| Alzheimer’s disease (AD) is one of the main types of senile dementia with symptoms of physical disabilities and varying degrees of loss of memory and cognitive ability. AD is correlated with aging. The morbidity rate of people over60years old is5.1%. The prevention and treatment of AD has become a hot topic among the government, medical institutions and pharmaceutical industries. Currently, although there are no specific medicines that can cure AD, traditional Chinese medicines and natural medicines provide abundant resources for the discovery of drug candidates for prevention and treatment of AD.Portulaca oleracea L.(purslane), known as longevity vegetable, is an edible plant and also a traditional medicine. Its aerial part has heat-clearing, detoxifying, blood-cooling and hemostasis functions. Multiple evidences indicated that P. oleracea possessed radical-scavenging, antioxidant and neuroprotective abilities, and it could improve learning and memory abilities of D-gal induced aging AD mouse. To date, the anti-AD principles of P. oleracea are not clear yet.Multiple types of chemical compounds present in P. oleracea among which amide alkaloids are one of the most important bioactive constituents. Preliminary work indicated that some amides displayed potent neuron-protection activities in vitro. Tetrahydroisoquinoline alkaloid oleracein E (OE), abounding in the amides of P. oleracea, has a pyrrolidone moiety in its structure similar with piracetam (PA) or PA-like drugs which were used for the treatment of AD in clinic. Thus, we hypothesize that the standard amide extract PAAs and OE may be the important principles that account for the anti-AD function of P. oleracea. In present study, we investigated the anti-AD activities of PAAs and OE and tried to elucidate the underlying mechanisms.The AD KM mouse models were tried to be established by subcutaneously injection of150mg/(kg-d) D-gal, or300,500and1000mg/(kg-d) D-gal for60days. However, the results of cognitive ability tests and measurement of oxidative-stress related parameters indicated the AD models were not successfully established.The AD KM mouse model was successfully established by intraperitoneal injection of D-gal (1250mg/(kg-d)) and NaNO2(90mg/(kg-d)) for8weeks. Based on this model, assessment of the anti-AD activities of i.g. low dosage of PAAs (L-PAAs,360mg/(kg-d)) and high dosage of PAAs (H-PAAs,720mg/(kg-d)), or i.g. low dosage of OE (L-OE,3mg/(kg-d)) and high dosage of OE (H-OE,15mg/(kg·d)) for8weeks were performed, through assays of body weight, survival rate, cognitive ability, organ index, oxidative-stress related parameters in the brain and plasma, and morphological and immunohistological investigation of hippocampus. The results indicated that,(1) Compared with D-gal/NaNO2model group, piracetam (PA, positive control), L-PAAs and H-PAAs significantly improved the survival rate of AD mouse (p=0.001, p=0.001, p=0.001) and rearing times under the new circumstance (P=0.000, P±0.015, P=0.006); Water-maze test showed that L-PAAs and H-PAAs significantly decreased the escape latency (P=0.040, P=0.033), increased time spent in target quadrant and crossing number in former platform-located area (P=0.002, P=0.005; P=0.002, P=0.011). Moreover, L-PAAs and H-PAAs could significantly reduce kidney enlargement induced by D-gal/NaNO2(P=0.017, P=0.009). H-PAAs reversed the compensatory increase of SOD in the brain and plasma of AD mouse to normal levels (p=0.000, p=0.000); PA, L-PAAs and H-PAAs significantly improved CAT activity (p=0.001, p=0.009, p=0.003) and decreased MDA content in the plasma of AD mouse (p=0.000,p=0.010,p=0.002). Meanwhile, PA and H-PAAs could reduce MDA content in AD mouse brain (p=0.027,p=0.005). As a whole, PAAs could alleviate oxidative stress, decrease lipid peroxidation and protect hippocampus neurons, thus ameliorated cognitive functions of D-gal/NaNO2induced AD mouse.(2) Compared with D-gal/NaNO2model group, OE had a better effect on survival rate than PA. At the same time, OE regulated metabolic disorders of AD mouse and promoted urination and defecation. Water-maze test indicated that H-OE decreased the escape latency of AD mouse (P=0.056), increased time spent in target quadrant and crossing number in former platform-located area (P=0.023, P=0.048). The effect of H-OE to improve learning and memory ability of AD mouse was similar to PA, while L-OE had no effect. In addition, PA, L-OE and H-OE reversed the compensatory increase of T-AOC, SOD activity and GSH content of AD mouse brain and plasma to normal levels (P=0.059, P=0.013, P=0.000; P=0.039, P=0.051,P=0.015; P=0.084, P=0.010, P=0.008). At the same time, L-OE significantly increased CAT activity in AD mouse brain and plasma (P=0.016, P=0.006) and PA increased CAT activity in plasma (P=0.024), while H-OE had no effect on CAT. Further investigation indicated that H-OE and PA could protect the hippocampus neurons through inhibiting neuron apoptosis by upregulating the expression of Bcl-2and downregulating the expression of Bax and Caspase-3. L-OE had a weaker inhibition towards neuron apoptosis. Overall, H-OE decreased levels of oxidative stress, protected hippocampus neurons, thus improved learning and memory ability of D-gal/NaNO2induced AD mice. |
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