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New drug could flip the script for stroke treatment, but small Canadian biotech needs funding boost

Researchers used a new peptide drug in an animal model of severe ischemic stroke and found that it improved motor function, sensory function, spatial learning and memory. (iStock / Getty Images Plus)

What Does It Take to Cure Cancer? Plant Roots of Scientific Discovery and Grow Them into an Ecosystem of Collaboration and Innovation.

Once a stroke happens, the damage can’t be repaired by any drug on the market. But scientists think they have found an option that could protect and repair the damage that occurs with a stroke up to a week after onset—but limited resources may block its path to clinic. Providing the right conditions for science to thrive is crucial to uncovering a cure for cancer. Discover ways to cultivate an environment for growth to ultimately make an impact for patients.

There’s only one drug on the market for stroke treatment: Activase, sold by Roche’s Genentech, has to be administered within 4.5 hours of stroke onset. Most investigational stroke therapies currently under investigation also must be given within one to two days of the condition’s onset.

Researchers now believe they have identified a peptide that could change the script entirely for stroke treatment.

Scientists at the University of Cincinnati and Case Western Reserve University in Cleveland have found that the drug, dubbed NVG-291-R, supports nervous system repair and significant functional recovery in an animal model of severe ischemic stroke, as published in Cell Reports.

NVG-291-R reduced neuronal death and showed neuroreparative effects in animal models. The drug repaired damage by forming new neuronal connections and boosting migration of new neurons to the damaged site.

The researchers used NVG-291-R to block signaling pathways known as chondroitin sulfate proteoglycans, resulting in significant behavioral recovery including improved motor function, sensory function, spatial learning and memory. Researchers also found the drug to be effective even when administered as late as seven days after stroke onset.

NervGen Pharma, a clinical-stage biotech based in Canada, currently holds the rights to NVG-291-R and is planning trials in different neuronal damage diseases. Though the aforementioned research assessed the drug’s effect in neurorepair after stroke, NervGen is first launching clinical trials in patients with spinal cord injury, Alzheimer’s disease and multiple sclerosis, starting in 2022 and 2023.

When asked about the absence of stroke patients in its upcoming trial plans, the biotech cited limited resources. NervGen’s initial focus is based on the weight of scientific evidence to support those indications, the potential for positive impact on patients, feasibility of development, investor sentiment and commercial potential.

“Given this compelling new preclinical data in stroke, we believe there is a solid opportunity to secure non-dilutive funding to advance the program in the clinic through a partnership, either with industry or government,” NervGen said.

By Gabrielle Masson

Med info from their site

Indications

Activase® (alteplase) is indicated for the treatment of acute ischemic stroke. Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment. Initiate treatment as soon as possible but within 3 hours after symptom onset.

Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.

Activase is indicated for the lysis of acute massive pulmonary embolism (PE), defined as:

  • Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments.
  • Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

Important Safety Information

Contraindications

Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit: current intracranial hemorrhage (ICH); subarachnoid hemorrhage; active internal bleeding; recent (within 3 months) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms); bleeding diathesis; and current severe uncontrolled hypertension.

Do not administer Activase to treat acute myocardial infarction or pulmonary embolism in the following situations in which the risk of bleeding is greater than the potential benefit: active internal bleeding; history of recent stroke; recent (within 3 months) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding; bleeding diathesis; and current severe uncontrolled hypertension.

Warnings and Precautions

Bleeding

Activase can cause significant, sometimes fatal internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient. Perform venipunctures carefully and only as required. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. Aspirin and heparin have been administered concomitantly with and following infusion with Activase in the management of acute myocardial infarction and pulmonary embolism. The concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the Activase infusion, and treat appropriately.

In the following conditions, the risks of bleeding with Activase are increased and should be weighed against the anticipated benefits: recent major surgery or procedure; cerebrovascular disease; recent intracranial hemorrhage; recent gastrointestinal or genitourinary bleeding; recent trauma; hypertension; acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age; and patients currently receiving oral anticoagulants, or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Hypersensitivity

Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of Activase. Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors. Monitor patients treated with Activase during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine).

Thromboembolism

The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

Cholesterol Embolization

Cholesterol embolism, sometimes fatal, has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

Coagulation Tests May be Unreliable during Activase Therapy

Coagulation tests and/or measures of fibrinolytic activity may be unreliable during Activase therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.

Adverse Reactions

The most frequent adverse reaction associated with Activase therapy is bleeding.

Please see full Prescribing Information for additional Important Safety Information.

find out more directly from the company medication site www.activase.com

]]> How Does Exercise Affect The Gut Microbiome? https://goodshepherdmedia.net/how-does-exercise-affect-the-gut-microbiome/ Sat, 12 Feb 2022 12:11:31 +0000 https://goodshepherdmedia.net/?p=11785 How Does Exercise Affect The Gut Microbiome?

Your gut microbiome is a symbiotic ecosystem that adapts to you — that’s why physical activity is good for your gut microbes.

 

There’s a whole world living inside your colon (i.e., the large intestine), and it does a bunch of important stuff. This ecosystem is mainly made up of bacteria that perform a range of essential functions for digestive and overall health.

It’s called the gut microbiome. It eats what you eat, it gets stressed when you do, and now science shows that the composition and functions of your gut bacteria are enhanced by exercise and physical activity.

Table of contents

 

In this article, we’ll review some microbiome basics before diving into the exciting findings about physical exercise, like how it increases microbial diversity and how to apply these findings to your daily life.

