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An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid

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Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.
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molecules
Review
An Updated Review on Pharmaceutical Properties of
Gamma-Aminobutyric Acid
Dai-Hung Ngo 1and Thanh Sang Vo 2, *
1Faculty of Natural Sciences, Thu Dau Mot University, Thu Dau Mot City 820000, Vietnam
2NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam
*Correspondence: vtsang@ntt.edu.vn; Tel.: +84-28-6271-7296
Academic Editors: María Dolores Torres and Elena FalquéLópez
Received: 27 May 2019; Accepted: 19 July 2019; Published: 24 July 2019


Abstract:
Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present
in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory
neurotransmitter in the central nervous system. Its physiological roles are related to the modulation
of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention
of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal
peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer,
antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection,
and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for
prevention and treatment of various diseases. Accordingly, this updated review was mainly focused
to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding
human health.
Keywords: anti-hypertension; bioactivity; Gaba; Gaba-rich product; health benefit
1. Introduction
Gamma-aminobutyric acid (Gaba) is a non-protein amino acid that is widely distributed in nature.
Especially, Gaba is present in high concentrations in dierent brain regions [
1
]. Besides, it was also
found in various foods such as green tea, soybean, germinated brown rice, kimchi, cabbage pickles,
yogurt, etc. Generally, Gaba was produced by l-glutamic acid under the catalyzation of glutamic
acid decarboxylase [
2
]. In the nervous system, newly synthesized Gaba is packaged into synaptic
vesicles and then released into the synaptic cleft to diuse to the target receptors on the postsynaptic
surface [
3
]. Numerous studies have identified two distinct classes of Gaba receptor including Gaba
A
and Gaba
B
[
4
]. These receptors are dierent due to their pharmacological, electrophysiological, and
biochemical properties. Gaba
A
receptor is Gaba-gated chloride channels located on the postsynaptic
membrane, while GabaBreceptor is G protein-coupled receptors located both pre- and postsynaptic.
Gaba is well known as the major inhibitory neurotransmitter in the mammalian central nervous
system. It was reported to play vital roles in modulating synaptic transmission, promoting neuronal
development and relaxation, and preventing sleeplessness and depression [
5
9
]. Notably, various
biological activities of Gaba were documented due to anti-hypertension, anti-diabetes, anti-cancer,
antioxidant, anti-inflammation, anti-microbial, and anti-allergy. Moreover, Gaba was also reported as a
protective agent of liver, kidney, and intestine against toxin-induced damages [
10
]. In this contribution,
the pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were mainly
focused to emphasize its beneficial role in prevention and treatment of various diseases.
Molecules 2019,24, 2678; doi:10.3390/molecules24152678 www.mdpi.com/journal/molecules
Molecules 2019,24, 2678 2 of 23
2. Pharmaceutical Properties of Gaba
2.1. Neuroprotective Eect
It has been reported that the damage of nervous tissue triggers inflammatory response, causing
the release of various inflammatory mediators such as reactive oxygen species (ROS), nitric oxide, and
cytokines. These mediators can cause several neuronal degenerations in the central nervous system such
as Alzheimer’s, Parkinson’s, and multiple sclerosis [
11
,
12
]. So far, numerous studies have been reported
regarding the important roles of Gaba on neuro-protection against the degeneration induced by toxin
or injury (Figure 1and Table 1). According to Cho et al. (2007), Gaba produced by the kimchi-derived
Lactobacillus buchneri exhibited a protective eect against neurotoxic-induced cell death [
13
]. Moreover,
Gaba-enriched chickpea milk can protect neuroendocrine PC-12 cells from MnCl
2
-induced injury,
improve cell viability, and reduce lactate dehydrogenase release [
14
]. On the other hand, Zhou
and colleagues have determined that Gaba receptor agonists also possessed neuroprotective eect
against brain ischemic injury. Both Gaba
A
and Gaba
B
receptor agonist (muscimol and baclofen) could
significantly protect neurons from the death induced by ischemia through increasing nNOS (Ser847)
phosphorylation [
15
]. Likewise, the administration of Gaba
B
receptor agonist baclofen significantly
alleviated neuronal damage and suppressed cytodestructive autophagy via up-regulating the ratio
of Bcl-2/Bax and increasing the activation of Akt, GSK-3
β
, and ERK [
16
]. Additionally, co-activation
of Gaba receptor agonists (muscimol and baclofen) resulted in the attenuation of Fas/FasL apoptotic
signaling pathway, inhibition of the kainic acid-induced increase of thioredoxin reductase activity,
the suppression of procaspase-3 activation, and the decrease in caspase-3 cleavage. It indicates
that co-activation of Gaba receptor agonists results in neuroprotection by preventing caspase-3
denitrosylation in kainic acid-induced seizure of rats [17].
Table 1. Neuroprotective eect of Gaba.
STT Source Dose, Model
Time of
Treatment/
Administration
Eect Ref.
1
Kimchi-derived
Lactobacillus
buchneri
100 µg/mL,
neuronal cells 24 h
Preventing
neurotoxic-induced
cell death
[13]
2
Lactobacillus
plantarum-fermented
chickpea milk
537.23 mg/L,
PC12 cells 30 min Preventing
MnCl2-induced injury [14]
3Gaba receptor
agonist
Muscimol (1
mg/kg) and
baclofen (20
mg/kg), rat
30 min
Preventing brain
ischemic injury and
decreasing apoptosis
[15,17]
4Gaba receptor
agonist
Baclofen (10
mL/kg), rat
Once daily/five
weeks
Alleviating neuronal
damage and
suppressing
cytodestructive
autophagy
[16]
Molecules 2019,24, 2678 3 of 23
Molecules 2019, 24, x FOR PEER REVIEW 2 of 23
were mainly focused to emphasize its beneficial role in prevention and treatment of various
diseases.
