Effects of lifetime cumulative ginseng intake on cognitive function in late life

Effects of lifetime cumulative ginseng intake on cognitive function in late life
Alzheimers Res Ther. 2018; 10: 50.
Published online 2018 May 24. doi: 10.1186/s13195-018-0380-0

(complete article in link)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968575/

Abstract

Background

We investigated the effects of lifetime cumulative ginseng intake on cognitive function in a community-dwelling population-based prospective cohort of Korean elders.

Methods

Community-dwelling elders (N = 6422; mean age = 70.2 ± 6.9 years, education = 8.0 ± 5.3 years, female = 56.8%) from the Korean Longitudinal Study on Cognitive Aging and Dementia were included. Among them, 3918 participants (61.0%) completed the 2-year and 4-year follow-up evaluations. Subjects were categorized according to cumulative ginseng intake at baseline evaluation; no use group, low use (< 5 years) group, and high use (≥ 5 years) group. One-way analysis of covariance (ANCOVA) was conducted to compare the impact of cumulative ginseng intake on baseline Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet neuropsychological battery total score (CERAD total score) and Mini-Mental State Examination (MMSE) score among the three groups while adjusting for potential covariates. A repeated-measures ANCOVA was performed to investigate the impacts on the changes in CERAD total scores and MMSE scores during the 4 years of follow-up.

Results

The high use group showed higher CERAD total scores compared to the no use group after controlling for age, sex, education years, socioeconomic status, smoking, alcohol intake, presence of hypertension, stroke history, Geriatric Depression Scale, Cumulative Illness Rating Scale, and presence of the APOE e4 allele (F(2, 4762) = 3.978, p = 0.019). The changes of CERAD total score for 2 or 4 years of follow-up did not differ according to the use of ginseng.

Conclusions

Cumulative ginseng use for longer than 5 years may be beneficial to cognitive function in late life.
Background

Ginseng, which has been used for at least 2000 years in Asian countries [1], is one of the most widely sold medicinal herbs worldwide [2]. The estimated world ginseng market is dramatically increasing, worth approximately $2085 million in 2009 [1]. An analysis of the Korean Ministry of Food and Drug Safety in the year 2015 reported that ginseng products, including red ginseng and white ginseng, reached KRW 725.0 billion, with the highest market share reaching 39.8% of the dietary supplement market in South Korea.

Ginseng is popular because it is effective in boosting immune function, it has antifatigue effects, and it improves cognitive functions [3]. Ginseng has the potential to slow cognitive decline in elderly individuals or reduce the risk of dementia, which is of great scientific and public health interest. Biological data suggest that various functional constituents, especially ginseng saponins (also known as ginsenosides), improve brain cholinergic function, decrease inflammation, and reduce production of amyloid beta proteins that directly limit the progression of Alzheimer’s disease (AD) pathology [4–7].

Recently, four randomized control trials (RCTs) [8–11] of patients with AD revealed that red ginseng might be effective for cognitive improvement. Among the four RCTs, one study reported that the cognitive functions of AD patients improved and were maintained with both 4.5 g/day and 9.0 g/day of red ginseng supplements during 2 years of follow-up [10]. However, a systematic review and meta-analysis [12] based on these four RCTs concluded that the findings regarding the effects of ginseng on AD were inconclusive due to the limitations of these studies, which included small sample sizes and lack of placebo control design. In terms of participants without dementia, a systematic review published in 2010 [2], which was based on the results of nine double-blind RCTs, showed that there is insufficient evidence regarding the efficacy of ginseng on cognitive function due to limited sample sizes and only short-term follow-up (up to 12 weeks).

Due to their inherent design characteristics, RCTs cannot sufficiently reflect long-term ginseng intake; therefore, the effects of long-term ginseng intake on cognition should be studied in a longitudinal prospective cohort. To our knowledge, the only instance of such a study is the one by Persson et al. [13], a prospective cohort study in Sweden that reported no association between long-term ginseng use and cognitive performance. However, the participants in that study were aged 35–80 years, therefore making it difficult to assess the effects of ginseng on the elderly population. Additionally, the study was conducted in a western country, where ginseng intake is generally lower than it is in Asian countries. Among 3500 participants, 86 subjects (2.5%) had previously used ginseng; therefore, if the effect size was small, the effect of ginseng would be difficult to observe. The study focused on revealing the relationship between long-term ginseng intake and memory function, but there was no follow-up evaluation showing the trajectory of cognitive performance over time.

There is still little research regarding how ginseng usage correlates with cognitive function in elderly populations with and without cognitive impairment, and we also have little information on the longitudinal effects of ginseng. Furthermore, to our knowledge, a large population cohort has never been studied in Asia, especially not in Korea, where the amount of ginseng distribution is the highest worldwide [1].

In this study, we investigated the correlation between lifetime cumulative use of ginseng and cognitive function in a large, community-dwelling, population-based prospective cohort of elders in Asia, especially in Korea. In addition, we sought to determine the effect of cumulative ginseng intake on cognitive function during a follow-up period of 4 years.