☝DISCLAIMER☝ This article is for informational purposes. Always consult your GP if you plan on implementing changes to your exercise routine, especially if you have been leading a sedentary lifestyle with little or no physical activity.

Your microbiome is a self-portrait

 

Imitation is the sincerest form of flattery, we’re told. And in this case, you should be very flattered, because your microbiome looks just like you (well nearly).

Thanks to genetic sequencing technology, humanity recently discovered how essential our gut microbes are for good health, and how much they reflect our daily lives and naughty indulgences. But first, we should probably explain what the fuss is about bacteria.

Your gut bacteria belong in an ecosystem that also includes some yeasts and other microscopic creatures. It performs many important functions for human health, like producing and breaking down food molecules into nutrients that complement the physiological functions of the human body.

In a nutshell, your gut bacteria produce fatty acids, vitamins, and amino acids that have a range of beneficial effects for the body, from promoting healthy immune system function to maintaining the integrity of the gut lining.

You can learn more about the composition of your gut microbiome and how it affects your health with the Atlas Biomed Microbiome Test.

Microbial diversity is essential for health

 

We have a win-win arrangement with our microbes when we live a healthy life: we give these single-celled organisms a home, and they work hard alongside us.

The microbiome influences nutrition, metabolic health, and immune system function among many other things, including the human brain. So it wasn’t a stretch when scientists considered the possibility of physical exercise having an impact on the microbiome.Diversity is a key parameter for measuring microbiome health, and this ecosystem is made up of hundreds of species. A diverse microbiota profile is associated with enhanced vitamin and short-chain fatty acid (SCFA) production, dietary fibre metabolism, and even increased disease protection.

On the other hand, there’s a word for a poor or imbalanced ecosystem that can’t adequately do its job for the host, a human. It’s called dysbiosis. When dysbiosis affects the gut, the communities of beneficial and benign bacteria that usually make up the microbiota are altered, leading to digestive symptoms and conditions.

What can exercise do for my microbiome?

 

Recent studies suggest that exercise has a number of benefits for the gut microbiota. It is linked to increases in the number of beneficial microbial species and enriching microbial diversity, as well as enhanced short-chain fatty acid synthesis and carbohydrate metabolism.
≤ 50% reduction in colon cancer risk by physical activity

Studies have shown, for example, that even little changes can yield results. For example, increasing the frequency of moderate exercise from never to daily leads to a greater diversity in Firmicutes.

This phylum (a taxonomic rank) of bacteria includes Faecalibacterium prausnitzii, species of Oscillospira, as well as members of the Lachnospira and Coprococcus genera that contribute to a healthier gut environment.

Body fat percentage, muscle mass, and physical activity are significantly correlated with several bacterial populations

Another study we will explore later looked at how physical exercise in women affects the microbiome. It found that doing exercise was correlated with higher representation of bacteria with health-promoting functions in females.

These included F. prausnitzii and Roseburia hominis, known for their butyrate-producing abilities, and Akkermansia muciniphila that is abundant in athletes, and low levels are associated with metabolic conditions, like obesity and diabetes.

Research comparing elite athletes to sedentary controls (average human participants that don’t do much physical exercise) also highlights that the microbiome is much more than just a gut thing.

One major study investigated the microbiomes of 40 professional international rugby union players compared to control groups of people of similar age with either high or low BMI. It highlighted “significantly greater intestinal microbial diversity among the athletes”.

A number of other parameters also showed significantly improved results versus those of the controls. These included short-chain fatty acids (SCFAs): they recorded “significantly higher levels of acetate, propionate, butyrate and valerate in athletes relative to controls.”SCFAs are organic compounds produced by gut bacteria from tough-to-digest plant fibres in your diet. In particular, butyrate has been shown to have a number of health-promoting functions.

Among other things, butyrate is the main source of fuel for the cells of the gut lining, helping to maintain its integrity, reduce inflammation, and prevent organic compounds from foods, toxins, and metabolites from crossing into the bloodstream.

The study also identified increases in the metabolic pathways of the microbiome (a series of chemical reactions within a cell):

  • production of amino acids, essential building blocks of cells
  • antibiotic biosynthesis that supports immune system function
  • carbohydrate metabolism that provides fuel

In short, physical exercise has been shown to provide tangible improvement for several markers associated with physical performance and health, particularly in terms of beneficial types of bacteria and their functions.

REMEMBER ☝Protection from obesity and diabetes, as well as potential for butyrate production and the composition of your microbiome, are traits you can check with the Atlas Biomed Tests.

Gut microbial diversity and physical activity

 

You may rightly wonder whether physical exercise transforms the microbiota, or if having a healthy microbiota makes you more inclined to be active. It’s a chicken-or-egg scenario that scientists are looking at from both angles.

Because, for example, it’s true that dysbiosis can cause inflammation that leads to depressive symptoms, and depression is not conducive to getting out and doing things. But on the other hand, several studies indicate that doing sports can actually change your gut ecosystem.A 2017 study, this time in women, demonstrated that physical exercise “can modify the composition of gut microbiota” in a positive way. Differences in gut microbiota profile between women with active lifestyle and sedentary women by Carlo Bressa and colleagues studied two groups of women between the ages of 18 and 40.

Active participants were selected for the group that performed at least 10 hours of physical exercise over a 7-day period during the trial. The sedentary group participated in quiet activities and were selected from women who weren’t particularly active in their daily lives, performing less than 30 minutes of moderate exercise three times per week.

Eleven genera (a taxonomic rank of bacteria) were “significantly different between active and sedentary women”. Importantly, the active group of women had a “higher abundance of health-promoting bacterial species, including Faecalibacterium prausnitzii, Roseburia hominis, and Akkermansia muciniphila”.

