Novel phosphodiesterase 4 inhibitor chlorbipram enhanced memory deficits in AD rats and its mechanisms involved / 中国药学杂志

ABSTRACT

OBJECTIVE: To investigate the effect and mechanism of novel phosphodiesterase 4 inhibitor chlorbipram on learning and memory disorders in Alzheimer's disease animal model. METHODS: The rat model of learning and memory deficits with AD was used by bilateral microinjection of Aβ25-35 into the CA1 region of the hippocampus. Then the rats were randomly divided into six groups; sham-operated group, Aβ25-35 microinjected (model group), chlorbipram treatment(0.05 and 0.15 mg · kg-1) group, rolipram-treated (0.05 mg · kg-1) and donepezil (1.0 mg · kg-1) group. The effect of chlorbipram on memory behavioral performance were evaluated with Morris water maze and step-through passive avoidance test, and the open field test was performed to determine the animal locomotor activity. After the last behavioral performance test, the hippocampus were dissected for further molecular analysis. The protein level of BDNF and the phosphorylation of PKA and CREB were analyzed by Western blotting; the mRNA level of BDNF in the hippocampus was detected by real-time PCR. RESULTS: Microinfusion with Aβ25-35 produced impairment of spatial memory in behavioral tests, which was reversed by either PDE4 inhibitor or donepezil administration. Chlorbipram, rolipram and donepezil increased the number of crossing and percent of time in the target quadrant in the Morris water maze probe trial. In the step-through passive avoidance test, the 24 h latency was significantly decreased in rats treated with either chlorbipram or positive control drugs, while no significant difference were shown in total locomotor activity among the groups. Western blot analyses showed that Aβ25-35-microinjection decreased the phosphorylation of PKA and CREB and inhibited the protein expression of BDNF in the hippocampus. Chlorbipram, rolipram and donepezil reversed the reduction of the phosphorylated PKA and CREB induced by Aβ25-35. Moreover, these drugs also enhanced both the mRNA and protein levels of BDNF. CONCLUSION: Chlorbipram produces a significant improvement of learning and memory in AD animal, and this effect is due to the mediation of cAMP/PKA/CREB/BDNF signal pathway.