuroinflammation. Methods: Effects of LPS and/ or ITI-214 on mRNA cytokine expression were measured by qPCR using BV2 cells or iPSC-derived astrocytes in vitro and mouse brain tissue. RNAseq was performed (GENEWIZ, LLC) followed by gene ontology using AmiGo 2 software. Results: LPS-induced in- creases in TNFa, IL-1b, and Ccl2 mRNA expression were reduced by >50% by ITI-214 in BV2 cells in vitro and in mice in vivo in brain regions with high PDE1 expression (striatum, cortex and hip- pocampus) while brain expression of the anti-inflammatory cyto- kine IL-10 was increased after ITI-214. Effects of ITI-214 appeared microglial-specific as it did not attenuate induction of IL-6 levels in hiPSC-derived astrocytes after proinflammatory cyto- kine stimulation. We then employed RNA-Seq to identify a subset of genes whose transcript expression was significantly changed with PDE1 inhibition in LPS-treated BV2 cells. These genes were significantly enriched in cell migration and extravasation pathways as well as inflammatory pathways. Of genes induced by LPS, a subset were attenuated by PDE1 inhibition, all of which were significantly associated with inflammatory pathways. Impor- tantly, inhibition of another PDE isoform, PDE4, attenuated a different subset of LPS-induced genes, demonstrating the unique properties of our target. Conclusions: The data demonstrate a key role for PDE1 inhibition in regulating inflammatory responses in microglia and support PDE1 inhibition as a viable therapeutic approach in disorders in which neuroinflammation and microglia activation are known components of the disease, like Alzheimer’s disease. P4-588 EVALUATION OF THE NEUROPROTECTIVE EFFECT OF INTEPIRDINE IN AN IN VITRO OXYGEN/ GLUCOSE DEPRIVATION-INDUCED CYTOTOXICITY MODEL Ebenezer Asare 1 , Rosemarie Roeloffs 2 , Brante P. Sampey 3 , Shankar Ramaswamy 1 , Bote Bruinsma 4 , Harald Murck 1,5 , Lawrence Friedhoff 1 , 1 Axovant Sciences, Inc., New York, NY, USA; 2 Roivant Sciences, New York, NY, USA; 3 Roivant Sciences, Inc., New York, NY, USA; 4 Axovant Sciences, New York, NY, USA; 5 Philipps-Universit€ at Marburg, Clinic of Psychiatry and Psychotherapy, Marburg, Germany. Contact e-mail: lawrence.friedhoff@roivant.com Background: Intepirdine is a novel 5HT6 receptor antagonist in development for the treatment of patients with mild-moderate Alz- heimer’s disease (AD) and dementia with Lewy bodies (DLB). In a prior Phase 2b study of 684 subjects with mild-moderate AD on sta- ble background donepezil treatment, intepirdine demonstrated sta- tistically significant benefits on measurements of cognition (ADAS-cog) and function (ADCS-ADL). As a 5HT6 receptor antagonist, intepirdine works in part by relieving interneuron-medi- ated inhibition and promoting the release of acetylcholine and other neurotransmitters in the brain. We hypothesized that intepirdine may be neuroprotective against vascular injury and neuronal meta- bolic dysfunction, which are early features of AD reported to pre- cede clinical dementia. We explored this in an oxygen and glucose deprivation (OGD) model in rat neuronal cultures. Methods: Mixed cortical neurons (MCN) were isolated from E18 Wistar rat embryos. MCN cultures were pretreated with intepirdine (0.01 – 1.0 mM) for 24 hours and subjected to oxygen/glucose deprivation (OGD) with intepirdine for 5 hours. Following OGD, the medium was replaced with normal, glucose-containing culture medium dosed with intepirdine and cultures were incubated for an additional 20 hours under normoxic conditions. As controls, MCN cultures were exposed to 10 mM MK-801 þ 100 mM CNQX and 300 mM NMDA, respectively. MCN cultures were also dosed with intepirdine without OGD. Cytotoxicity was determined by quantifying LDH release. Results: When pre-treated with intepir- dine for 24 hours, a decrease in LDH release was observed in MCN cultures exposed to OGD (P<0.05 for intepirdine concentra- tions 0.03 – 1.0 mM), with a maximum reduction of 40% at 0.3 mM concentration (Figure 1). In the absence of OGD, intepirdine was not cytotoxic to MCN cultures at any dose. Conclusions: In this OGD model, intepirdine demonstrated neuroprotective effects un- der hypoxic and hypoglycemic conditions in MCN cultures at clin- ically relevant human concentrations. This supports the hypothesis that intepirdine is protective against vascular injury and neuronal metabolic dysfunction and could protect against neuronal loss in AD patients. This finding warrants further investigation. Poster Presentations: Wednesday, July 19, 2017 P1579