They also found that “body fat percentage, muscular mass, and physical activity significantly correlated with several bacterial populations.” Basically, leading an active lifestyle was more pleasing to some bacteria than others, and that’s a very good thing.

What sports can improve your microbiome?

 

Physical activity is divided into two categories, strength and endurance, that are determined by how your body produces energy to fuel your performance.

VO2 max accounts for 20% of the variation in taxonomic richness

Strength sports require high-intensity effort, like weight lifting, sprinting, and boxing. These sports build muscle mass by exercising your cells’ anaerobic pathways. That means that your muscles use their limited glycogen stores to create ATP (the fuel for your muscles) without using oxygen.

This differs from endurance sports that allow the body to perform exercise at a lower intensity, but for much longer periods, like long-distance running, cycling, and skiing. Such activities are considered aerobic because the muscles use oxygen to transform fats and sugars into ATP for fuel.

The most popular way of measuring cardiovascular fitness is V02 max that looks at the maximum amount of oxygen your body can use during intense exercise. It is used to assess endurance performance, and can be significantly improved with high-intensity exercises.Several studies indicate a relationship between microbiota composition and cardiorespiratory fitness that can account for more than 20% of the variation in “taxonomic richness” (diversity of bacteria identified in the microbiome). These changes were noted to be independent of other factors, including age, fat intake, and carbohydrate intake.

Cardio is the way to go

 

As we’ve seen, studies indicate that aerobic exercise, commonly known as cardio, has benefits for your microbiota, both in terms of increased abundance of beneficial bacteria and overall diversity.

Cardio is about going long and steady, ensuring the supply of oxygen to your muscles so they can create fuel (ATP). This includes any exercise that gets your heart rate up and keeps it up for a prolonged period of time.Walking, running, dancing, cycling, the elliptical machine, and the rower at the gym are all examples of cardio workouts. However, the intensity and duration of your workout will vary depending on your general fitness level.

If you are just dipping your toes into the exercise pond, you might not be able to sustain your effort for long. And that is totally okay because cardio is all about the long run. Take it easy, keep at it, and your body will adjust! #PunIntended

The NHS has issued recommendations for physical activity in adults, here is what they say:

  • At least 150 minutes of moderate aerobic activity, such as cycling or brisk walking, every week
    and
  • Strength exercises on 2 or more days a week that work all the major muscles (legs, hips, back, abdomen, chest, shoulders, and arms).

OR

 

  • 75 minutes of vigorous aerobic activity, such as running or a game of singles tennis, every week
    and
  • Strength exercises on 2 or more days a week that work all the major muscles (legs, hips, back, abdomen, chest, shoulders, and arms).

OR

 

  • A mix of moderate and vigorous aerobic activity every week — for example, two 30-minute runs plus 30 minutes of brisk walking equates to 150 minutes of moderate aerobic activity,
    and
  • Strength exercises on 2 or more days a week that work all the major muscles (legs, hips, back, abdomen, chest, shoulders, and arms).

Don’t forget to stretch all the major muscle-tendon groups (a total of 60 seconds per group) two or more times per week to maintain the range of movement of your joints. You should also make sure to break up long periods of sitting by getting up and moving around.

REMEMBER ☝Predisposition to athletic performance, as well as potential for butyrate production and the composition of your microbiome, are traits you can check with the Atlas Biomed Tests.

Do I need a microbiome test?

 

You can learn more about the composition of your gut microbiome and how it affects your health with the Atlas Biomed Microbiome Test. Your health report includes:

  • an overall score for microbiome functions and disease protection
  • in-depth profile of your microbes and a probiotics report
  • potential for nutrient synthesis, including butyrate and vitamins
  • ability to break down fibre and personalised food recommendations

We use advanced genetic sequencing to analyse your microbiome, generating results and recommendations using algorithms based on the results of thousands of clinical trials and scientific papers.

This allows us to identify your individual traits and tailor recommendations for your unique body to enhance your health and wellbeing.

Sources:

source

]]> GABA and L-theanine mixture Improves REM Sleep, Antidepressant, and Mood-stabilizing Study Says https://goodshepherdmedia.net/gaba-and-l-theanine-mixture-improves-rem-sleep-antidepressant-and-mood-stabilizing-study-says/ Sat, 08 Jan 2022 08:32:10 +0000 https://goodshepherdmedia.net/?p=4625 GABA and L-theanine mixture Improves
REM Sleep, Antidepressant, and Mood-stabilizing Study Says

Abstract

Context: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter and it is well established that activation of GABAA receptors favours sleep. l-Theanine, a naturally occurring amino acid first discovered in green tea, is a well-known anti-anxiety supplement with proven relaxation benefits.

Objective: This study investigated the potential synergistic sleep enhancement effect of GABA/l-theanine mixture.

Materials and methods: Pentobarbital-induced sleep test was applied to find proper concentration for sleep-promoting effect in ICR mice. Electroencephalogram (EEG) analysis was performed to investigate total sleeping time and sleep quality in normal SD rats and caffeine-induced awareness model. Real-time polymerase chain reaction (RT-PCR) was applied to investigate whether the sleep-promoting mechanism of GABA/l-theanine mixture involved transcriptional processes.