2. Pharmaceutical Properties of Gaba
2.1. Neuroprotective Effect
It has been reported that the damage of nervous tissue triggers inflammatory response, causing
the release of various inflammatory mediators such as reactive oxygen species (ROS), nitric oxide,
and cytokines. These mediators can cause several neuronal degenerations in the central nervous
system such as Alzheimer’s, Parkinson’s, and multiple sclerosis [11,12]. So far, numerous studies
have been reported regarding the important roles of Gaba on neuro-protection against the
degeneration induced by toxin or injury (Figure 1 and Table 1). According to Cho et al. (2007), Gaba
produced by the kimchi-derived Lactobacillus buchneri exhibited a protective effect against
neurotoxic-induced cell death [13]. Moreover, Gaba-enriched chickpea milk can protect
neuroendocrine PC-12 cells from MnCl2-induced injury, improve cell viability, and reduce lactate
dehydrogenase release [14]. On the other hand, Zhou and colleagues have determined that Gaba
receptor agonists also possessed neuroprotective effect against brain ischemic injury. Both GabaA
and GabaB receptor agonist (muscimol and baclofen) could significantly protect neurons from the
death induced by ischemia through increasing nNOS (Ser847) phosphorylation [15]. Likewise, the
administration of GabaB receptor agonist baclofen significantly alleviated neuronal damage and
suppressed cytodestructive autophagy via up-regulating the ratio of Bcl-2/Bax and increasing the
activation of Akt, GSK-3β, and ERK [16]. Additionally, co-activation of Gaba receptor agonists
(muscimol and baclofen) resulted in the attenuation of Fas/FasL apoptotic signaling pathway,
inhibition of the kainic acid-induced increase of thioredoxin reductase activity, the suppression of
procaspase-3 activation, and the decrease in caspase-3 cleavage. It indicates that co-activation of
Gaba receptor agonists results in neuroprotection by preventing caspase-3 denitrosylation in kainic
acid-induced seizure of rats [17].
Figure 1. Therapeutic targets for neuroprotective activity of Gaba.
Table 1. Neuroprotective effect of Gaba.
STT Source Dose, Model Time of
Treatment/Administration Effect Ref.
1 Kimchi-derived
Lactobacillus buchneri
100 µg/mL,
neuronal cells 24 h
Preventing
neurotoxic-induced
cell death
[13]
2
Lactobacillus
plantarum-fermented
chickpea milk
537.23 mg/L,
PC12 cells 30 min Preventing
MnCl2-induced injury [14]
3 Gaba receptor agonist
Muscimol (1
mg/kg) and
baclofen (20
mg/kg), rat
30 min
Preventing brain
ischemic injury and
decreasing apoptosis
[15,17]
Figure 1. Therapeutic targets for neuroprotective activity of Gaba.
2.2. Neurological Disorder Prevention
Neurologic disorder is associated to dysfunction in part of the brain or nervous system, resulting
in physical or psychological symptoms. It includes epilepsy, Alzheimer’s disease, cerebrovascular
diseases, multiple sclerosis, Parkinson’s disease, neuroinfections, and insomnia [
18
]. It was evidenced
that Gaba can suppress neurodegeneration and improve memory as well as cognitive functions of the
brain (Figure 2and Table 2). According to Okada et al. (2000), the usefulness of Gaba-enriched rice germ
on sleeplessness, depression, and autonomic disorder was examined [
19
]. Twenty female patients were
administered by Gaba-rich rice germ for three times per day. It was observed that the most common
mental symptoms during the menopausal and pre-senile period such as sleeplessness, somnipathy, and
depression were remarkedly improved in more than 65% of the patients with such symptoms. Likewise,
oral administration of Gaba-rich Monascus-fermented product exhibited the protective eect against
depression in the forced swimming rat model. Its antidepressant eect was suggested due to recovering
the level of monoamines norepinephrine, dopamine, and 5-hydroxytryptamine in the hippocampus [
20
].
Meanwhile, Yamatsu et al. (2016) reported that Gaba administration significantly shortened sleep
latency and increased the total non-rapid eye movement sleep time, indicating the essential role of Gaba
in the prevention of a sleep disorder [
21
]. Moreover, the mixture of Gaba and l-theanine could decrease
sleep latency, increase sleep duration, and up-regulate the expression of Gaba and glutamate GluN1
receptor subunit [
22
]. On the other hand, the electroencephalogram assay has revealed the significantly
roles of Gaba in increasing alpha waves, decreasing beta waves, and enhancing IgA levels under
stressful conditions. It indicates that Gaba is able to induce relaxation, diminish anxiety, and enhance
immunity under stressful conditions [
23
]. The administration of Gaba-enriched product fermented by
kimchi-derived lactic acid bacteria also improved long-term memory loss recovery in the cognitive
function-decreased mice and increased the proliferation of neuroendocrine PC-12 cells
in vitro
[
24
].
Moreover, the Gaba-enriched fermented Laminaria japonica (GFL) provided a protective eect against
cognitive impairment associated with dementia in the elderly [
25
]. In addition, Reid and colleagues
have shown that GFL could improve cognitive impairment and neuroplasticity in scopolamine-
and ethanol-induced dementia model mice [
26
]. Especially, GFL was eective in increasing serum
brain-derived neurotrophic factor level that associated with lower risk for dementia and Alzheimer’s
disease in middle-aged women [
27
]. These results indicate that the use of Gaba-enriched functional
foods may improve depression, sleeplessness, cognitive impairment, and memory loss.
Molecules 2019,24, 2678 4 of 23
Molecules 2019, 24, x FOR PEER REVIEW 3 of 23
4 Gaba receptor agonist Baclofen (10
mL/kg), rat Once daily/five weeks
Alleviating neuronal
damage and
suppressing
cytodestructive
autophagy
[16]
2.2. Neurological Disorder Prevention
Neurologic disorder is associated to dysfunction in part of the brain or nervous system,
resulting in physical or psychological symptoms. It includes epilepsy, Alzheimer’s disease,
cerebrovascular diseases, multiple sclerosis, Parkinson’s disease, neuroinfections, and insomnia [18].
It was evidenced that Gaba can suppress neurodegeneration and improve memory as well as
cognitive functions of the brain (Figure 2 and Table 2). According to Okada et al. (2000), the
usefulness of Gaba-enriched rice germ on sleeplessness, depression, and autonomic disorder was
examined [19]. Twenty female patients were administered by Gaba-rich rice germ for three times per
day. It was observed that the most common mental symptoms during the menopausal and
pre-senile period such as sleeplessness, somnipathy, and depression were remarkedly improved in
more than 65% of the patients with such symptoms. Likewise, oral administration of Gaba-rich
Monascus-fermented product exhibited the protective effect against depression in the forced
swimming rat model. Its antidepressant effect was suggested due to recovering the level of
monoamines norepinephrine, dopamine, and 5-hydroxytryptamine in the hippocampus [20].
