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Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (-)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (-)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (-)clau. The principal pharmacological effects of (-)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit β-amyloid (Aβ) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (-)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.
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Aim To explore the effects of clausenamide(Clau) on hippocampal heme oxygenase(HO-1 and HO-2) expressions in diabetic rats.Methods The diabetic rats model was produced by injecting streptozotocin (48 mg?kg-1). After 3 months,the HO-1 and HO-2 mRNA and protein expressions in hippocampus of diabetic rats were detected by RT-PCR and immunohistochemistry respectively.Results ① The results of RT-PCR showed that the protein expressions of HO-1 and HO-2 mRNA in hippocampus of diabetic group were higher than those of control group(P
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Objective To study the protective effect of(-)clausenamide on the damage of PC12 cells induced by serum deprivation and to explore its related mechanism. Methods The cell viability was detected by MTT assay and morphological observation. The effect of(-)clausenamide on the PC12 cell apoptosis was analyzed by flow cytometry. Then western blotting and confocal microscope was used for the further study of effect of(-)clausenamide on the protein expression of GSK-3?,Bax and Bcl-2. Results(-)Clausenamide remarkably increased PC12 cell survival rate through inhibiting the PC12 cell apoptosis induced by serum deprivation at the concentration of 1 or 10 ? mol/L(P
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Aim To study the effect of synapsinⅠon synaptic transmission in rat dentate gyrus induced by(-) clausenamide.Methods The basal synaptic transmission experiment was conducted through electrophysiological recordings.The effect of(-) clausenamide on synapsinⅠ phosphorylation was measured by western blot and confocal microscopy.Results(-)Clausenamide increased the population spike(PS) of hippocampal dentate gyrus.The phosphorylation of synapsinⅠ was increased both in cortex and hippocampus,the maximum effect was observed at 5 min in hippocampus and at 15 min in cortex.Furthermore,(-)clausenamide promoted the phosphorylation of synapsinⅠat a dose-denpendent manner in PC12 cells.The phosphorylation of synapsinⅠ in PC12 cells and synaptosomes incubated with(-)clausenamide was increased and reached maximum at 1~2 min.However,H89,PKA inhibitor,blocked the effect of(-)clausenamide on synapsinⅠ phosphorylation.Conclusion(-)Clausenamide activated synapsinⅠ via PKA signal pathway,which may contribute to the effect of(-)clausenamide on potentiating basal synaptic transmission.
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Aim To explore the effects of Clausena-mide(Clau) on hippocampus cyclooxygenase-2 (COX-2) mRNA and protein expressions in diabetic rats. Methods The diabetic rat model was produced by injecting streptozotocin (STZ,48 mg?kg-1). After 3 months,the COX-2 gene and protein expressions in hippocampus of diabetic rats were detected by RT-PCR and immunohistochemistry respectively. Results ① The results of RT-PCR showed that the expression of COX-2 mRNA in hippocampus of diabetic group rats increased significantly (P