Results: GABA/l-theanine mixture (100/20 mg/kg) showed a decrease in sleep latency (20.7 and 14.9%) and an increase in sleep duration (87.3 and 26.8%) compared to GABA or theanine alone. GABA/l-theanine mixture led to a significant increase in rapid eye movement (REM) (99.6%) and non-REM (NREM) (20.6%) compared to controls. The use of GABA/l-theanine mixture rather than GABA or l-theanine alone restored to normal levels sleep time and quality in the arousal animal model. The administration of GABA/l-theanine led to increased expression of GABA and the glutamate GluN1 receptor subunit.

Conclusions: GABA/l-theanine mixture has a positive synergistic effect on sleep quality and duration as compared to the GABA or l-theanine alone. The increase in GABA receptor and GluN1 expression is attributed to the potential neuromodulatory properties of GABA/l-theanine combination, which seems to affect sleep behaviour.

Keywords: γ-Aminobutyric acid, insomnia, pentobarbital-induced sleep test, electroencephalography

Introduction

Sleep loss and other related disturbances pose an important health problem, as they can lead to significant functional impairments. Sleep disturbances can affect daily life considerably and reduce the quality of life. The importance of a good night’s sleep is well-established, nevertheless many people suffering from sleep disorders prefer not to use hypnotic drugs, despite providing effective symptomatic relief.

Hypnotic drugs, such as benzodiazepine analogues, zolpidem and doxepin, can cause unexpected side effects and can lead to drug resistance and dependence (Longo and Johnson ; Victorri-Vigneau et al. ; Lichstein et al. ). These types of sleeping drugs are not suitable for the treatment of temporary anxiety or sleep disturbances due to the observed drug resistance and dependence that has been associated with their long-term use (Oh et al. ). However, herbal remedies have been reported as effective and with a relatively low side effect risk for the treatment of insomnia (Wheatley ). Therefore, it is necessary to develop new bioactive substances derived from natural sources that present with similar efficacy but fewer side effects than hypnotic drugs, for the successful treatment of sleep-related disturbances.

γ-Glutamylethylamine, also known as l-theanine, and γ-aminobutyric acid (GABA) are known agents for improving sleep disturbances (Khan et al. ). GABA is a non-proteinogenic amino acid and is the main inhibitory neurotransmitter in the mammalian brain. Hence GABAA receptors are a primary target in the search for natural anxiolytic compounds or sedatives (Khom et al. ; Trauner et al. ). There is an increasing interest in investigating the effect of GABA-mediated inhibitory neurotransmission, in respect to its potential benefit on counteracting sleep disruption caused by various conditions, such as stress, diseases and caffeine intake, etc. (Wong et al. ). Therefore, GABA is widely used in functional food and pharmaceutical industries, and various researches have been investigated for biosynthesis and their efficacy as metabolites of plants and microorganisms produced by the decarboxylation of glutamic acid (Coda et al. ; Dhakal et al. ; Yang et al. ) l-Theanine, an amino acid exclusively found in tea leaves, composes only 1–2% (w/w) of the weight of dried tea leaves (Graham ) and is chemically or biologically synthesized for use as an active ingredient that induces sedation (Juneja et al. ; Yan et al. ). There are several reports indicating that l-theanine exerts neuroprotective effects (Kim et al. ), modulates neurotransmitter activity (Kakuda ) and reduces psychological stress (Kimura et al. ) and sleep disturbances (Jang et al. ). Nathan et al. () also reported that l-theanine intake increases serotonin, dopamine and GABA levels in the brain.

In recent years, there have been numerous ‘relaxation beverages’ available on the market containing relaxation-inducing nutraceuticals, such as valerian, l-theanine, GABA, 5-hydroxytryptophan (5-HTP) and the sleep-aid, melatonin. Therefore, the combination of GABA and l-theanine may synergistically promote symptomatic relief for sleep disorders, despite the scarce experimental data supporting this process. The purpose of this study was to investigate whether the effect of GABA/l-theanine mixture on sleep disturbances is greater than GABA or l-theanine alone and to determine the most effective dosing combination.

Materials and methods

Materials

GABA (90.8%) and l-theanine (99.3%) was supplied by Neo Cremar Co. Ltd (Seoul, Korea) and BTC Co. Ltd (Ansan, Korea), respectively. Caffeine was purchased from Sigma-Aldrich (St. Louis, MO) and pentobarbital sodium was purchased from Hypharm. Co. Ltd. (Gyeonggi-do, Korea). All other reagents were purchased at the highest commercial grade available.

Animals

Male ICR mice (4 weeks old, 18–20 g) and Sprague-Dawley (SD) rats (8 weeks old, 160–180 g) were purchased from Orient Bio (Orient Bio Inc., Seongnam, Korea). All animals were caged at 22 ± 2 °C and 55 ± 5% humidity with a 12 h light/dark cycle. Normal pellet diet and water were freely provided. Rodents were acclimatized for at least one week before starting pentobarbital-induced sleep testing and electroencephalography (EEG) analysis. The ages of the animals used in this study were to ensure the functional integrity of the brain and central nervous system, which usually does not occur in older animals, which normally have degraded morphological and functional characteristics (Verdú et al. ). In this study, all animal experimental protocols were approved by the Korean University Animal Care Committee (KUIACUC-2017-49, Seoul, Korea).

Pentobarbital-induced sleep test

Pentobarbital-induced sleep was performed according to previously established methods with slight modifications (Yang et al. ). Sodium pentobarbital (42 mg/kg) was administered intraperitoneally in each mouse 40 min after oral administration of GABA, l-theanine or both (GABA/l-theanine). The time elapsed from compound administration to the loss of righting reflex (sleep latency) and the time from the loss of righting reflex to its return (sleep duration) were measured in seconds. Mice that did not sleep 15 min after the injection were excluded from the experiment.

