American Ginseng

Ginseng root has been used for thousands of years in the traditional medical system in oriental countries. Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius L.) are the two most recognized herbal medicines in the world. Throughout the past few decades, American ginseng has become increasingly popular in the West.

Like Asian ginseng, American ginseng has been reported to have a wide range of pharmacological effects such as cardiovascular and central nervous system effects, anti-diabetes effects, and immunomodulation (1-3). It is generally accepted that the triterpene saponins called ginsenosides are the major active constituents in ginseng (3,4). The therapeutic importance of ginseng has led to the development of a wide spectrum of analytical methods for the determination of the total saponin content, group-specific analysis, and target compound determination. The pharmacokinetics and metabolism of different ginseng saponin compounds have been studied in both animals and humans (5).

Compared to the long history and widespread research of Asian ginseng, the study of American ginseng and its constituents is much less extensive. However, many investigations on American ginseng have been published in past decade.

More than 100 ginsenosides have been isolated from roots, leaves, stems, flower buds, and berries of Asian ginseng and American ginseng and these ginsenosides exhibit considerable structural variation (4). Ginsenosides differ from one another by the type of sugar moieties, sugar number, and site of sugar attachment at positions C-3, C-6, or C-20. The structural isomerism and stereoisomerism, the number and site of attachment of hydroxyl groups, and available modified side chain at C-20 also increase their diversity.

Effects on the central nervous system

Ginseng has both stimulatory and inhibitory effects on the central nervous system, and may modulate neurotransmission. Ginsenosides are responsible for ginseng’s effects on the central nervous system (CNS) and the peripheral nervous system (6). The effect of ginsenoside Rg1 or Rb1 was also examined and both enhance CNS activities, but the effect of the latter is weaker (7), sometimes even having an inhibitory effect on the CNS. Since American ginseng has a lower ratio of Rg1/Rb1 content, American ginseng is “cool” or calming to the CNS.

Neurodegeneration

The protective effects of Ginsenosides Rb1, Rg1, Rg3, and Rh2 on neurodegeneration are well studied (8,9). Rb1 has been shown to partially prevent the memory deficits caused by the cholinergic agent scopolamine in an animal model (10). Ginsenosides regulate various types of ion channels, such as voltage-dependent and ligand-gated ion channels, in neuronal and heterologously expressed cells. Ginsenosides inhibit voltage-dependent Ca2+, K+, and Na+ channel activities in a stereospecific manner. They also inhibit ligand-gated ion channels such as Nmethyl-d-aspartate, some subtypes of nicotinic acetylcholine, and 5-hydroxytryptamine type 3 receptors (11).

In vivo studies have demonstrated that ginsenosides improve spatial learning and increase hippocampal synaptophysin levels, reduce infarct and neuronal deficit on transient cerebral (13), and effectively attenuate Tau protein hyperphosphorylation of hippocampal neurons (14). In addition, ginsenosides promote neurotransmitter release by increasing the phosphorylation of synapsins (15). Competition and site-directed mutagenesis experiments revealed that ginsenosides interact with ligand-binding sites or channel pore sites and inhibit open states of ion channels (16).

Cognitive Function

Recent reports show that long-term ginsenoside consumption could prevent memory loss and impairment by decreasing oxidative stress and up-regulating the plasticity-related proteins in the hippocampus (17,18). These observations suggest that ginseng and some ginsenosides may rescue or protect neurons from insult, and may be a promising candidate to improve the cognitive deficit of Alzheimer’s disease.

American ginseng (Panax quinquefolius) has a distinct ginsenoside profile from P. ginseng, promising cognitive enhancing properties in preclinical studies and benefits processes linked to human cognition. Ginsenoside expression is substantially higher in P. quinquefolius (American Ginseng) than P. ginseng (19). One study observed that scopolamine-associated spatial learning impairment was partially reversed by P. quinquefolius, which also increased choline uptake in synaptosomal preparations (20).

Another well documented effect of P. quinquefolius is its action on blood glucose. P. quinquefolius appears to have significant hypoglycaemic action (21,22) in both diabetics and non diabetics (23-25) and there is growing interest in the relationship between blood glucose and cognitive function.

The mechanism(s) by which extracts of Ginseng or individual components derived from Ginseng exert their effects on cognition are not known. A number of potentially complementary effects may be involved. For example neuroprotective effects of ginsenosides have been demonstrated in vitro (26) and in vivo. Such effects include protection of hippocampal CA1 neurons, reduction of infarct area (27), reduced lipid peroxidation, scavenging of oxygen free radicals (28) and preservation of local cerebral glucose utilisation (29) following ischaemia. Increased nitric oxide (NO) synthesis has been proposed to underlie these neuroprotective effects. The enzyme NO synthase has been shown to be present throughout the brain with a particular prevalence in the cerebellum and is reported to be involved in general memory processes (30).

Cholinergic Effects

The effects of Ginsengosides are not limited to neuroprotective effects. As well as increased NO-mediated blood flow, ginsenosides can increase choline uptake (31), acetylcholine release (32) and monoamine metabolism (33) all of which may contribute to acute positive neurocognitive effects.

It has been well documented that the cholinergic pathways projecting to the cerebral cortex and hippocampus play a key role in learning and memory. It has also been argued that the cholinergic system is a specific target for cognitively enhancing agents (34). A number of studies have identified cholinergic properties associated with isolated ginsenosides. A direct interaction between Rg2 and nicotinic receptor subtypes has been observed (35). Moreover Benshin (36) demonstrated modulation by Rb1 of acetylcholine release and reuptake, along with a number of choline uptake sites in the hippocampus, and to a lesser extent, the cortex. Both ginsenosides Rg1 (37) and Rb1 (38) have also been shown to increase choline acetyltransferase levels in the brain. Scopolamine-induced deficits are attenuated by P. quinquefolius (39) and protection against scopolamine-induced amnesia by P. quinquefolius was most evident in trials where subjects were required to remember the task learned the previous day.

Positive Effects on Working Memory

A recent randomised, double-blind, placebo-controlled, crossover trial in healthy young adults assessed the acute mood, neurocognitive and glycaemic effects of standardised P. quinquefolius (40). Participants' mood, cognitive function and blood glucose were measured 1, 3 and 6 h following administration.

There was a significant improvement of working memory (WM) performance associated with P. quinquefolius. Corsi block performance was improved at all testing times, as were WM tasks which were maintained across the testing day. Choice reaction time accuracy and ‘calmness’ were significantly improved. This trial demonstrates enhancement effects of P. quinquefolius predominantly on working memory processes (Corsi blocks, and both numeric and alphabetic working memory). There is also some evidence of positive effects on short-term verbal declarative memory (immediate word recall) and attention (choice reaction time).

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