Novel Anti-Inflammatory Compound SEN1176 Alleviates Behavioral Deficits Induced Following Bilateral Intrahippocampal Injection of Aggregated Amyloid-β1-42

Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-beta (A beta)(1-42)-induced macrophage production of nitric oxide, TNF-alpha, IL-1 beta, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated A beta(1-42). The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated A beta(1-42) injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 20, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH A beta(1-42) injections. When treatment with SEN1176 was instigated 30 days after IH A beta(1-42) injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH A beta(1-42) injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated A beta(1-42) injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain A beta deposition that affect learning and memory in Alzheimer's disease.