Electrophysiological analysis

Male SD rats were anesthetized with 2% isoflurane (Troikaa Pharmaceutical Ltd., Gujarat, India), using a gas anesthesia mask in a stereotaxic instrument frame (Stoelting Inc., Wood Dale, IL). For the EEG recording, EEG screw electrodes were implanted into the cortex, striatum and hippocampus, as previously described (Hong et al. ). All rats received antibiotics and were kept individually in cages under a temperature-controlled facility with water and food. The rats were randomly divided into control and treatment groups at 7 days after recovery. Experiments were conducted from 10 am to 5 pm for 9 days. GABA, l-theanine or GABA/l-theanine mixture was orally administered 1 h before EEG signal analysis. EEG signals were amplified, filtered (0.5–30 Hz), recorded and stored using Iox2 (version. 2.8.0.13, emka Technologies, Paris, France). EEG spectra were analyzed in 1 Hz frequency bins and standard frequency bands (β: 13–30 Hz; α: 8–13 Hz; θ: 4–8 Hz; δ: 0.5–4 Hz). After the EEG recording, fast Fourier transform (FFT) was performed every 2 sec. Based on the FFT average data obtained at 10-sec intervals in the range of 0–30 Hz, the ecgAUTO3 program (version. 3.3.0.20, emka Technologies) was used to calculate the awake and sleep time. Caffeine (10 mg/kg) was used to induce the arousal condition before the experiments.

Quantification of receptor mRNA levels

Total RNA was extracted from mouse brains using TRIzol® (Invitrogen, CA), while genomic DNA was removed using Direct-zolTM RNA Miniprep (ZYMO Research, CA) according to the manufacturer’s protocol. Quality-controlled RNA (1 μg) was reverse transcribed using SuperScript® III Reverse Transcriptase (Invitrogen) with oligo d(T) as the primer. The generated cDNA was subjected to quantitative real-time PCR (qRT-PCR) using a Power Taqman PCR Master Mix kit (Applied Biosystems, Foster City, CA). For qRT-PCR, cycling conditions were 50 °C for 2 min, 95 °C for 10 min, followed by 40 cycles at 95 °C for 15 s and 60 °C for 1 min. Quantitative analysis was conducted using StepOne plus Software version 2.0 (Applied Biosystems, Inc., Foster City, CA). The endogenous housekeeping gene, GAPDH (NM_008084.2), was used for result normalization. Information for the target genes used for qRT-PCR is as follows: GABAA receptor (NM_008076.3), GABAB receptor 1 (NM_01 9439.3), GABAB receptor 2 (NM_001081141.1), GluA1 (NM_00111 3325.2), GluN1 (NM_001177656.2) and GluN2A (NM_008170.2).

Statistical analysis

Testing results were evaluated for statistical differences using SPSS version 12.0 (SPSS, Chicago, IL) by one-way analysis of variance (ANOVA) followed by both Tukey’s multiple comparisons and Bonferroni post hoc test. Different letters indicate significant differences (p < 0.05) among groups by Tukey’s multiple comparison tests. All data are expressed as the means ± standard error (SE) comparisons between groups, n = 8.

Results

Effects of GABA and l-theanine on sleep latency and duration in the pentobarbital-induced sleep model

Sleep latency and duration time following GABA or l-theanine administration were measured in the pentobarbital-included sleep model to identify the optimal combination ratio for sleep enhancement (Figure 1). Sleep latency showed a tendency to decrease with increasing GABA concentration and sleep duration to increase with increasing GABA concentration (Figure 1(A,B)). Regarding sleep latency, there was a significant difference (p < 0.05) following the administration of 100 mg/kg of GABA (3.1 min), as compared to control (3.7 min), but no significant differences with other GABA concentrations were observed (Figure 1(A)). With regards to sleep duration, there was also a significant difference (p < 0.05) following 100 mg/kg of GABA, as compared to control. No significant differences of sleep duration were observed following the administration of any other GABA concentrations (Figure 1(B)). Pentobarbital-induced sleep testing was carried out to assess the potential sleep enhancement effect of l-theanine (Figure 1(C,D)). Following the administration of 20 or 30 mg/kg of l-theanine, sleep latency significantly decreased (2.8 and 2.7 min, respectively), as compared to controls (3.7 min) (p < 0.05 and p < 0.01, respectively). However, the administration of 40 mg/kg of l-theanine not decreased sleep latency (3.7 min). When compared to controls (39.9 min), total sleep time increased in l-theanine-treated animals at a dose of 20 mg/kg (55.2 min), but not with 30 or 40 mg/kg of l-theanine (Figure 1(D), p < 0.01). In summary, administration of 20 mg/kg of l-theanine in mice, resulted in a decrease in sleep latency (23.3%) and an increase in sleep duration time (38.1%).

 

Effects of GABA or l-theanine on sleep latency (A, C) and sleep duration (B, D) in mice administered with a hypnotic dosage of pentobarbital (42 mg/kg, i.p.). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as **p < 0.01, *p < 0.05.

Effects of GABA/l-theanine combination on sleep latency and duration in the pentobarbital-induced sleep model

The induced changes in sleep latency and duration time by different ratio combinations of GABA (80 and 100 mg/kg) and l-theanine (20 and 30 mg/kg) were measured (Figure 2). The sleep latency of animals that were administered with either of the GABA/l-theanine dose combinations (80/30 and 100/20 mg/kg) was slightly lower than the control group (Figure 2(A)) (16.8 and 17.7%, respectively). With respect to sleep duration, sleep time showed a tendency increase in all dose combination groups (Figure 2(B)). In particular, the GABA/l-theanine mixture administered at a dose ratio of 100/20 mg/kg, evoked the highest sleep duration increase (100.6 min) (p < 0.01).