Meanwhile, Yamatsu et al. (2016) reported that Gaba administration significantly shortened sleep
latency and increased the total non-rapid eye movement sleep time, indicating the essential role of
Gaba in the prevention of a sleep disorder [21]. Moreover, the mixture of Gaba and L-theanine could
decrease sleep latency, increase sleep duration, and up-regulate the expression of Gaba and
glutamate GluN1 receptor subunit [22]. On the other hand, the electroencephalogram assay has
revealed the significantly roles of Gaba in increasing alpha waves, decreasing beta waves, and
enhancing IgA levels under stressful conditions. It indicates that Gaba is able to induce relaxation,
diminish anxiety, and enhance immunity under stressful conditions [23]. The administration of
Gaba-enriched product fermented by kimchi-derived lactic acid bacteria also improved long-term
memory loss recovery in the cognitive function-decreased mice and increased the proliferation of
neuroendocrine PC-12 cells in vitro [24]. Moreover, the Gaba-enriched fermented Laminaria japonica
(GFL) provided a protective effect against cognitive impairment associated with dementia in the
elderly [25]. In addition, Reid and colleagues have shown that GFL could improve cognitive
impairment and neuroplasticity in scopolamine- and ethanol-induced dementia model mice [26].
Especially, GFL was effective in increasing serum brain-derived neurotrophic factor level that
associated with lower risk for dementia and Alzheimer’s disease in middle-aged women [27]. These
results indicate that the use of Gaba-enriched functional foods may improve depression,
sleeplessness, cognitive impairment, and memory loss.
Figure 2. Preventive action of Gaba on neurological disorders.
Figure 2. Preventive action of Gaba on neurological disorders.
Table 2. Neurological disorder prevention of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Eect Ref.
1
Gaba-enriched rice germ
26.4 mg/3
times/day,
patient
N/A
Improving
sleeplessness,
somnipathy, and
depression
[19]
2
Gaba-rich
Monascus-fermented
product
2.6 mg/kg, rat 30 days Preventing
depression [20]
3
Gaba powder from
natural fermentation
using lactic acid bacteria
100 mg
Gaba/day,
Japanese
volunteers
1 week Prevention of sleep
disorder [21]
4
Gaba (90.8%) and
l-theanine (99.3%) was
supplied by Neo Cremar
Co. Ltd. (Seoul, Korea)
and BTC Co. Ltd.
(Ansan, Korea),
respectively
Gaba/L-theanine
mixture (100/20
mg/kg)/day,
mice and rat
9 days
Decreasing sleep
latency and
increasing sleep
duration
[22]
5
Gaba from natural
fermentation using lactic
acid bacteria
(Pharma-GABA, Pharma
Foods International Co.,
Japan)
Gaba/L-theanine
mixture
(100/200
mg/kg)/day
Japanese
volunteers
7 days
Increasing
relaxation,
diminishing
anxiety, and
enhancing
immunity
[23]
6
Gaba-enriched product
fermented by
kimchi-derived lactic
acid bacteria
46.69 mg/mL
Gaba, mice and
PC-12 cells
24 h
Improving
long-term memory
loss and increasing
neuronal cell
proliferation
[24]
7
Gaba-enriched
fermented Laminaria
japonica product
1.5 g/day,
volunteers 6 weeks
Preventing
cognitive
impairment in the
elderly
[25]
2.3. Anti-Hypertensive Eect
Hypertension is known to relate to a high blood pressure condition, causing various cardiovascular
diseases such as ischemic and hemorrhagic stroke, myocardial infarction, and heart and kidney
Molecules 2019,24, 2678 5 of 23
failure [
28
]. Particularly, angiotensin-I converting enzyme (ACE) was revealed to play an important
role in the regulation of blood pressure via converting angiotensin I into the potent vasoconstrictor
angiotensin II [
29
]. Hence, ACE is one of the among therapeutic targets for the control of hypertension.
According to Nejati et al. [
30
], the milk fermented by Lactococcus lactis DIBCA2 and Lactobacillus
plantarum PU11 exhibited an ACE inhibitory activity up to an IC
50
value of 0.70
±
0.07 mg/mL. Similarly,
high ACE inhibitory activity was also observed by Gaba, which was achieved from L. plantarum NTU
102-fermented milk [
31
]. Moreover, L. brevis-fermented soybean containing approximately 1.9 g/kg
Gaba was found to possess higher ACE inhibitory activity than the traditional soybean product [
32
].
Besides, the fermentation of a soybean solution by kimchi-derived lactic acid bacteria in the optimized
condition has achieved a Gaba content of up to 1.3 mg/g soybean seeds, and its ACE inhibitory activity
was observed up to 43% as compared to the control [
33
]. Notably, high Gaba content (10.42 mg/g
extract) and significant ACE inhibitory activity (92% inhibition) was also determined by the fermented
lentils [34].
On the other hand, the anti-hypertensive activity of Gaba was also reported in numerous studies
using dierent experimental models (Table 3). Kimura et al. [
35
] have investigated the eect of
Gaba on blood pressure in spontaneously hypertensive rats. It was observed that the intraduodenal
administration of Gaba (0.3 to 300 mg/kg) caused a dose-related decrease in the blood pressure in 30 to
50 min. The hypotensive eect of Gaba was suggested due to attenuating a sympathetic transmission
through the activation of the Gaba
B
receptor at presynaptic or ganglionic sites. Moreover, the lowering
eect of Gaba-enriched dairy product on the blood pressure of spontaneously hypertensive and
normotensive Wistar-Kyoto rats was also determined [
36
]. Notably, the clinical trial has confirmed
that daily supplementation of 80 mg of Gaba was eective in the reduction of blood pressure in adults
with mild hypertension [
37
]. Therefore, the consumption of Gaba-enriched dairy product would
be beneficial for the down-regulation of hypertension. Indeed, the administration of Gaba-enriched
rice grains brings about 20 mmHg decrease in blood pressure in spontaneously hypertensive rats,
while there was no significant hypotensive eect in normotensive rats [
38
]. Likewise, the significant
anti-hypertensive activity and the serum cholesterol-lowering eect of Gaba-rich brown rice were
shown in spontaneously hypertensive rats as compared to the control [
39
,
40
]. In the clinical trial,
the eects of Gaba-enriched white rice on blood pressure in 39 mildly hypertensive adults has been
examined in a randomized, double blind, placebo-controlled study [
41
]. It was revealed that the
consumption of the Gaba rice could improve the morning blood pressure as compared with the placebo
rice after the 1st week and during the 6th and 8th weeks. In the same trend, Tsai and colleagues have
determined that Gaba-enriched Chingshey purple sweet potato-fermented milk by lactic acid bacteria
(L. acidophilus BCRC 14065, L. delbrueckii ssp. lactis BCRC 12256, and L. gasseri BCRC 14619) was able to
reduce both systolic blood pressure and diastolic blood pressure in spontaneously hypertensive rats [
42
].