I prefer as a general tonic the American ginseng (panax quinquefolius) is more relaxing, cheaper and has similar benefit profile.

A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system
(complete article in link)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659622/
(snip)
ALZHEIMER’S DISEASE

With the in-depth understanding of molecular and cellular pathophysiology and neurobiology of AD during last couple of decades, many plausible targets to treat AD have been suggested which include but not restricted to followings: 1) increase in the uptake of choline in central nervous system, 2) release of acetylcholine from hippocampus, 3) increased activity or expression of choline acetyltransferase, 4) protection against the Aβ or tau protein-induced neurotoxic effects by several mechanisms including inhibition of neuroinflammation, increased production of neurotrophic factor, and regulation of apoptotic processes, 5) repair of Aβ-damaged neuronal networks by increased neurogenesis and synaptic plasticity, and 6) reducing the level of Aβ by decreased production or increased elimination. Actually, many of these pathophyiological targets and the effects of ginseng and ginsenosides on them are subjected to the intense investigation and covered by several recent reviews [5,6].
Regulation of neurite outgrowth and synaptic plasticity by ginseng

Based on the fact that protopanaxadiol-type saponins were active constituents mediating neurite outgrowth in human neuroblastoma SK-N-SH [7], it has been demonstrated that ginsenoside Rb1 and its intestinal metabolic compounds M1 recovered the impaired spatial memory and expression levels of phosphorylated NF-H and synaptophysin in an animal model of AD induced by intracerebroventricular injection of Aβ(25-35) [8]. In cultured cortical neurons, M1 increased axonal outgrowth even after substiantial progress of neurite degeneration, suggesting a neuro-regenerative potential of this compound. Similar neurite outgrowth potential of crude ginseng saponin was also reported in cultured rat cerebral cortical neurons [9]. In addition, ginsenoside Rb1 potentiated the nerve growth factor (NGF)-mediated neurite outgrowth of cultured chick embryonic dorsal root ganglia [10]. Interestingly, the memory impairment induced by intracerebroventricular injection of Aβ(25-35) as well as synaptic marker protein expression is only marginally increased by donepezil, if any, consistent with its primary mechanism of action, i.e., the inhibition of acetylcholine esterase [8]. In addition, the memory improving effects of Rb1 or M1 were maintained even after the discontinuation of Rb1 and M1 administration suggesting they induced a long lasting and probably structural reorganization of the damaged brain circuits, which is ideal for the treatment of neurodegenerative conditions including AD although further verification in other animal models of AD is needed in the future. Neurite outgrowth is one of the foremost phenotypical changes in network reorganization, which might be one of the cellular and molecular changes happening during synaptic plasticity, which suggests that the observed neurite extension effects of ginseng may underlie the memory enhancing effects of ginseng in both normal and pathological conditions, although clinical studies produced both positive and negative results (see below).

In the dentate gyrus of anesthetized rats, i.c.v. injection of ginsenoside Rb1 (10, 100 nM) inhibited the induction phase of long term potentiation (LTP) and accelerated the maintenance phase of LTP induced by high frequency stimulation in a dose-dependent manner [11]. In addition, treatment with nonsaponin fraction of ginseng significantly ameliorated deficits in place-navigation learning in the aged rats in the place learning task along with significant augmentation in the increase in population spike amplitudes in the CA3 subfield after LTP induction in vitro [12]. Similarly, ginsenoside Rg1 inhibited morphine induced spatial memory deficit which was determined by Morris water maze test and restored LTP impaired by morphine in both freely moving and anaesthetized rats, which was examined by electrophysiological recording after implantation of electrodes in vivo [13]. The electrophysiological recording in vitro also demonstrated that Rg1 restored the LTP in slices from the rats treated with morphine without affecting LTP in the slices from normal rats. The restoration LTP is inhibited by NMDA receptor antagonist MK801 suggesting the involvement of NMDA receptor activation in the Rg1-induced recovery of LTP [13]. Using acutely isolated rat hippocampal CA3 pyramidal neurons with a conventional whole-cell patch-clamp technique, it has been suggested that Compound K, a metabolite of Rb1, enhances spontaneous GABA release by increasing intraterminal Ca2+ concentration via Ca2+ release from pre-synaptic Ca2+ stores, although how these findings are related to the regulation of hippocampal excitability and learning and memory processes remains to be determined [14].

Morphologically, Rg1 increased chronic mild stress induced decrease in dendritic spine number and hippocampal neurogenesis [15], which also suggests the modulation of processes involved in synaptic plasticity by ginsenosides.