Effects of GABA/l-theanine mixture on sleep latency (A, C) and sleep duration (B, D) in mice administered with a hypnotic dosage of pentobarbital (42 mg/kg, i.p.). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as **p < 0.01, *p < 0.05.

The effects of the best sleep-promoting GABA/l-theanine dose combination (100/20 mg/kg) were compared to the changes in sleep latency and duration induced by the single administration of GABA or l-theanine (Figure 2(C,D)). The combined use of GABA/l-theanine (100/20 mg/kg) showed a decrease in sleep latency (20.7% and 14.9%, respectively) and an increase in sleep duration (87.3% and 26.8%, respectively) compared to a single administration of GABA (100 mg/kg) or theanine (20 mg/kg). The combined use of GABA/l-theanine showed synergy effects on sleep latency and sleep duration time.

Effects of GABA and l-theanine mixture on sleep architecture

EEG parameters were recorded to more accurately confirm the synergistic effect of GABA/l-theanine mixture observed in the pentobarbital-induced sleep model (Figure 3). The changes in sleep time and architecture were measured after a single administration of GABA 100 mg/kg or l-theanine 20 mg/kg and after GABA/l-theanine mixture (100/20 mg/kg). Figure 3 depicts the longest sleep time recorded following the oral administration of GABA/l-theanine. However, no significant difference in sleep time was detected between GABA/l-theanine mixture and l-theanine alone (Figure 3(A)). The most reduced awake time was detected after oral administration of GABA/l-theanine mixture (1.2 h) and was significantly different from control (2.2 h) (Figure 3(B), p < 0.001). Single GABA administration (100 mg/kg) significantly increased rapid-eye-movement (REM) sleep time, as compared to the control group (71.5%) (p < 0.01), but there was no significant difference in non-REM (NREM) sleep time compared to the control group (Figure 3(C,D)). Single l-theanine administration (20 mg/kg) significantly increased REM time, when compared to controls (88.6%) (p < 0.01), but there was no significant difference in NREM sleep time compared to the control group. NREM (20.7%) and REM (99.6%) were also significantly increased than control levels, after GABA/l-theanine mixture was orally administered (Figure 3(C,D), p < 0.05 and p < 0.001, respectively). The oral administration of GABA/l-theanine mixture improved sleep time and quality, as compared to GABA or l-theanine alone.

Effects of the GABA, l-theanine, and GABA/l-theanine mixture on sleep quantity and quality. Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences at ***p < 0.001, **p < 0.01, *p < 0.05 by Bonferroni test. NS: not significant.

The θ wave was significantly increased after GABA (1.8 h) or l-theanine (2.2 h) single infusion, as well as after GABA/l-theanine combined administration (2.5 h) (Figure 3(E)). The δ wave showed a tendency to decrease when GABA or l-theanine was separately administered and after GABA/l-theanine, but there were no significant differences between groups (Figure 3(F)).

Effects of GABA and l-theanine combination on sleep architecture during three sleep periods

Figure 4 depicts the sleep pattern measured for 9 days divided into 3 periods. Total sleep time increased and awakening time decreased from 1st to 3rd period in all sample groups (Figure 4(A,B)). NREM sleep was significantly increased in the GABA/l-theanine mixture group, as compared to controls during all three periods (Figure 4(C); 1st period: p < 0.05, 2nd period: p < 0.05, 3rd period: p < 0.001). REM sleep was significantly increased at all periods compared to control levels in the GABA or l-theanine alone groups, as well as the GABA/l-theanine mixture group (Figure 4(D)).

Effects of GABA, l–theanine, and GABA/l-theanine mixture on sleep quantity and quality during administration periods. Values are presented as the means ± standard error (SE) for each group, n = 8. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01, *p < 0.05.

NREM sleep consists of θ and δ waves, with 4.0–8.0 and 0.5–4.0 Hz bandwidths, respectively. The use of l-theanine alone and GABA/l-theanine mixture increased θ waves over the ones detected in the control group during all periods. Single l-theanine administration led to a significant decrease in δ waves during the 1st period (2.0 h) (p < 0.01), which gradually increased in the 3rd period (3.1 h). When GABA/l-theanine mixture was administered, δ wave oscillations also gradually increased from 1st (2.2 h) to 3rd period (2.7 h) (Figure 4(E,F)). In conclusion, the combined treatment with GABA and l-theanine led to a significant increase in sleep time (22.4%), especially NREM (28.8%), when administered over a long period. In addition, the use of GABA/l-theanine mixture increased θ wave and decreased δ wave oscillations in NREM sleep, when compared to the control group. Nevertheless, δ waves gradually increased with long-term administration. Therefore, the longer the administration of GABA/l-theanine mixture the better the sleep quality and the longer the sleep duration, induced.