The alleviative eect of probiotic-fermented purple sweet potato yogurt on cardiac hypertrophy in
spontaneously hypertensive rat hearts was also further determined by Lin and colleagues [43].
In addition, the other Gaba-rich products from bean, tomato, and bread were also reported to be
eective in the attenuation of hypertension
in vivo
. Definite decreases in systolic and diastolic blood
pressure values and blood urea nitrogen level were achieved in spontaneously hypertensive rats fed
with Gaba-enriched beans [
44
,
45
]. Likewise, the anti-hypertensive activity of a Gaba-rich tomato was
evidenced to decrease blood pressure in spontaneously hypertensive rats significantly [
46
]. Moreover,
the blood pressure of patients with pre- or mild- to moderate hypertension was significantly decreased
during the consumption of 120 g/day of Gaba-rich bread [
47
]. Accordingly, Gaba-enriched dairy foods
may be preferred to use for anti-hypertensive therapeutics.
Molecules 2019,24, 2678 6 of 23
Table 3. Anti-hypertensive eect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Eect Ref.
1
Milk fermented by
Lactococcus lactis DIBCA2
and Lactobacillus
plantarum PU11
0.70 mg/ml 5 min Inhibiting 50%
ACE activity [30]
2Gaba form
LAB-fermented soybean
1.3 mg Gaba/g
soybean 10 min Inhibiting 43%
ACE activity [33]
3
Gaba from the fermented
lentils
10.42 mg
Gaba/g extract 60 min Inhibiting 92%
ACE activity [34]
4Gaba from Wako Pure
Chemicals (Tokyo)
0.3 to 300 mg
Gaba/kg, rat
Every 20 min
for i.v.
administration
Decreasing blood
pressure [35]
5
Gaba from skim cows’
milk fermented with
Lactobacillus casei strain
Shirota and Lactococcus
lactis YIT 2027
5 mL (102 mg
Gaba/kg) of the
fermented
solution/kg
body weight,
rat
10 h Lowering blood
pressure [36]
6Gaba-enriched rice
grains
0.1 mg–0.5 mg
Gaba/kg, rat 6 weeks Decreasing blood
pressure [38]
7
Gaba-enriched white rice
150 g of
Gaba-enriched
white rice (11.2
mg Gaba/100 g
rice),
volunteers
8 weeks Decreasing blood
pressure [41]
8
Gaba-enriched
Chingshey purple sweet
potato-fermented milk
by lactic acid bacteria
2.5-mL dose of
fermented-milk,
rat
8 weeks
Reducing both
systolic blood
pressure and
diastolic blood
pressure
[42]
9
Gaba from
probiotic-fermented
purple sweet potato
yogurt
1500 µg/2.5
mL/kg, rat 8 weeks Alleviating cardiac
hypertrophy [43]
10 Gaba-rich tomato 2–10 g/kg, rat 2–24 h Decreasing blood
pressure [46]
11 Gaba-rich bread 120 g/day,
patient 3 days Decreasing blood
pressure [47]
2.4. Anti-Diabetic Eect
Diabetes is an endocrine disorder that is associated with dysregulation of carbohydrate metabolism
and deficiency of insulin secretion or insulin action, causing chronic hyperglycemia [
48
]. So far, diabetic
diseases can be managed by pharmacologic interventions [
49
]. However, the lowering blood glucose
eect of pharmacological drugs is accompanied with various disadvantages such as drug resistance,
side eects, and even toxicity [
50
]. Therefore, the proper diet and exercise have been recommended
and preferred as alternative therapeutics for the regulation of diabetic diseases. Notably, Gaba and
Gaba-enriched natural products have been evidenced as eective agents in lowering blood glucose,
attenuating insulin resistance, stimulating insulin release, and preventing pancreatic damage (Figure 3
and Table 4). Soltani and colleagues have shown that Gaba enhanced islet cell function via producing
Molecules 2019,24, 2678 7 of 23
membrane depolarization and Ca
(2+)
influx, activating PI3-K/Akt-dependent growth and survival
pathways, and restoring the
β
-cell mass [
51
]. Moreover, Gaba preferentially up-regulated pathways
linked to
β
-cell proliferation and rose to a distinct subpopulation of
β
cells with a unique transcriptional
signature, including urocortin3, wnt4, and hepacam2 [
52
]. Especially, the combined use of Gaba and
sitagliptin was superior in increasing
β
-cell proliferation, reducing cell apoptosis, and suppressing
α
-cell mass [
53
]. On the other hand, Gaba was found to enhance insulin secretion in pancreatic INS-1
β
-cells [
54
]. In the pre-clinical trial model, Gaba administration could decrease the ambient blood
glucose level and improve the glucose excursion rate in streptozotocin-induced diabetic mice [
53
].
Furthermore, oral treatment with Gaba significantly reduced the concentrations of fasting blood
glucose, improved glucose tolerance and insulin sensitivity, and inhibited the body weight gain in the
high fat diet-fed mice [
55
]. Notably, Gaba potentially inhibited the diabetic complication related to the
nervous system via suppressing the Fas-dependent and mitochondrial-dependent apoptotic pathway
in the cerebral cortex [56].
Molecules 2019, 24, x FOR PEER REVIEW 7 of 23
significantly decreased blood glucose and plasma insulin levels, adipokine concentrations, and
hepatic glucose-regulating enzyme activities in ovariectomized rats [62]. Meanwhile, glucose
homeostasis was greatly improved through the intervention of Gaba-enriched wheat bran in the
context of a high-fat diet rat [63]. The supplement of Gaba-enriched rice bran to obese rats also
exhibited an efficient effect on lowering serum sphingolipids, a marker of insulin resistance [64]. In
clinical trials, Ito and colleagues have suggested that the intake of pre-germinated brown rice was
effective in lowering postprandial blood glucose concentration without insulin secretion increase
[65]. Likewise, Hsu et al. [66] and Suzuki et al. [67] have confirmed that pre-germinated brown rice
decreased blood glucose and hypercholesterolemia in type 2 diabetes patients.