Ginsenoside Rg1 and Rb1increased proliferation and differentiation of neural progenitor cells in dentate gyrus of hippocampus of normal adult mice and global ischemia model in gerbils. In addition, Rg1 increased expression of brain derived neurotrophic factor, Bcl-2 and antioxidant enzyme and increased the number of synapses and mossy fiber sprouting in CA3 regions of hippocampus suggesting the role of Rg1 in the modulation of synaptic plasticity and possibly to the increased cognitive function in AD [16]. Similarly, when the mixture of brain-derived neurotrofic factors (BDNF) and ginsenosides Rg1 and Rb1 was treated to human neural stem cell during the differentiation procedure, it promoted cell survival and enhanced neurite outgrowth and the expression of synaptic marker proteins, which was evidenced by time lapse microscopy, immunostaining, and Western blot [17].
Neuroprotection

Ginsenosides have direct neuroprotective effects against glutamate or Aβ stimulation. In cultured PC12 cells, glutamate decreased cell viability and increased intracellular calcium concentration and lipid peroxidation, which is evidenced by the excessive production of malondialdehyde and nitric oxide (NO) [18], all of which are prevented by ginsenosides. Whether the neuroprotective effects against glutamate has been related with the reported antagonistic activity of many ginsenoside such as Rg3 and Rh2 against NMDA receptors remains to be determined (for a review, see [19]). The antioxidant effects of ginseng has also been implicated in a study showing the neuroprotective effects of ginseng extracts in human neuroblastoma SY-5Y cells [20]. Treatment of SY-5Y cells with cyclosporine A inhibited calcineurin activity, which results in hyperphosphorylation of tau protein. Pretreatment of ginseng extracts effectively enhanced calcineurin activity, which ameliorates tau phosphorylation providing possible neuroprotective activity [20]. Treatment of ginsenoside Rg2 effectively and significantly attenuated the glutamate-induced toxicity and changes in above mentioned factors. In addition, ginsenoside Rg2 decreased the level of glutamate-induced increased protein expression such as calpain II, caspase-3, and Aβ(1-40) in PC12 cells. In addition, treatment of water extracts of American ginseng significantly attenuated the cellular apoptosis of SH5-SY cells induced by Aβ(25-35), which was determined by staining with Hoechst 33258 [21]. Treatment of 50 μM Aβ(25-35) for 48 h also produced cell toxicity in PC12 cells and treatment of ginsenoside Rg1 inhibited β-secretase activity in vitro and protected PC12 cells from cell death along with inhibition of NO release, lipid peroxidation, reactive oxygen species (ROS) production, and elevation of intracellular calcium concentration. Similar neuroprotective action of Rb1 in PC12 cells treated with Aβ(25-35) has been reported by a separate group of researchers [22], which is also related to the increased ratio of anti-apoptotic/apoptotic protein Bcl-2/Bax. Not only neuron but also astrocytes is protected by ginsenosides [23]. In cultured type I rat brain astrocytes (RBA), ginsenoside Rh2 inhibited Aβ-induced inhibition of RBA growth, which is mediated by induction of pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP receptor PAC1 [24].

Many thanks Yoly …

A bit more about Ginseng, which has been used in traditional Chinese medicine for centuries.
This slow-growing, short plant with fleshy roots can be classified three ways, depending on how long it is grown: fresh, white or red.
Fresh ginseng is harvested before 4 years, while white ginseng is harvested between 4–6 years and red ginseng is harvested after 6 or more years.
There are many types of this herb, but the most popular are American ginseng (Panax quinquefolius) and Asian ginseng (Panax ginseng).
American and Asian ginseng vary in their concentration of active compounds and effects on the body. It is believed that American ginseng works as a relaxing agent, whereas the Asian variety has an invigorating effect (1, 2).
Ginseng contains two significant compounds: ginsenosides and gintonin. These compounds complement one another to provide health benefits (3).
Here are 8 evidence-based health benefits of ginseng.

https://www.healthline.com/nutrition/ginseng-benefits


Also within the health-line article ...
According to research, ginseng appears to be safe and should not produce any serious adverse effects.
However, people taking diabetes medications should monitor their blood sugar levels closely when using ginseng to ensure these levels do not go too low.
Additionally, ginseng may reduce the effectiveness of anticoagulant drugs.
For these reasons, talk to your doctor before supplementing with it.
Note that due to the lack of safety studies, ginseng is not recommended for children or women who are pregnant or breastfeeding.
Lastly, there is evidence suggesting that the extended use of ginseng could decrease its effectiveness in the body.
To maximize its benefits, you should take ginseng in 2–3-week cycles with a one or two week break in between (14).

Summary
While ginseng appears to be safe, people taking certain medications should pay attention to possible drug interactions.
The Bottom Line
Ginseng is an herbal supplement that has been used for centuries in Chinese medicine.
It is commonly touted for its antioxidant and anti-inflammatory effects. It could also help regulate blood sugar levels and have benefits for some cancers.
What’s more, ginseng may strengthen the immune system, enhance brain function, fight fatigue and improve symptoms of erectile dysfunction.
Ginseng can be consumed raw or lightly steamed. It can also easily be added to your diet via its extract, capsule or powder form.
Whether you want to improve a certain condition or simply give your health a boost, ginseng is definitely worth a try.

All the best Jan

All very interesting. Back when I was a hippy I tried ginseng and came to the conclusion it was just an expensive placebo. Perhaps I should have taken it for longer.

Of course in retrospect being alternately marinated in glucose, insulin and cortisol outweighed the effects of everything else.