EEG acquisition and analysis in a caffeine-induced wakefulness model

EEG was performed to assess the sleep-inducing effects of GABA, l-theanine or the combination of both (GABA/l-theanine mixture) in a caffeine-induced awakening animal model (Figure 5). A significant difference (p < 0.001) in sleeping and awakening times were observed between the arousal group, which was orally administered 10 mg/kg of caffeine and the control group which was orally administered with saline (Figure 5(A,B)). Administration of GABA, l-theanine, or the combination of both, in the caffeine-induced awakening model led to significant differences in sleep and awakening times, when compared to the arousal group (p < 0.001). In the wakefulness model, the use of l-theanine alone or GABA/l-theanine mixture restored NREM sleep time to the control group level (Figure 5(C)). However, the use of GABA/l-theanine mixture in the wakefulness model had a tendency to restore REM sleep time, but there was no significant difference to arousal group. The administration of GABA/l-theanine mixture increased θ wave (1.9 h) and increased δ wave (2.0 h) oscillations in NREM sleep, when compared to the arousal group (1.4 and 2.5 h, respectively) (Figure 5(E,F), p < 0.01). These results suggest that the combined use of GABA and l-theanine rather than GABA or l-theanine alone restores sleep time and quality to normal levels, in the arousal animal model.

Effects of the GABA, l-theanine, and GABA/l-theanine mixture on caffeine-induced wakefulness in rats at a dosage of caffeine (10 mg/kg). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01 compared with arousal group.

Effects of GABA and l-theanine combination on the mRNA levels of neurotransmitter receptors

To investigate whether the sleep-promoting mechanism of GABA/l-theanine mixture mediates neurotransmitter receptor expression changes, the mRNA levels of GABA and glutamate receptors were evaluated (Figure 6). Transcript levels for the GABAA receptor following the combined administration of GABA/l-theanine were 1.53-fold higher than control levels (Figure 6(A), p < 0.01). Moreover, GABA/l-theanine combined infusion led to significant changes in the mRNA levels of GABAB-R2 (21.4%), as compared to controls (Figure 6(C), p < 0.001). However, there was no significant difference in the mRNA levels of GABAB-R1 compared to the control group (Figure 6(B)).

Effects of the GABA/l-theanine mixture on GABA and glutamate receptors mRNA expression in the mouse brain. Values are presented as mean ± standard error of the mean (SEM) for the brain regions of 8 mice and for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01, *p < 0.05. NS: not significant.

GABA/l-theanine mixture significantly increased the mRNA levels of the GluN1 glutamate receptor subunit, as compared to control (13.8%) (Figure 6(E), p < 0.05). However, administration of l-theanine alone also altered the GluR1 glutamate receptor (12.5%) and GluN1 glutamate subunit (7.2%) expressions when compared to controls (Figure 6(D,E), p < 0.05). These results indicate that increased expression of GABA receptors GABAA, GABAB-R1 and GABAB-R2, and the GluN1 glutamate receptor subunit observed with GABA/l-theanine, may possibly lead to improved sleep behaviour and neurological regulation.

Sleep-promoting effects of the GABA/5-HTP mixture in vertebrate models

Abstract

The aim of this study was to investigate the sleep-promoting effect of combined γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) on sleep quality and quantity in vertebrate models. Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of two amino acids and GABA/5-HTP mixture. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. The GABA/5-HTP mixture significantly regulated the sleep latency, duration (p<0.005), and also increased the sleep quality than single administration of the amino acids (p<0.000). Long-term administration increased the transcript levels of GABAA receptor (1.37-fold, p<0.000) and also increased the GABA content compared with the control group 12h after administration (1.43-fold, p<0.000). Our available evidence suggests that the GABA/5-HTP mixture modulates both GABAergic and serotonergic signaling. Moreover, the sleep architecture can be controlled by the regulation of GABAA receptor and GABA content with 5-HTP.

Keywords: 5-Hydroxytryptophan; Electroencephalogram; Pentobarbital; Sleep; Vertebrate; γ-Aminobutyric acid.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent

Abstract

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

A Novel Theanine Complex, Mg-L-Theanine Improves Sleep Quality via Regulating Brain Electrochemical Activity

Discussion

The pentobarbital-induced sleeping model was used to identify the optimal sleep enhancement dosing ratio for GABA and l-theanine. In this study, the combination of GABA and l-theanine (100/20 mg/kg) not only did it reduce sleep latency but also prolonged sleep duration in pentobarbital-induced sleep model. The key finding of this study is the confirmation of the synergistic action (p < 0.01, compared to control) of GABA and l-theanine on sleep behaviour, which significantly decreased sleep latency and increased sleep duration.

Amino acid neurotransmitters are important for the function of the central nervous system (CNS). They are fast-acting, inducing responses within milliseconds and play an important role in physiological brain function and neurological diseases (Krystal et al. ). Rapid neurotransmitter regulation and nerve function, facilitation of relaxation without drowsiness, stress relief (including physical stress), and l-theanine-mediated excitement are known strategies used for the improvement of sleep quality and for exhaustion recovery (Rao et al. ).

Sleep deprivation is known to cause serious illnesses such as cardiovascular disease, diabetes, and cancer (Davis and Mirick ; Laposky et al. ; Baron and Reid ). The pentobarbital-induced sleep test and the EEG measurement that have been performed usually in a study of sleep enhancement were used to confirm the synergy effect of GABA/l-theanine mixture in sleep enhancement (Jeon et al. ).

The combination of GABA and l-theanine (80/20 and 100/30 mg/kg) did not show a synergistic effect in sleep latency and sleep duration unlike the GABA/l-theanine mixture (100/20 mg/kg). Lin et al. () reported that the synergistic effects were different depending on the ratio of taurine and caffeine, and it is important to identify specific synergistic ratio in the study of combined sample administration. However, further research is needed to determine that synergistic effects are achieved only at a specific ratio with any pharmacokinetic mechanism.