Beside germinated rice, fermented foods are also known to contain a significant amount of
Gaba and possess potential anti-diabetic activity. The oral administration of hot water extract of the
fermented tea obtained by tea-rolling processing of loquat (Eriobotrya japonica) significantly
decreased the blood glucose level and serum insulin secretion in maltose-loaded Sprague–Dawley
rats [68]. Similarly, anti-diabetic effects of green tea fermented by cheonggukjang was observed via
decreasing water intake and lowering blood glucose and HbA1c levels in diabetic mice [69]. In
addition, mung bean fermented by Rhizopus sp. [70], yogurt fermented by Streptococcus salivarius
subsp. thermophiles fmb5 [71], and soybean extract fermented by Bacillus subtilis MORI [72] could
enhance their anti-hyperglycemic effect via reducing blood glucose, HbA1c, cholesterol, triglyceride,
and low-density lipoprotein levels in diabetic mice. In the same trend, the milk fermented by
commercial strain YF-L812 (S. thermophilus, L. delbrueckii subsp. bulgaricus), standard strains. B. breve
KCTC 3419, and L. sakei LJ011. Fermented milk was effective in decreasing fasting blood glucose,
serum insulin, leptin, glucose and insulin tolerance, total cholesterol, triglycerides, and low density
lipoprotein cholesterol [73]. Especially, the consumption of probiotic-fermented milk (kefir) by type
2 diabetic patents lowered HbA1C level, homeostatic model assessment of insulin resistance, and
homocysteine amount [74,75]. Accordingly, the germinated rice and fermented foods, which contain
a high amount of Gaba, could be used as anti-diabetic functional food for maintaining health and
preventing complications in type 2 diabetes.
Figure 3. Therapeutic targets for anti-diabetic activity of Gaba.
Table 4. Anti-diabetic effect of Gaba.
STT Source Dose/Model
Time of
Treatment/Ad
ministration
Effect Ref.
1 Gaba (Source: N/A) Dose: N/A,
mice 8–15 weeks
Activating
PI3-K/Akt-dependent
growth and survival
pathways and
restoring the β-cell
mass
[51]
Figure 3. Therapeutic targets for anti-diabetic activity of Gaba.
The fact that the germination of rice and the fermentation of foods are accompanied with the
increase in Gaba content [
57
,
58
], therefore, the pre- and germinated rice and fermented foods were
highly appreciated for their roles in positive regulation of diabetes and its complication. According to
Hagiwara and colleagues, the feeding of pre-germinated brown rice diet to diabetic rats significantly
decreased blood glucose, adipocytokine PAI-1 concentration, and plasma lipid peroxide [
59
]. Moreover,
pre-germinated brown rice lowered HbA(1c) and adipocytokine (TNF-
α
and PAI-1) concentration
and increased the adiponectin level in type-2 diabetic rats, leading to the prevention of potential
diabetic complications [
60
]. In addition, high fat diet-induced diabetic pregnant rats fed with
the germinated brown rice lead to the increase in adiponectin levels and the reduction of insulin,
homeostasis model assessment of insulin resistance, leptin, and oxidative stress in their ospring [
61
].
On the other hand, blackish purple pigmented rice with a giant embryo significantly decreased
blood glucose and plasma insulin levels, adipokine concentrations, and hepatic glucose-regulating
enzyme activities in ovariectomized rats [
62
]. Meanwhile, glucose homeostasis was greatly improved
through the intervention of Gaba-enriched wheat bran in the context of a high-fat diet rat [
63
]. The
supplement of Gaba-enriched rice bran to obese rats also exhibited an ecient eect on lowering serum
sphingolipids, a marker of insulin resistance [
64
]. In clinical trials, Ito and colleagues have suggested
that the intake of pre-germinated brown rice was eective in lowering postprandial blood glucose
concentration without insulin secretion increase [
65
]. Likewise, Hsu et al. [
66
] and Suzuki et al. [
67
]
have confirmed that pre-germinated brown rice decreased blood glucose and hypercholesterolemia in
type 2 diabetes patients.
Beside germinated rice, fermented foods are also known to contain a significant amount of Gaba
and possess potential anti-diabetic activity. The oral administration of hot water extract of the fermented
tea obtained by tea-rolling processing of loquat (Eriobotrya japonica) significantly decreased the blood
glucose level and serum insulin secretion in maltose-loaded Sprague–Dawley rats [
68
]. Similarly,
Molecules 2019,24, 2678 8 of 23
anti-diabetic eects of green tea fermented by cheonggukjang was observed via decreasing water intake
and lowering blood glucose and HbA1c levels in diabetic mice [
69
]. In addition, mung bean fermented
by Rhizopus sp. [
70
], yogurt fermented by Streptococcus salivarius subsp. thermophiles fmb5 [
71
], and
soybean extract fermented by Bacillus subtilis MORI [
72
] could enhance their anti-hyperglycemic eect
via reducing blood glucose, HbA1c, cholesterol, triglyceride, and low-density lipoprotein levels in
diabetic mice. In the same trend, the milk fermented by commercial strain YF-L812 (S. thermophilus,
L. delbrueckii subsp. bulgaricus), standard strains. B. breve KCTC 3419, and L. sakei LJ011. Fermented
milk was eective in decreasing fasting blood glucose, serum insulin, leptin, glucose and insulin
tolerance, total cholesterol, triglycerides, and low density lipoprotein cholesterol [
73
]. Especially, the
consumption of probiotic-fermented milk (kefir) by type 2 diabetic patents lowered HbA1C level,
homeostatic model assessment of insulin resistance, and homocysteine amount [
74
,
75
]. Accordingly,
the germinated rice and fermented foods, which contain a high amount of Gaba, could be used as
anti-diabetic functional food for maintaining health and preventing complications in type 2 diabetes.
Table 4. Anti-diabetic eect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Eect Ref.
1
Gaba (Source: N/A)
Dose: N/A, mice 8–15 weeks
Activating
PI3-K/Akt-dependent
growth and survival
pathways and
restoring the β-cell
mass
[51]
2
Gaba
(MilliporeSigma,
Burlington, MA,
USA)
Gaba (6 mg/mL/day),
mice 10 weeks
Up-regulating β-cell
proliferation and rising
a distinct
subpopulation of β
cells
[52]
3Gaba (Sigma, St.
