Effects of 4-phenylbutyric acid on chronic cerebral hypoperfusion-induced cognitive dysfunction / 中华行为医学与脑科学杂志

ABSTRACT

Objective To explore the effects of 4-phenylbutyric acid(PBA) on cognitive dysfunction after chronic cerebral hypoperfusion and underlying mechanisms.Methods 62 male Sprague Dawley rats in clean degree were divided into sham group(n=14),chronic cerebral ischemia group(bilateral carotid arteries occlusion,2VO group,n=24),and chronic cerebral ischemia with PBA treatment(2VO+PBA group,n=24).The chronic cerebral ischemia models were produced by the occlusion of bilateral common caroid artery for 1 month.During the hypoperfusion,the rats were injected intraperitoneally with 11.25 mg · ml-1 PBA(90 mg · kg-1 · d-1) or equal volume of saline once a day for 3 days followed by every other day for 27 days.Learning and memory abilities were tested by Morris water maze and novel object recognition test.The expression and distribution of NR2A in hippocampus were examined by Western blot and immunohistochemistry.Results Morris water maze test showed that the 2VO group had significantly longer latent time than sham group in searching platform (P＜0.01) (from 2nd day to 7th day latency time),and the 2VO+PBA group had dramatically shorter latent time than 2VO group (2nd,5th,6th,7th (P＜0.01),3rd(P＜0.05)).Then the rats' memory test showed that 2VO group spent markedly longer time than sham group to reach the location of the former platform(P＜0.01),but the 2VO+PBA group spent dramatically shorter latent time than 2VO group (P＜0.01).The novel object recognition test showed the exploration ratio and discrimination index of novel object in 2VO group were noticeably smaller than that in sham group (P＜0.01),but the exploration ratio and discrimination index of novel object in 2VO+PBA group were noticeably higher than that in 2VO group (P＜0.01).The Western blot data showed that the level of NR2A in 2VO group was significantly lower than that in sham group (P＜0.01),but the level of NR2A in 2VO+PBA group was significantly higher than that in 2VO group (P＜0.05).The level of NR2B in hippocampus of 2VO group had no significant difference with sham group and 2VO+PBA group (P＞0.05).Immunohistochemistry data was consistent with the data of Western blot for NR2A level and distribution.The ratio of p-CREB/total CREB in 2VO group(0.62±0.04) was remarkably lower than that in sham group(1.00±0.07),but the ratio of p-CREB/total CREB in 2VO+PBA group(0.97±0.07) was remarkably higher than that in 2VO group(P＜0.01).Conclusion NR2A reduction is associated with chronic cerebral hypoperfusion-induced cognitive impairment,which is rescued by the PBA treatment.It suggests that PBA may have a therapeutic effect on preventing chronic cerebral hypoperfusion-induced cognitive impairment.