Neurotrophic and neuroprotective actions of ginsenosides Rb(1) and Rg(1).

The ginsenosides have many pharmacological actions, including various actions on the nervous system. Our previous studies have demonstrated that two ginsenosides, Rb(1) and Rg(1) improve performance in a passive avoidance-learning paradigm and enhance cholinergic metabolism. The present study was designed to examine the cellular neurotrophic and neuroprotective actions of two pure ginsenosides in two model systems. PC12 cells were grown in the absence or presence of nerve growth factor (NGF) as a positive control, and different concentrations of Rb(1) or Rg(1). To assess neurotrophic properties, neurite outgrowth was quantified for representative fields of cells. After 8 days in culture, both ginsenosides enhanced neurite outgrowth in the presence of a sub-optimal dose of (2 ng/ml) NGF, but did not significantly stimulate neurite outgrowth in the absence of NGF. However, after 18 days in culture, both ginsenosides increased neurite outgrowth in the absence of NGF. SN-K-SH cells were grown in the absence or presence of MPTP or beta-amyloid to assess neuroprotection. Rb(1) and Rg(1) both reversed MPTP-induced cell death. beta-Amyloid-induced cell death was not reversed by either ginsenoside, but Rg(1) produced a modest enhancement of cell death in this model. These results suggest that these two ginsenosides have neurotrophic and selective neuroprotective actions that may contribute to the purported enhancement of cognitive function.

American ginseng extract reduces scopolamine-induced amnesia in a spatial learning task.

OBJECTIVE: To determine if HT-1001, an extract of American ginseng, affects scopolamine-induced memory and performance deficits in a spatial learning task, alters brain concentrations of aminergic neurotransmitters, and alters choline uptake in synaptosome preparations. DESIGN: Animal study. ANIMALS: 48 Sprague Dawley rats. INTERVENTIONS: Long-term oral administration of a test material or control solution. Intraperitoneal administration of scopolamine (2 mg/kg) 30 minutes before testing. OUTCOME MEASURES: Performance on Morris water maze task, choline uptake, aminergic neurotransmitter analysis, in vitro monoamine oxidase analysis (of compounds). RESULTS: HT-1001 protected against scopolamine-induced amnesia and increased choline uptake in synaptosomal preparations. HT-1001 did not alter brain concentrations of norepinephrine, dopamine, 5-HT (serotonin), 3,4-dihydroxyphenylacetic acid or 5-hydroxyindoleactic acid. HT-1001 had a very weak ability to inhibit monoamine oxidase activity in vitro. CONCLUSIONS: HT-1001 demonstrates a capacity to protect against scopolamine-induced memory deficits.

Clinical aspects of parathyroid hypertensive factor.

To determine the clinical significance of parathyroid hypertensive factor (PHF), physiological studies previously performed in animal models of hypertension were parallelled by human studies. These studies revealed that PHF-like activity is present in human hypertension, where it correlates with the salt-sensitive, low-renin state. As in spontaneously hypertensive rats, both supplemental calcium and calcium-channel blockers appear to be useful in the treatment of PHF-related hypertension. In primary hyperparathyroid patients, PHF presence is linked with the presence of hypertension. Postparathyroidectomy blood pressure falls in parallel with PHF levels. These preliminary human studies suggest that PHF may be a useful marker in the treatment of hypertension.

Clinical aspects of parathyroid hypertensive factor.

Parathyroid hypertensive factor (PHF) in rats: PHF is an endogenous hypertensive substance which was originally associated with hypertension in spontaneously hypertensive rats (SHR). In this model, PHF was shown to act by increasing intracellular calcium levels in vascular smooth muscle and was linked with a characteristic pattern of abnormalities in overall calcium regulation. The action of PHF was blocked by calcium antagonists, suggesting that the effect of PHF was to increase extracellular calcium uptake. In SHR the parathyroid glands were shown to be the site of PHF secretion. This secretion was inhibited by an increase in dietary calcium. PHF was further shown to be unique to low-renin forms of hypertension, that is, those forms of hypertension characterized by abnormalities in calcium metabolism. PHF in humans: PHF was subsequently found in human low-renin salt-sensitive hypertension. As in SHR, calcium supplementation can lower PHF levels in humans. Similarly, there is circumstantial evidence for the parathyroid origin of PHF in humans. In human hypertensive patients, the presence of PHF has been shown to predict a favorable therapeutic response to calcium channel blockade. Recently, many of the abnormalities in calcium metabolism present in low-renin hypertension have also been described in other disease states. Notable among these diseases is non-insulin dependent diabetes mellitus. A survey of human non-insulin dependent diabetes mellitus has revealed that PHF was present in a disproportionate number of these patients independently of the blood pressure level. The significance of this latter finding needs to be explored, but PHF may prove to have relevance in diseases other than hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of ginsenoside Rb1 on choline uptake in central cholinergic nerve endings.

The ginsenoside Rb1 has previously been reported to improve memory deficits induced by anticholinergic drug treatment, and to facilitate acetylcholine (Ach) release from rat brain hippocampal slices. The increase in ACh release was not associated with an increase in calcium uptake into nerve terminals, but was associated with an increase in uptake of the precursor choline. In the present studies, analysis of choline uptake kinetics indicated that Rb1 increased the maximum velocity of choline uptake, while the affinity of the choline uptake carrier for choline (Km) was not significantly altered. Acute treatment with Rb1 did not alter the number of [3H]hemicholinium-3 (HC-3) binding sites in any of three cholinergic brain regions examined, suggesting that the increase in the maximum velocity of choline uptake was not associated with an increase in the number of choline carriers. However, chronic (3 day) administration of Rb1 did increase the number of choline uptake sites in the hippocampus, and to a lesser extent in the cortex.

Combined effect of dietary calcium and calcium antagonists on blood pressure reduction in spontaneously hypertensive rats.

Calcium supplementation and calcium channel blockers are known to have antihypertensive effects in similar subsets of hypertensive patients, as well as in spontaneously hypertensive rats (SHR). To investigate this apparent paradox, we placed 12-week-old SHR on one of three dietary levels of calcium (0.2, 0.4, or 0.8%), as well as on one of four doses of nifedipine (0, 50, 150, or 300 mg/kg food) for 8 weeks. We performed a similar experiment using four verapamil doses (0, 300, 900, or 1,800 mg/kg food). In the nifedipine experiment, two-way analysis of variance showed significant independent antihypertensive effects of both nifedipine (p less than or equal to 0.0001) and calcium (p less than 0.0001) and significant interaction (p = 0.0034), the latter suggesting a synergistic effect. In the verapamil experiment, both calcium and verapamil again had significant independent antihypertensive effects (p = 0.006 and p = 0.004, respectively), but there was no significant interaction. Although the effects of the calcium supplement or calcium antagonist alone were significant, such hypotensive responses were not optimal or predictable or clearly dose-dependent. However, the combination of a calcium supplement and calcium antagonist resulted in predictable or dose-dependent effects, and the optimal effect was reflected in the reduction of the SHR pressure to normal range for Wistar-Kyoto (WKY) rats. These results appear to indicate that supplementary calcium and calcium channel blockers act by different mechanisms in lowering blood pressure (BP), and that the combination of those differing mechanisms of action may have potential therapeutic benefit.