Louis, USA)
Gaba (2 mg/mL/day),
mice 20 weeks
Reducing the
concentrations of
fasting blood glucose,
improving glucose
tolerance and insulin
sensitivity, and
inhibiting the body
weight gain
[55]
4
Gaba from
pre-germinated
brown rice
Pre-germinated brown
rice (1387–1546 g/day),
rat
7 weeks
Decreasing blood
glucose, adipocytokine
PAI-1 concentration,
and plasma lipid
peroxide
[59]
5
Gaba from
germinated brown
rice
Gaba (200 mg/kg/day),
rat ospring 8 weeks
Increasing adiponectin
levels and reducing
insulin resistance and
oxidative stress
[61]
6
Gaba from blackish
purple pigmented
rice with a giant
embryo
Diet supplemented
with either 20% (w/w)
germinated
Keunnunjami rice
powder, rat
8 weeks
Decreasing blood
glucose and plasma
insulin levels,
adipokine
concentrations, and
hepatic
glucose-regulating
enzyme activities
[62]
7Gaba-enriched
wheat bran
15% Gaba-enriched
bran, rat 8 weeks Improving glucose
homeostasis [63]
Molecules 2019,24, 2678 9 of 23
Table 4. Cont.
STT Source Dose/Model
Time of
Treatment/
Administration
Eect Ref.
8
Gaba from
pre-germinated
brown rice
The test sample
contained 50 g of
available carbohydrate
per day for each
volunteer (185 g of
pre-germinated brown
rice), volunteers
7 weeks
Lowering postprandial
blood glucose
concentration without
insulin secretion
increase
[65]
9
Gaba from
pre-germinated
brown rice
180 g of the cooked
rice/three times per
day, patient
14 weeks
Decreasing blood
glucose and
hypercholesterolemia
[66]
10 Fermented tea
product 50 mg/kg, rat 120 min Decreasing blood
glucose level [68]
11
Mung bean
fermented by
Rhizopus sp.
200 mg/kg and 1000
mg/kg, mice 240 min
Reducing blood
glucose, HbA1c,
cholesterol,
triglyceride, and
low-density
lipoprotein levels
[70]
12
Yogurt fermented
by Streptococcus
salivarius subsp.
Gaba orally at a dose
of 2 g/Lor4g/L6 weeks
Reducing blood
glucose, HbA1c,
cholesterol,
triglyceride, and
low-density
lipoprotein levels
[71]
13
Soybean extract
fermented by
Bacillus subtilis
MORI
500 mg/kg, mice 8 weeks
Reducing blood
glucose, HbA1c,
cholesterol,
triglyceride, and
low-density
lipoprotein levels
[72]
14
Milk fermented by
strain YF-L812 (S.
thermophilus,L.
delbrueckii subsp.
bulgaricus),
standard strains. B.
breve KCTC 3419,
and L. sakei LJ011.
FM
Fermented milk 0.2%
and 0.6%/kg/day, mice 6 weeks
Decreasing fasting
blood glucose, serum
insulin, insulin
tolerance, total
cholesterol,
triglycerides, and LDL
cholesterol
[73]
2.5. Anti-Cancer Eect
Cancer is involved in the unregulated cell proliferation, apoptosis suppression, invasion, and
metastasis [
76
]. Current cancer therapies are related to surgery, radiation treatment, and chemotherapy
treatment, which are widely applied for treatment of all kinds of cancers. However, these therapies
possess major disadvantages including cancer recurrence, drug resistance, and side eects. Hence, the
discovery of alternative medicines with desirable properties is always necessary. In this regard, Gaba
was emerged as a promising compound that is able to regulate cancer due to the induction of apoptosis
and inhibition of proliferation and metastasis (Table 5). Gaba-enriched brown rice extract significantly
retarded the proliferation rates of L1210 and Molt4 leukemia cells and enhanced apoptosis of the
cultured L1210 cells [
77
]. Moreover, Schuller et al. [
78
] suggested that Gaba had a tumor suppressor
function in small airway epithelia and pulmonary adenocarcinoma, providing the approach for the
prevention of pulmonary adenocarcinoma in smokers. According to Huang and colleagues, Gaba
was determined to inhibit the activity and expression of MMP-2 and MMP-9 in cholangiocarcinoma
QBC939 cells, suggesting its role in prevention of invasion and metastasis in cancer [
79
]. Song and
Molecules 2019,24, 2678 10 of 23
colleagues also found the inhibitory eects of Gaba on the proliferation and metastasis of colon
cancer cells (SW480 and SW620 cells) due to the up-pressing cell cycle progression (G2/M or G1/S
phase), attenuating mRNA expression of EGR1-NR4A1 and EGR1-Fos axis, and disrupting MEK-EGR1
signaling pathway [
80
]. Especially, the co-treatment of Gaba and Celecoxib significantly inhibited
systemic and tumor VEGF, PGE
2
, and cAMP molecules and down-regulated COX-2 and p-5-LOX
protein in pancreatic cancer cells [
81
]. Moreover, the prolonged administration of Gaba at 1000 mg/kg
body weight significantly decreased the number of gastric cancers of the glandular stomach in Wk
52 rats. In parallel, the histological method also revealed the role of Gaba on decreasing the labeling
index of the antral mucosa and increasing the serum gastrin level [
82
]. Likewise, the pre-treatment of
Gaba also significantly reduced intrahepatic liver metastasis and primary tumor formation in mice
and inhibited human liver cancer cell migration and invasion via the induction of liver cancer cell
cytoskeletal reorganization [
83
]. Meanwhile, the increase in the activity of Gaba
A
receptor contributed
to the down-regulation of alpha-fetoprotein mRNA expression and cell proliferation in malignant
hepatocyte cell line [84].
Table 5. Anti-cancer eect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Eect Ref.
1Gaba-enriched
brown rice extract
20 µL extract/well (1 ×
105cells/200 mL/well),
leukemia cells and
HeLa cells
48 h
Retarding the
proliferation rates of
leukemia cells and
enhancing apoptosis of
leukemia cells
[77]
2
Gaba from Sigma
Company (St.
Louis, MO, USA)
Gaba (1–1000 µmol/L),
cholangiocarcinoma
QBC939 cells
24 h
Inhibiting the activity
and expression of
MMP-2 and MMP-9
[79]
3
Gaba was
purchased from
Sigma-Aldrich,
Shanghai, China
Gaba (100 µM), Colon
cancer cells 72 h
Inhibiting on cell
proliferation and
metastasis
[80]
4
Gaba from Sigma
Company (St.