GABA acts through GABA receptors. There are generally 2 types of GABA receptors: GABAA and GABAB. The most important receptor, with respect to sleep is the GABAA receptor (Gottesmann ). When GABA or another agonist binds to GABAA receptor, it triggers the influx of chloride ions in neuronal cells. This causes a negative membrane potential that inhibits action potential firing. In this way, GABA (and GABA-promoting compounds) reduce activity in brain cells through GABAA receptor activation. It is well-known that the activation of GABAA receptors is beneficial for sleep (Abdou et al. ). The structural similarity of l-theanine to the neurotransmitter glutamic acid has prompted researchers to study its potential competition binding on glutamate receptors in the nervous system (Shinozaki and Ishida ). l-Theanine rapidly induces changes in serotonergic and dopaminergic transmission (Yokogoshi et al. ). These components act as modulating receptors of the neurotransmitter GABA, which is the main inhibitory neurotransmitter in the CNS, and therefore, one of the main molecules responsible for sleeping behaviour (Zanoli and Zavatti ). The decreases in sleep latency, together with a slight improvement in sleep quality, are the possible reasons for the observed increase in sleep efficiency, in our study.

As characterized by EEG recordings, sleep is broadly divided into REM and NREM (Bersagliere et al. ). Combined oral administration of GABA and l-theanine significantly increased the amount of NREM sleep, as compared to controls (Figure 3, p < 0.05), via an increase in theta waves. Moreover, awake time was also significantly decreased following GABA/l-theanine administration, as compared to all other groups (p < 0.001, Figure 3). Brain waves can be classified into four types: α (less than 8–13 Hz), β (more than 13 Hz), θ (less than 4–8 Hz), and δ waves (less than 4 Hz) (Abdou et al. ). Each wave type is associated with a specific mental state. Delta and theta occur in the early stages of deep sleep and sleep, respectively (Ray and Cole ).

We observed a tendency for NREM sleep to increase with increasing dosing periods during the combined oral administration of GABA and l-theanine, probably due to l-theanine (Figure 4). This change in NREM is likely due to changes in delta waves after GABA/l-theanine administration. EEG frequency estimation revealed increased delta and decreased beta activity in the NREM state. Caffeine causes a variety of sleep disturbances, including total sleep time reduction, prolonged sleep onset latency and increased arousal in humans and rats through adenosine receptor blockade (Deckert and Gleiter ).

In Figure 5, caffeine decreased sleep time, especially NREM and increased the awake time in rats. The results indicate that GABA and l-theanine combined intake can reverse caffeine-induced sleep reduction, especially NREM, in rats (Figure 5). Administration of l-theanine has been reported to inhibit caffeine’s convulsive action and to increase GABA brain levels in mice (Kimuraand Murata 1971). l-Theanine is known to decrease norepinephrine levels in the rat brain and suppress caffeine-induced serotonin and 5-hydroxyindoleacetic acid increases in rats (Kimura and Murata ). Furthermore, the neuroprotective effect of theanine has been shown to be mediated via glutamate receptors, as theanine acts as a glutamate receptor antagonist (Kakuda et al. ). The above results suggested that the GABA/l-theanine mixture was significantly superior to GABA or l-theanine alone, for reducing sleep latency, awake time and extending NREM sleep duration. The l-theanine seems to play a major role in the synergistic effect of GABA and l-theanine combination. A trend for prolonged NREM with increasing l-theanine dosing was observed, which was similar to the delta wave increasing trend. In the caffeine-induced arousal model, combined GABA and l-theanine led to a similar synergistic effect on sleep enhancement. The combination of GABA and l-theanine is an attractive NREM sleep-promoting regimen as it increases delta wave oscillations.

As shown in Figure 6, GABAA receptor expression levels were significantly changed in mice with administration GABA/l-theanine mixture compared with the control group (p < 0.01). The GABAA receptor complex is a chloride ionophore, which consists primarily of GABA, barbiturate, benzodiazepine, steroid and picrotoxin binding sites (MacDonald and Olsen ). Parisky et al. () demonstrated that GABAA receptor over expression increases total sleep time, while down-regulation of the receptor decreases sleep duration. The metabotropic GABAB receptor can influence the activation of Ca+2 and K+ ion channels via G-protein coupled second messengers. The affinity of GABA to GABAB receptors is lower than that for GABAA receptors (Chu et al. ). The sedative or sleep-inducing effect of GABA is most likely mediated via GABA receptors. GABA receptor expression in the rat brain was significantly increased following the combined administration of GABA and l-theanine but not after GABA infusion alone. l-Theanine has a similar chemical structure to glutamate and l-theanine has micromolar affinities for kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) glutamate receptors (Kakuda et al. ). l-Theanine can act as a competitive glutamate antagonist. The mRNA level of the NDMA receptor subunit GluN1 was slightly higher following GABA/l-theanine infusion than after l-theanine treatment alone (Figure 6).

In conclusion, our results demonstrate that the combined use of GABA and l-theanine increase sleep activity to more than a single administration of either amino acid or these synergistic sleep-promoting effects are likely mediated via changes in GABA and/or glutamate receptor expression in the brain. In summary, this result suggests that GABA/l-theanine mixture could be used for treatment for insomnia and sleep disorders as a concept of nonpharmacological management of sleep.

Funding Statement

This research was supported by the Ministry of Trade, Industry & Energy (MOTIE), Korea Institute for Advancement of Technology (KIAT) through the Encouragement Program for The Industries of Economic Cooperation Region (R0004012).

Disclosure statement

No potential conflict of interest was reported by the authors.

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cited https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366437/

https://pubmed.ncbi.nlm.nih.gov/27150227/

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