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Showing posts with label Ginseng. Show all posts
Showing posts with label Ginseng. Show all posts

Thursday, 13 September 2018

Ginseng, as a GABAb Antagonist, as an "Add-on Therapy" for some Autism? Also Homotaurine and Acamprosate


Rather like negotiating with North Korea, today’s post does rather meander. It does in the end up with some interesting options for some people. 



Korea - the centre of Ginseng research
This post was prompted by research highlighted by our reader Ling, which suggested that bumetanide responders (i.e. people with high intracellular chloride) might benefit from a GABAB antagonist. 
There has been quite a lot of coverage in this blog about agonists of GABAB receptors, like Baclofen and Arbaclofen. Some people with an autism diagnosis do indeed seem to benefit, ranging from some with Fragile-X to others with Asperger’s. Russian-developed GABAB agonists like Phenibut and Pantogam are widely used by adults self-treating their behavioural/emotional disturbances.
Some Aspies have commented in this blog that far from helping, Baclofen made them feel worse; perhaps the opposite therapy might help? (the Goldilocks scenario, from the previous post) 
The paper below shows how a GABAB antagonist (the opposite of Baclofen) might benefit some with autism.

GABAB receptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABAA receptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABAB receptors results in a decrease in KCC2 function, which is associated with a reduction in the protein at the cell surface. These findings reveal a novel "crosstalk" between the GABA receptor systems, which can be recruited under conditions of high GABA release and which could be important for the regulation of inhibitory synaptic transmission.

SIGNIFICANCE STATEMENT Synaptic inhibition in the brain is mediated by ionotropic GABAA receptors (GABAARs) and metabotropic GABAB receptors (GABABRs). To fully appreciate the function and regulation of these neurotransmitter receptors, we must understand their interactions with other proteins. We describe a novel association between the GABABR and the potassium-chloride cotransporter protein, KCC2. This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. We demonstrate that GABABR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABAAR. Our data therefore support an additional mechanism by which GABABRs are able to modulate fast synaptic inhibition.

In bumetanide-responsive autism, neurons remain immature because the “GABA switch“ never flipped and so NKCC1 is overexpressed and KCC2 is underexpressed, chloride levels remain high and the neurotransmitter GABA works backwards (excitatory, rather than inhibitory).
Bumetanide partially counters the over-abundance of NKCC1 transporters that carry chloride into neurons, but is a partial solution.
The above research suggests that blocking GABAB receptors might increase the flow of chloride ions exiting through KCC2.
All very complicated sounding, but in effect it means that a GABAB antagonist might boost the effect of bumetanide.

Which GABAB antagonist?
This was Ling’s question.
Saclofen is a competitive antagonist for the GABAB receptor. This drug is an analogue of the GABAB agonist baclofen.
Phaclofen/phosphonobaclofen, is a selective antagonist for the GABAB receptor.
Since these “–aclofens” are not accessible we are left with a choice of homotaurine (developed to treat Alzheimer’s) or Ginsenosides from Korean/Panax ginseng.
Both homotaurine and Ginsenosides have various other effects beyond GABAB.
Since Ling is in Scandinavia, homotaurine is an option. It seems to be banned in the US, though it is approved in Canada and sold in Europe.
Ginseng is very widely used, indeed it is the most widely consumed herbal nutritional product in the world, with sales of $400 million in 2012.
I was surprised that there actually is research in both humans and animal models using Ginseng in autism and indeed ADHD.
N-Acetyl homotaurine,  a derivative of homotaurine, is a registered drug called Acamprostate. It is used to treat alcohol dependence. It affects both NMDA and GABA receptors. Acamprostate has been shown to benefit Fragile-X, as has bumetanide. A drug that affects GABAB will inevitably also affect NMDA receptors.
This was covered in this post from 2015.

which highlighted this paper:


Homotaurine has been reported as a GABA antagonist as well as a GABA agonist. In vitro studies have found that homotaurine is a GABAA partial agonist as well as a GABAB receptor partial agonist with low efficacy, becoming an antagonist and a displacing full agonist of GABA or baclofen at this receptor.[15] In a study in rats, homotaurine reversed the catatonia induced by baclofen (the prototypical GABAB agonist),[16] and was able to produce analgesia via the GABAB receptor, an effect that was abolished when CGP 35348, a GABAB receptor antagonist was applied.[17][18] 
One study suggests Homotaurine increases dopamine levels.[19]

One study in rats showed that homotaurine suppressed ethanol-stimulated dopamine release, as well as ethanol intake and preference in rats in a way similar to the N-acetyl derivative of homotaurine, acamprosate.[20] Acamprosate was approved by the FDA in 2004 to treat alcohol dependence.[3]

Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission.
Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.

