Inhibitory alkaloids from Dictamnus dasycarpus root barks on lipopolysaccharide-induced nitric oxide production in BV2 cells.

The methanolic extract of Dictamnus dasycarpus root barks afforded one new glycosidic quinoline alkaloid, 3-[1ß-hydroxy-2-(ß-D-glucopyranosyloxy)-ethyl)-4-methoxy-2(1H)-quinolinone (1), together with nine known compounds, preskimmianine (2), 8-methoxy-N-methylflindersine (3), dictamine (4), γ-fagarine (5), halopine (6), skimmianine (7), dictangustine-A (8), iso-γ-fagarine (9), isomaculosidine (10). The isolated alkaloids significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 cells. Among them, compounds 3 and 7 showed the most potent inhibitory activities on LPS-induced NO production.

Limonoids from Dictamnus dasycarpus protect against glutamate-induced toxicity in primary cultured rat cortical cells.

In our previous report, four limonoids, obacunone, limonin, fraxinellone, and calodendrolide, isolated from Dictamnus dasycarpus showed significant neuroprotective activity against glutamate toxicity in primary cultured rat cortical cells. This study investigated neuroprotective mechanism of these compounds using the same in vitro culture system. These four compounds showed significant neuroprotective activity at the concentration of 0.1 muM. They effectively inhibited calcium influx and overproduction of cellular nitric oxide and reactive oxygen species accompanied by glutamate-induced neurotoxicity. In addition, these compounds significantly preserved mitochondrial membrane potential and activities of antioxidative enzymes. Our results showed that obacunone, limonin, fraxinellone, and calodendrolide significantly protect primary culture cortical cells against glutamate-induced toxicity by preserving the antioxidant defense system. These compounds might offer potential drug development candidate for various neurodegenerative diseases involved with glutamate.

Neuroprotective limonoids of root bark of Dictamnus dasycarpus.

A methanolic extract of Dictamnus dasycarpus root bark afforded four new degraded limonoids, 9alpha-hydroxyfraxinellone-9- O-beta- d-glucoside ( 1), dictamnusine ( 2), dictamdiol A ( 3), and dictamdiol B ( 4), together with eight known compounds, dictamdiol ( 5), fraxinellone ( 6), fraxinellonone ( 7), 9beta-hydroxyfraxinellone ( 8), calodendrolide ( 9), obacunone ( 10), limonin ( 11), and rutaevin ( 12). Compounds, 2, 3, 6, 9, 10, and 11 showed significant neuroprotective activity against glutamate-induced neurotoxicity in primary cultures of rat cortical cells at a concentration of 0.1 microM.

Neuroprotective 2-(2-phenylethyl)chromones of Imperata cylindrica.

Bioactivity-guided fractionation of the methanolic extract of the rhizomes of Imperata cylindrica afforded a new compound, 5-hydroxy-2-(2-phenylethyl)chromone (1), together with three known compounds, 5-hydroxy-2-[2-(2-hydroxyphenyl)ethyl]chromone (2), flidersiachromone (3), and 5-hydroxy-2-styrylchromone (4). Among these four compounds, 1 and 2 showed significant neuroprotective activity against glutamate-induced neurotoxicity in primary cultures of rat cortical cells.

ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, significantly improved scopolamine-induced memory impairment in mice.

We assessed the effects of oral treatments of ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, on learning and memory deficit. The cognition-enhancing effect of ESP-102 was investigated in scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze performance tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with ESP-102 (doses in the range of 10 to 100 mg/kg body weight) significantly reduced scopolamine-induced memory deficits in the passive avoidance performance test. Another noteworthy result included the fact that prolonged oral daily treatments of mice with much lower amounts of ESP-102 (1 and 10 mg/kg body weight) for ten days reversed scopolamine-induced memory deficits. In the Morris water maze performance test, both acute and prolonged oral treatments with ESP-102 (single administration of 100 mg/kg body weight or prolonged daily administration of 1 and 10 mg/kg body weight for ten days, respectively, significantly ameliorated scopolamine-induced memory deficits as indicated by the formation of long-term and/or short-term spatial memory. In addition, we investigated the effects of ESP-102 on neurotoxicity induced by amyloid-beta peptide (Abeta25-35) or glutamate in primary cultured cortical neurons of rats. Pretreatment of cultures with ESP-102 (0.001, 0.01 and 0.1 mug/ml) significantly protected neurons from neurotoxicity induced by either glutamate or Abeta25-35. These results suggest that ESP-102 may have some protective characteristics against neuronal cell death and cognitive impairments often observed in Alzheimer's disease, stroke, ischemic injury and other neurodegenerative diseases.

Anti-acetylcholinesterase and anti-amnesic activities of a pregnane glycoside, cynatroside B, from Cynanchum atratum.

We previously reported that seven pregnane glycosides including cynatroside B isolated from the roots of Cynanchum atratum significantly inhibited acetylcholinesterase (AChE) activity. In the present study, we have characterized the mode of AChE inhibition of cynatroside B, the most potent of these isolated pregnane glycoside inhibitors. We have also examined the anti-amnesic activity of cynatroside B. Cynatroside B inhibited AChE activity in a dose-dependent manner and its IC50 value was 3.6 microM. The mode of AChE inhibition by cynatroside B was reversible and non-competitive in nature. Moreover, cynatroside B (1.0 mg/kg body weight i.p.) significantly ameliorated memory impairments induced in mice by scopolamine (1.0 mg/kg body weight s.c.) as measured in the passive avoidance and the Morris water maze tests. We suggest, therefore, that cynatroside B has both anti-AChE and anti-amnesic activities that may ultimately hold significant therapeutic value in alleviating certain memory impairments observed in Alzheimer's disease.

Flavonoids from Spatholobus suberectus.

Two pterocarpans [(6aR,11aR)-maackiain, (6aR,11aR)-medicarpin], one flavanone [(2S)-7-hydroxy-6-methoxy-flavanone], one isoflavan (sativan) and two isoflavones (pseudobaptigenin, genistein) were isolated from the Spatholobus suberectus (Leguminosae). Their chemical structures were determined by comparison of their spectroscopic parameters of CD, EIMS, 1D-NMR and 2D-NMR with those reported in the literatures. All of these compounds are reported for the first time from this plant through the present study.

Iridoids from Scrophularia buergeriana attenuate glutamate-induced neurotoxicity in rat cortical cultures.

In previous work, we isolated 7 neuroprotective iridoid glycosides from the 90% MeOH fraction of Scrophularia buergeriana (Scrophulariaceae). We therefore investigated the mode of action of 8-O-E-p-methoxycinnamoyl-harpagide (8-MCA-Harp), the most potent neuroprotective iridoid, and its aglycone, harpagide (Harp) using primary cultures of rat cortical cells in vitro. 8-MCA-Harp only revealed its neuroprotective activity in a pretreatment paradigm; this iridoid had more selectivity in protecting neurons against N-methyl-D-aspartate (NMDA)-induced neurotoxicity as opposed to that induced by kainic acid (KA). On the other hand, Harp exerted significant neuroprotective activity when it was administered either before or after glutamate insult and protected cultured neuronal cells from neurotoxicity induced by NMDA or KA. Furthermore, Harp significantly prevented the decrease of glutathione, an antioxidative compound in the brain, in our cultures. Finally, 8-MCA-Harp and Harp could successfully reduce the overproduction of nitric oxide and the level of cellular peroxide in cultured neurons. Collectively, these results suggested that Harp and 8-MCA-Harp protected primary cultured neurons against glutamate-induced oxidative stress primarily by acting on the antioxidative defense system and on glutamatergic receptors, respectively.