| Objective:To explore the change of cerebral blood flow（CBF）and cognitive impairment in chronic cerebral hypoperfusion（CCH）model.To investigate the active effects and mechanism of DL-3-n-butylphthalide（NBP）against CCH.Methods:To investigate the CBF of the CCH rats model induced by modified two-step BCCAO using Laser-Doppler scanning at surgery or using Positron Emission Tomography（PET）at 4 weeks after modeling.Additionally,the cognitive functions were assessed by Morris water maze test.Experiments were carried out on Sprague Dawley rats（age 6-8 weeks weighing 250–300 g）and we randomly divided these SD rats into four groups:model groups,sham groups,high-dose NBP groups（H-NBP,80mg/kg,d,i.p.）and low-dose NBP groups（L-NBP,40mg/kg,d,i.p.）.We also evaluated the effects of H-NBP and L-NBP on the cognitive functions at 4 weeks after BCCAO,and the effects of the blood-brain barrier（BBB）disruption and tight junction（TJ）ZO-1 and Claudin-5,using Evans Blue extravasation,Western blot.Results:1)A CCH rat model was successfully established and TTC staining suggested that there was no cerebral infarction in CCH model at 24 hours after surgery.CBF decreased significantly after right common carotid artery occlusion（RCCAO）and BCCAO,and then recovered after 1 week,but it was still far below the baseline CBF value.2)Compared with the sham groups,the escaped latency and the length of CCH rats were obviously prolonged（P<0.001）while the number of platform crossing decreased（P<0.05）.The results suggested that CCH promoted the cognitive impairment.3)The CBF of cortex,hippocampus,thalamus and cerebellum were assessed by13N-Ammonia-PET at 4 weeks after BCCAO.Compared with the sham groups,the group CBF of model groups is lower and the differences between this two groups are more pronounced in hippocampus thalamus,motor cortex and somatosensory cortex.4)The performance of CCH rats in behavioral test were significantly improved by NBP treatment and H-NBP has an added value for the treatment strategies in CCH.In model rats,treatment with H-NBP decreased the Evans blue content in brain tissue（P<0.05）and increased the expression of claudin-5（P<0.01）and ZO-1（P<0.05）at 7 days after BCCAO.There was no significant difference in TJ protein expression between L-NBP groups and model groups.（P>0.05）Conclusion:The CBF of the CCH rats model at 4 weeks after two-step BCCAO using PET is lower than sham group,and the differences between two groups are more pronounced in hippocampus,thalamus,motor cortex and somatosensory cortex.NBP improves the spatial memory and barrier function of BBB in CCH rats model by upregulating the expression of TJ proteins.These results suggest that NBP might be potential drugs for the treatment of VCI disease. |