Back to Ginseng
Background
Autism spectrum disorder (ASD) is heterogeneous neurodevelopmental disorders that primarily display social and communication impairments and restricted/repetitive behaviors. ASD prevalence has increased in recent years, yet very limited therapeutic targets and treatments are available to counteract the incapacitating disorder. Korean Red Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range of therapeutic effects and nutritional benefits and has recently been gaining great scientific attention, particularly for its positive effects in the central nervous system.

Objectives

Thus, in this study, we investigated the therapeutic potential of KRG in alleviating the neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models of ASD.

Design

Starting at 21 days old, VPA-exposed mice were given daily oral administrations of KRG solution (100 or 200 mg/kg) until the termination of all experiments. From P28, mice behaviors were assessed in terms of social interaction capacity, locomotor activity, repetitive behaviors, short-term spatial working memory, motor coordination, and seizure susceptibility.

Results

VPA-exposed mice showed sociability and social novelty preference deficits, hyperactivity, increased repetitive behavior, impaired spatial working memory, slightly affected motor coordination, and high seizure susceptibility. Remarkably, long-term KRG treatment in both dosages normalized all the ASD-related behaviors in VPA-exposed mice, except motor coordination ability.

Conclusion

As a food and herbal supplement with various known benefits, KRG demonstrated its therapeutic potential in rescuing abnormal behaviors related to autism caused by prenatal environmental exposure to VPA.

In the trial below the dose appears very low at 250mg. In the more encouraging study in ADHD the dose was 1000mg twice a day.

Autism is a pervasive developmental disorder, with impairments in reciprocal social interaction and verbal and nonverbal communication. There is often the need of psychopharmacological intervention in addition to psychobehavioral therapies, but benefits are limited by adverse side effects. For that reason, Panax ginseng, which is comparable with Piracetam, a substance effective in the treatment of autism, was investigated for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of Panax ginseng, at least as an add-on therapy.
Three male outpatients (age range 18.4–22.2 years; mean=21.3 years; SD =4.1 years) meeting ICD-10 criteria for autistic disorder participated in our observation. IQs ranged from 54 to 82 (68 +/− 14), which were obtained from the Wechsler Intelligence Scale. At least two child and adolescent psychiatrists independently diagnosed the subjects for autistic disorder. All subjects had no additional medical or neurological illnesses. They had been treated with either methylphenidate, or neuroleptics before entry into the study, without any positive effect (nonresponder). One patient’s language consisted of monosyllabic utterances, second patient’s language consisted of single words(10-word vocabulary),and the third patient spoke in sentences. Parents and mentors’ (i.e., the person who takes care of the patient in daily life, and supports the patient’s educational efforts) rated instruments included weekly ratings by means of the Aberrant Behavior and Symptom Checklist. Clinician ratings consisted of the Global Assessment Scale, Psychiatric Rating Scale (CPRS), and Clinical Global Improvement. Panax ginseng (oral administration of tablets containing 250-mg alcoholic Panax ginseng berry extract, pure encapsulations) was administered for 4 weeks (dosage: 250 mg daily). Patients were free of medication for at least 4 weeks before the beginning of the study. During that time, there were no changes in the symptoms of the patients. Subjects continued to receive educational and behavioral interventions, which were not altered substantially in any of the patients during their participation in the study. The means of parent and mentor ratings were averaged over the 4-week treatment period. Clinician and mentor ratings were made at the beginning of the treatment period and then weekly up to the end of the treatment. Ratings were compared by paired t-test.

RESULTS
Panax ginseng slightly improved the ratings on the ABC factors: irritability (before treatment, 13.2 +/− 5.9; after treatment, 11.3 +/− 6.2; p =.41), hyperactivity (before treatment, 20.6+/−12.4;     after,18.4+/− 9.4; p = .33), inadequate eye contact (before treatment, 8.6 +/− 5.4; after, 7.5 +/− 3.2; p .35), and inappropriate speech (before treatment, 6.1+/−2.2;after, 4.3 +/− 3.6; p = .41). The symptom checklist scores revealed a slight increase in drowsiness (before treatment, 1.6 +/− 2.2; after, 2.9+/−4.2; p =.31) and decreased activity (before treatment, 2.5 +/− 3.3; after, 4.4 +/− 3.1; p = 0.40). None of the clinician ratings showed significant improvement. This may result from different impressions of clinical visits and daily life observations of caregivers. Panax ginseng has some moderate sedative effect with effects especially on daily life, a fact that also makes it effective in the treatment of attention deficit/hyperactive disorders. None of the subjects appeared to have headaches or stomach aches, although report of such side effects was limited by the expressive language and social skills of these subjects. Medication was continued after the observation period. We did not see any significant changes in symptoms.

