D5 receptor agonist 027075 promotes cognitive function recovery and neurogenesis in a Aβ1-42-induced mouse model

Abstract

In this study, a high throughput screening system was set up to identify D5 receptor agonists-027075. Then, a series of behavior tests were used to evaluate the beneficial effects of 027075 in Aβ1-42-induced mice model including morris water maze, passive avoidance, active avoidance, open field and step-down test. The neuroprotective effect of 027075 was assessed by a high content screening in vitro. In behavior tests, the cognitive function impairment caused by Aβ1-42 was significantly ameliorated by 027075 in a dose-dependent manner. 027075 (8 mg/kg) significantly prolonged the time spent in the target quadrant when compared to the model group in morris water maze test. The latency was significantly increased and the number of errors was decreased in both passives avoidance task and step down test when compared to the model group. In active avoidance and open field test, latency, stimulation time, number of errors were significantly reduced, while number of avoidance and line crossing and central distance were increased by 027075 (8 mg/kg). All the results above was significantly reversed by 027075-H + SCH39166 (5 mg/kg) when compared to 027075-H (8 mg/kg). The neuroprotective effect of 027075 was demonstrated by promotion of cell differentiation and extension of neurite length. But the effects were abrogated by the specific D1/D5 antagonist, SCH39166. These results indicate that D5 receptor might be used as an ideal target for the treatment of AD and its agonists might become a new AD drugs in the future.

Keywords: Apoptosis; Aβ peptide; Cognitive dysfunction; D5 receptor; High-content screening.