Louis, MO, USA)
Gaba (1000 mg/kg), rat 25 weeks
Decreasing the number
of gastric cancers of the
glandular stomach
[82]
5
Gaba from Sigma
Company (St.
Louis, MO, USA)
Gaba (10 µM), Human
liver cancer cells 24 h
Reducing intrahepatic
liver metastasis and
inhibiting human liver
cancer cell migration
and invasion
[83]
2.6. Antioxidant Eect
The free radicals contain one or more unpaired electrons that are generated from the living
organisms and external sources. The high level of free radicals could cause the damage of the body’s
tissues and cells, leading to human aging and various diseases [
85
,
86
]. Thus, consumption of natural
products with high anti-oxidant eect is useful for the prevention of free radical-caused diseases [
86
].
Herein, the antioxidant property of Gaba has been evidenced in numerous studies (Figure 4). It was
shown that Gaba was able to trap the reactive intermediates during lipid peroxidation and react
readily with malondialdehyde under physiological conditions [
87
]. Moreover, the administration of
Gaba significantly decreased malondialdehyde concentration and increased the activity of superoxide
dismutase and glutathione peroxidase in the cerebral cortex and hippocampus of acute epileptic
state rats [
88
]. In other studies, the protective eect of Gaba against H
2
O
2
-induced oxidative stress
in pancreatic cells [
89
] and human umbilical vein endothelial cells [
90
] was observed via reducing
cell death, inhibiting reactive oxygen species (ROS) production, and enhancing antioxidant defense
systems. Similarly, gamma rays-induced oxidative stress in the small intestine of rats was significantly
Molecules 2019,24, 2678 11 of 23
ameliorated via decreasing malondialdehyde and advanced oxidation protein productions, increasing
catalase and glutathione peroxidase activities, preventing mucosal damage and hemorrhage, and
inducing the regeneration of the small intestinal cells [
91
]. Gaba also attenuated brain oxidative
damage associated with insulin alteration in streptozotocin-treated rats [
92
]. On the other hand, Gaba
from L. brevis-fermented sea tangle solution was observed to exhibit stronger antioxidant activity than
positive control BHA in scavenging DPPH and superoxide radicals and inhibiting xanthine oxidase [
93
].
Meanwhile, the Gaba-rich germinated brown rice extract considerably scavenged hydroxyl radical
and thiobarbituric acid-reactive substances in both cell-free medium and post-treatment culture
media, indicating its radical scavenging capacity in both direct and indirect action [
94
]. Recently,
brew-germinated pigmented rice vinegar was also suggested as a new product with high antioxidant
activity [95].
Molecules 2019, 24, x FOR PEER REVIEW 11 of 23
reducing cell death, inhibiting reactive oxygen species (ROS) production, and enhancing antioxidant
defense systems. Similarly, gamma rays-induced oxidative stress in the small intestine of rats was
significantly ameliorated via decreasing malondialdehyde and advanced oxidation protein
productions, increasing catalase and glutathione peroxidase activities, preventing mucosal damage
and hemorrhage, and inducing the regeneration of the small intestinal cells [91]. Gaba also
attenuated brain oxidative damage associated with insulin alteration in streptozotocin-treated rats
[92]. On the other hand, Gaba from L. brevis-fermented sea tangle solution was observed to exhibit
stronger antioxidant activity than positive control BHA in scavenging DPPH and superoxide
radicals and inhibiting xanthine oxidase [93]. Meanwhile, the Gaba-rich germinated brown rice
extract considerably scavenged hydroxyl radical and thiobarbituric acid-reactive substances in both
cell-free medium and post-treatment culture media, indicating its radical scavenging capacity in
both direct and indirect action [94]. Recently, brew-germinated pigmented rice vinegar was also
suggested as a new product with high antioxidant activity [95].
Figure 4. Modulatory activity of Gaba for antioxidant promotion.
2.7. Anti-Inflammatory Effect
Inflammation response is triggered by the stimulation of various factors such as physical
damage, ultra violet irradiation, microbial invasion, and immune reactions [96]. It is associated with
the production of a large range of pro-inflammatory mediators such cytokine, NO, and PGE2 [97].
Notably, Gaba was indicated as an inhibitor of inflammation via decreasing pro-inflammatory
mediator production and ameliorating inflammatory symptom (Figure 5). At the early time, Han et
al. [98] have determined the anti-inflammatory activity of Gaba via inhibiting the production and
expression of iNOS, IL-1β, and TNF-α in LPS-stimulated RAW 264.7 cells. As the result, it
contributed to the reduction of the whole healing period and enhancement of wound healing at the
early stage. Likewise, Gaba suppressed inflammatory cytokine production and NF-kB inhibition in
both lymphocytes and pancreatic islet beta cells [99]. Recently, Gaba-enriched sea tangle L. japonica,
Gaba-rich germinated brown rice, and Gaba-rich red microalgae Rhodosorus marinus were reported
for their inhibitory capacities on inflammatory response. Gaba-enriched sea tangle L. japonica extract
suppressed nitric oxide production and inducible nitric oxide synthase expression in LPS-induced
mouse macrophage RAW 264.7 cells [100]. Gab-rich germinated brown rice inhibited IL-8 and
MCP-1 secretion and ROS production from Caco-2 human intestinal cells activated by H2O2 and
IL-1β [101]. Gaba-rich red microalgae Rhodosorus marinus extract negatively modulated expression
and release of pro-inflammatory IL-1α in phorbol myristate acetate-stimulated normal human
keratinocytes, therefore indicating the potential treatment of sensitive skins, atopia, and dermatitis
[102]. Besides, the roles of Gaba in the attenuation of gut inflammation and improvement of gut
epithelial barrier were suggested via inhibiting IL-8 production and stimulating the expression of
tight junction proteins as well as the expression of TGF-β cytokine in Caco-2 cells [103].
Figure 4. Modulatory activity of Gaba for antioxidant promotion.