DISCUSSION 
Although this was a very small study (n = 3), which revealed very modest therapeutic effect of Panax ginseng in the management of autistic patients in some of the subjects (which might be due to the small sample size), it may be mentioned that its role in the management of these symptoms in patients with autistic disorder may be limited, especially because of its risk for estrogen-associated problems in females (Papapetropoulos, 07). Since there does not seem to be any significant improvement caused by Panaxginseng, its effect as an add-on therapy remains completely open and requires further investigation. Before knowing its efficacy for adults, Panax ginseng should not be recommended for treating children suffering from autism.

Ginseng for ADHD? 

Objective: There is evidence that Korean red ginseng (KRG) can reduce the production of the adrenal corticosteroids, cortisol, and dehydroepiandrosterone (DHEA), and thus may be a viable treatment for attention-deficit/hyperactivity disorder (ADHD). The present randomized double-blind placebo-controlled clinical trial tested the effect of KRG on children with ADHD symptoms.
Methods: Subjects 6–15 years, who satisfied the inclusion criteria and had ADHD symptoms, were randomized into a KRG group (n=33) or a control group (n=37). The KRG group received one pouch of KRG (1g KRG extract/pouch) twice a day, and the control group received one pouch of placebo twice a day. At the 8 week point, the primary outcomes were the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for inattention and hyperactivity scale scores, which were measured at baseline and 8 weeks after starting treatment. Secondary outcomes were quantitative electroencephalography theta/beta ratio (QEEG TBR) (measured at baseline and week 8) and salivary cortisol and DHEA levels (measured at baseline and at 4 and 8 weeks).
Results: The baseline characteristics of the KRG and control groups were not statistically different. The mean ages of the KRG and control groups were 10.94±2.26 and 10.86±2.41, respectively. The KRG group had significantly decreased inattention/hyperactivity scores compared with the control group at week 8 (least squared means of the differences in inattention adjusted for baseline scores: −2.25 vs. −1.24, p=0.048; hyperactivity: −1.53 vs. −0.61, p=0.047). The KRG group had significantly decreased QEEG TBR compared with the control group (least squared means of the differences: −0.94 vs. −0.14, p=0.001). However, neither the KRG group nor the control group exhibited significant differences in salivary cortisol or DHEA levels at week 8 compared with the baseline levels. No serious adverse events were reported in either group.
Conclusions: These results suggest that KRG extract may be an effective and safe alternative treatment for children with inattention and hyperactivity/ impulsivity symptoms. Further studies to investigate the efficacy and safety of KRG are warranted. 
Although medications to treat psychiatric disorders for children and adolescents have been widely researched and several are on the market, natural products may also be effective in these patients while inducing fewer significant adverse effects. The present randomized controlled trial was performed to assess whether KRG, a well-known traditional medicine plant that is used particularly frequently in Eastern Asia, can improve the adrenal function and inattention/hyperactivity symptoms of chronically stressed children with ADHD symptoms. KRG extract significantly improved the inattention and hyperactivity of the subjects and had a good safety profile. However, the KRG extract did not have significant effects on cortisol or DHEA levels

Clinical Significance
To our knowledge, this is the first randomized controlled trial to investigate the efficacy and safety of Korean red ginseng extract for children with ADHD. The stimulant medications for ADHD have demonstrated not only clinical efficacy, but also significant adverse events such as poor growth, tics, and psychosis. Although KRG extract did not affect the salivary cortisol or DHEA, it significantly improved ADHD symptoms and QEEG TBR. And the safety profile of KRG extract was good. The results imply that KRG extract is a possible effective alternative medication for ADHD children.


OBJECTIVE:


A combination herbal product containing American ginseng extract, Panax quinquefolium, (200 mg) and Ginkgo biloba extract (50 mg) (AD-FX; CV Technologies, Edmonton, Alta.) was tested for its ability to improve the symptoms of attention-deficit hyperactivity disorder (ADHD). 

DESIGN:


Open study. 

PATIENTS:


36 children ranging in age from 3 to 17 years who fit the diagnostic criteria for ADHD. 

INTERVENTIONS:


AD-FX capsules were taken twice a day on an empty stomach for 4 weeks. Patients were instructed not to change any other medications during the study. 

OUTCOME MEASURES:


At the beginning of the study, after 2 weeks, and then at the end of the 4-week trial, parents completed the Conners' Parent Rating Scale--revised, long version, a questionnaire that assesses a broad range of problem behaviours (and was used as an indication of ADHD symptom severity). 

