Protective Effects And Its Mechanisms Of Flz On Vascular Dementia In Rats

Vascular dementia and Alzheimer's disease are the two most common types of dementia. Alzheimer's disease is the most predominant. Stroke increases the risk of dementia. There is evident that oxidative stress, an environment where pro-oxidant species overwhelm antioxidant species, is involved in the pathogenesis of vascular dementia. At present, no satisfying drug for treating stroke is available. To finding new therapeutics for stroke is very necessary. FLZ is a novel synthetic cyclic analogue of squamosamide from the leaves of Annoma squamosa. Previous studies showed that FLZ had potent action against oxidative stress and of neuroprotection. Our previous studies had investigated the effects of FLZ on cerebral blood flow (CBF), infarct volume and neurological function in transient focal cerebral ischemia. An animal model of tMCAO for 2 hours followed by 24 hours reperfusion was used. Rats received FLZ (150 or 300 mg/kg) orally 10 minutes after the onset of tMCAO. The results showed that FLZ (150 or 300 mg/kg) could reduce significantly the infarct volume and improve neurological deficit in rat tMCAO model as the result of regulation of cerebral blood flow (CBF). In order to investigate whether FLZ could influence cerebral ischemia-induced neuronal and cognitive impairments, the effect of FLZ on tMCAO model was studied. A vascular dementia rat model was induced by tMCAO. FLZ (75 or 150 mg/kg) was orally administered for 30 days once daily. The Morris water maze test and the inclined plateform test were used to evaluate the learning and memory function and motor function. The TTC staining was used to evaluate the infarct volume. The alterations in cortex and hippocampus morphology were assessed by HE staining. Immunoreactive cells of VEGF and BDNF were calculated after immunohistochemical staining. Furthermore, FLZ (150 or 300 mg/kg) was orally administered once 10 minutes after the onset of tMCAO. The Western blot test was used to evaluate the expression of HIF-1αin cortex of ipsilateral and contralateral hemispheres after different time of reperfusion. The content of malondialdehyde (MDA) was determined using biochemical assay kit. The results indicate that in comparison with the control group, the escape latency time in tMCAO group increased significantly by 52.0% in Morris water maze test. The behavioral score in tMCAO group decreased significantly by 52.2% in the inclined platform test. The infarct volume in tMCAO group increased significantly by 35.3%. Remarkable pathological changes of neurons in the cortex and hippocampus in tMCAO group were observed. tMCAO-induced focal cerebral ischemia increased the expression of VEGF while decreasing the expression of BDNF. After 24 hours of reperfusion, tMCAO-induced focal cerebral ischemia was associated with increasing significantly HIF-la expression and MDA content in ischemic regions. Oral administration of FLZ (75 mg/kg) for 30 days increased significantly the behavioral score, the improvement rate was 75%. FLZ (75 and 150 mg/kg) reduced remarkably the escape latency time, the improvement rates were 79.7% and 78.4% respectively. FLZ (75 and 150 mg/kg) reduced significantly the infarct volume by 52.7 and 45.9% respectively. FLZ also ameliorated the neuropathological alterations in rat cortex and hippocampus. FLZ (75 and 150 mg/kg) decreased the VEGF expression. FLZ (75 mg/kg) also decreased the BDNF expression. After 24 hours of reperfusion, FLZ (150 and 300 mg/kg) inhibited significantly HIF-la expression. FLZ (150 and 300 mg/kg) resulted in a remarkable decrease of MDA content by 29.2% and 25.4% respectively. These results suggest that tMCAO induced severe neurological deficit and memory impairment in rats. Neuronal cell loss was observed both in the cortex and hippocampus. FLZ improved memory deficit and pathological injury in vascular dementia rats, its protective effect was related to inhibiting HIF-la expression and reducing MDA content, indicating that FLZ may be a potential candidate drug for the treatment of vascular dementia.