Abstract:

Objective

To investigate the effects of butylphthalide on serum inflammatory markers in a rat model of vascular cognitive impairment （VCI）， and to clarify the specific mechanism of butylphthalide.

Methods

A total of 49 specific pathogen-free Sprague-Dawley rats， aged two months and weighing approximately （170±20） grams， were randomly assigned， with 40 males and 40 females used for VCI rat model creation. The VCI rat model was established by repeated bilateral carotid artery occlusion combined with modified hypotension. The successfully modeled rats were randomly divided into three groups: model， positive control， and butylphthalide treatment. Sham-operated rats in the sham group underwent the same surgical procedures as the model group but without carotid occlusion，receiving only normal saline via oral gavage. Seven days after successful modeling， the model group received intragastric administration of normal saline， the positive drug group received intragastric administration of nimodipine hydrochloride solution， and the butylphthalide treatment group received intragastric administration of butylphthalide solution. After 30 days of continuous administration， serum levels of tumor necrosis factor-alpha （TNF-α） and interleukin （IL）-6 were measured， and cognitive function was assessed using the Morris water maze method ［including positioning cruise experiment（5 consecutive days of testing）， spatial exploration experiment， and visible platform experiment］. ANOVA and non-parametric test were used to analyze the escape latency of seeking the platform measured by the positioning cruise experiment， the time required to cross the platform for the first time measured by the space exploration experiment， the time to find the platform measured by the visual platform experiment， and the TNF-α and IL-6 data of the brain tissue of the rats in each group. LSD method was used to compare pairwise differences between groups.

Results

After treatment， the escape latency of the positive drug group ［1-5 d:（70.23±25.20） s， （68.44±19.29） s， （42.92±22.30） s， （32.33±21.42） s， （26.68±22.40） s］， the butylphthalide treatment group ［1-5 d: （62.81±19.73） s， （52.02±15.51） s， （35.55±12.80） s， （26.25±7.52） s， （19.28±6.17） s］，and the model group ［1-5 d: （96.23±6.67） s， （87.35±27.57） s， （77.90±20.56） s， （54.27±19.11） s，（49.01±27.26） s］， with the most significant reduction observed in the positive control and butylphthalide treatment groups compared to the model group （F=23.950， P＜0.001）. In the spatial exploration experiment，the time required for the first platform crossing by rats in the positive drug group ［（16.54±5.64） s］and butylphthalide treatment group ［（15.28±4.86） s］ was significantly shorter than that in the model group［（27.45±13.69） s］ （all P＜0.001）. In the visible platform experiment， significant differences in escape latency were found among the positive control group ［（15.64±6.51） s］， butylphthalide treatment group ［（14.02±6.71） s］，model group ［（16.00±5.80） s］， and sham group ［（11.19±2.94） s］， but no significant pairwise differences were observed between the model， positive control， and butylphthalide treatment groups （all P＞0.05）. Serum levels of TNF-α and IL-6 in the positive drug group ［（29.09±4.76） pg/ml， （70.61±8.34） pg/ml］ and the butylphthalide treatment group ［TNF-α: （29.11±4.79） pg/ml， IL-6: （56.39±8.23） pg/ml］ were significantly lower than those in the model group ［TNF-α: （35.68±5.76） pg/ml， IL-6: （90.61±15.23） pg/ml］ （all P＜0.001）.

Conclusion

Butylphthalide may improve the cognitive function in VCI rats by reducing the levels of TNF-α and IL-6 in the cerebral cortex of VCI rats.

Key words: Butylphthalide, Inflammatory factor, Vascular cognitive impairment