RESULTS: 

After 2 weeks of treatment, the proportion of the subjects exhibiting improvement (i.e., decrease in T-score of at least 5 points) ranged from 31% for the anxious-shy attribute to 67% for the psychosomatic attribute. After 4 weeks of treatment, the proportion of subjects exhibiting improvement ranged from 44% for the social problems attribute to 74% for the Conners' ADHD index and the DSM-IV hyperactive-impulsive attribute. Five (14%) of 36 subjects reported adverse events, only 2 of which were considered related to the study medication. 

CONCLUSIONS:


These preliminary results suggest AD-FX treatment may improve symptoms of ADHD and should encourage further research on the use of ginseng and Ginkgo biloba extracts to treat ADHD symptoms.

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.


Abstract


1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding.

3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding.
4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

very detailed paper

Also (Ling) note that there is an effect on ERbeta

A ginseng-derived oestrogen receptor beta (ERbeta) agonist, Rb1 ginsenoside, attenuates capillary morphogenesis.

 Ginseng extracts contain a variety of active ingredients and have been shown to promote or inhibit angiogenesis, depending on the presence of different ginsenosides that exert opposing effects on blood vessel growth. Leung et al. in this issue of the British Journal of Pharmacology report that Rb1, a ginsenoside that constitutes only 0.37–0.5% of ginseng extracts (depending on manufacturing and processing methods), blocks tube-like network formation by endothelial cells in vitro. At the molecular level, Rb1 binds to the oestrogen receptors and stimulates the transcription of pigment epithelium-derived factor that, in turn, inhibits matrix-driven capillary morphogenesis.

Ginseng, the root of Panax ginseng and related species, has been a key component of traditional medicine in the Far East for over a thousand years. The genus name Panax means ‘cure all' in Greek; it, thus, comes as no surprise that ginseng has been described as beneficial in many different ailments (Huang, 1999; Kiefer and Pantuso, 2003; Ng, 2006). Perhaps the most studied biological actions of ginseng extracts and constituents are those relating to its inhibitory effects on solid tumour growth (Yun, 2001). The main active ingredients in ginseng-based herbal preparations are thought to be the ginsenosides, comprising 3–6% of ginseng extracts (Huang, 1999). 


Reviewed here is the existing evidence for the effects of ginseng extracts and isolated ginsenosides relevant to cognition in humans. Clinical studies in healthy volunteers and in patients with neurological disease or deficit, evidence from preclinical models of cognition, and pharmacokinetic data are considered. Conditions under which disease modification may indirectly benefit cognition but may not translate to cognitive benefits in healthy subjects are discussed. The number of chronic studies of ginseng effects in healthy individuals is limited, and the results from acute studies are inconsistent, making overall assessment of ginseng's efficacy as a cognitive enhancer premature. However, mechanistic results are encouraging; in particular, the ginsenosides Rg3 , Rh1 , Rh2 , Rb1 , Rd, Rg2 , and Rb3 , along with the aglycones protopanaxadiol and protopanaxatriol, warrant further attention. Compound K has a promising pharmacokinetic profile and can affect neurotransmission and neuroprotection. Properly conducted trials using standardized tests in healthy individuals reflecting the target population for ginseng supplementation are required to address inconsistencies in results from acute studies. The evidence summarized here suggests ginseng has potential, but unproven, benefits on cognition.

Ginseng is the most widely consumed herbal nutritional product in the world. According to the most recent data available, ginseng had a total world export value in 2010 of over US$350 million, which was expected to rise to more than US$400 million in 2012


The survey had 54 respondents and 4 (8.5%) used Ginseng.

Conclusion
There is a long list of substances shown to have a benefit in some autism. Today we can add the Asian type of Ginseng and also Acamprosate (at least for Fragile-X).
It would be interesting to see the effect of Phaclofen and Saclofen which may be more selective for GABAB receptors.
Ginseng has so many effects there is no way to know which is the one that benefited autism and ADHD in today’s highlighted posts.
We also have the problem with natural substances that there is natural variation and that supplement companies are known to cheat with ingredients. Ginseng roots are not cheap and apparently ginseng is known to get adulterated.  Drug companies are usually much more reliable.
If anyone tries out homotaurine or ginseng, let us all know the result.
Homotaurine was originally developed as an Alzheimer’s drug, but did not work well enough, its developer then tried to sell it as a supplement called Vivimind, but it was rejected by the FDA. It is sold in Canada and Europe. 
For our Aspie readers, here is a link for them:-