2.7. Anti-Inflammatory Eect
Inflammation response is triggered by the stimulation of various factors such as physical damage,
ultra violet irradiation, microbial invasion, and immune reactions [
96
]. It is associated with the
production of a large range of pro-inflammatory mediators such cytokine, NO, and PGE
2
[
97
]. Notably,
Gaba was indicated as an inhibitor of inflammation via decreasing pro-inflammatory mediator
production and ameliorating inflammatory symptom (Figure 5). At the early time, Han et al. [
98
]
have determined the anti-inflammatory activity of Gaba via inhibiting the production and expression
of iNOS, IL-1
β
, and TNF-
α
in LPS-stimulated RAW 264.7 cells. As the result, it contributed to the
reduction of the whole healing period and enhancement of wound healing at the early stage. Likewise,
Gaba suppressed inflammatory cytokine production and NF-kB inhibition in both lymphocytes and
pancreatic islet beta cells [
99
]. Recently, Gaba-enriched sea tangle L. japonica, Gaba-rich germinated
brown rice, and Gaba-rich red microalgae Rhodosorus marinus were reported for their inhibitory
capacities on inflammatory response. Gaba-enriched sea tangle L. japonica extract suppressed nitric
oxide production and inducible nitric oxide synthase expression in LPS-induced mouse macrophage
RAW 264.7 cells [
100
]. Gab-rich germinated brown rice inhibited IL-8 and MCP-1 secretion and ROS
production from Caco-2 human intestinal cells activated by H
2
O
2
and IL-1
β
[
101
]. Gaba-rich red
microalgae Rhodosorus marinus extract negatively modulated expression and release of pro-inflammatory
IL-1
α
in phorbol myristate acetate-stimulated normal human keratinocytes, therefore indicating the
potential treatment of sensitive skins, atopia, and dermatitis [
102
]. Besides, the roles of Gaba in
the attenuation of gut inflammation and improvement of gut epithelial barrier were suggested via
inhibiting IL-8 production and stimulating the expression of tight junction proteins as well as the
expression of TGF-βcytokine in Caco-2 cells [103].
Molecules 2019,24, 2678 12 of 23
Molecules 2019, 24, x FOR PEER REVIEW 12 of 23
Figure 5. Therapeutic targets for anti-inflammatory activity of Gaba.
2.8. Anti-Microbial Effect
Gaba tea is a kind of Gaba-enriched tea by the repeating treatments of alternative anaerobic and
aerobic conditions. The Gaba tea extract exhibited inhibitory activity against Vibrio parahaemolyticus,
Staphylococcus aureus, Bacillus cereus, Salmonella typhimurium, and Escherichia coli [104]. Gaba could
increase Pseudomonas aeruginosa virulence due to stimulation of cyanogenesis, reduction in oxygen
accessibility, and overexpression of oxygen-scavenging proteins. Gaba also promotes specific
changes in the expression of thermostable and unstable elongation factors involved in the interaction
of the bacterium with the host proteins [105]. Recently, the role of Gaba in anti-microbial host
defenses was elucidated by Kim and colleagues [106]. Treatment of macrophages with Gaba
enhanced phagosomal maturation and anti-microbial responses against mycobacterial infection.
This study identified the role of Gabaergic signaling in linking anti-bacterial autophagy to enhance
host innate defense against intracellular bacterial infection including Mycobacteria, Salmonella, and
Listeria.
2.9. Anti-Allergic Effect
Allergy is a disorder of the immune system associating with an exaggerated reaction of the
immune system to harmless environmental substances. Allergic reaction is characterized by the
excessive activation of mast cells and basophils, leading to release various mediators such as
histamine and an array of cytokines [107]. Among them, histamine is considered as the major target
for potential anti-allergic therapeutics. Herein, the inhibitory activity of Gaba on histamine release
from the activated mast cells was investigated in vitro [108,109]. Rat basophilic leukemia cells and
rat peritoneal exudate cells sensitized with anti-dinitrophenyl (DNP) IgE and challenged with
DNP-conjugated bovine serum albumin resulted in the release of histamine in a cell culture medium.
However, IgE-mediated histamine release was inhibited by Gaba treatment in both cells.
Conversely, the inhibitory activities of Gaba were lowered by the addition of CGP35348, a GabaB
receptor antagonist. It indicated that Gaba inhibited degranulation from basophils and mast cells via
GabaB receptor on the cell surface. On the other hand, Hokazono et al. [110] have evaluated the
protective effect of Gaba against the development of atopic dermatitis (AD)-like skin lesions in
NC/Nga mice. It was observed that Gaba could prevent the development of AD-like skin lesions in
mice via alleviating serum immunoglobulin E (IgE) and splenocyte IL-4 production. The combined
administration of Gaba and the fermented barley extract remarkedly increased splenic cell
interferon-γ production, indicating the domination of Th1/Th2 balance to Th1 response. Hence, the
simultaneous intake of Gaba and the fermented barley extract was encouraged to ameliorate allergic
symptoms such as atopic dermatitis (Figure 6).
Figure 5. Therapeutic targets for anti-inflammatory activity of Gaba.
2.8. Anti-Microbial Eect
Gaba tea is a kind of Gaba-enriched tea by the repeating treatments of alternative anaerobic and
aerobic conditions. The Gaba tea extract exhibited inhibitory activity against Vibrio parahaemolyticus,
Staphylococcus aureus, Bacillus cereus, Salmonella typhimurium, and Escherichia coli [
104
]. Gaba could
increase Pseudomonas aeruginosa virulence due to stimulation of cyanogenesis, reduction in oxygen
accessibility, and overexpression of oxygen-scavenging proteins. Gaba also promotes specific changes
in the expression of thermostable and unstable elongation factors involved in the interaction of the
bacterium with the host proteins [
105
]. Recently, the role of Gaba in anti-microbial host defenses was
elucidated by Kim and colleagues [
106
]. Treatment of macrophages with Gaba enhanced phagosomal
maturation and anti-microbial responses against mycobacterial infection. This study identified the
role of Gabaergic signaling in linking anti-bacterial autophagy to enhance host innate defense against
intracellular bacterial infection including Mycobacteria, Salmonella, and Listeria.
2.9. Anti-Allergic Eect
Allergy is a disorder of the immune system associating with an exaggerated reaction of the
immune system to harmless environmental substances. Allergic reaction is characterized by the
excessive activation of mast cells and basophils, leading to release various mediators such as histamine
and an array of cytokines [
107
]. Among them, histamine is considered as the major target for potential
anti-allergic therapeutics. Herein, the inhibitory activity of Gaba on histamine release from the activated
mast cells was investigated
in vitro
[
108
,
109
]. Rat basophilic leukemia cells and rat peritoneal exudate
cells sensitized with anti-dinitrophenyl (DNP) IgE and challenged with DNP-conjugated bovine
serum albumin resulted in the release of histamine in a cell culture medium. However, IgE-mediated
histamine release was inhibited by Gaba treatment in both cells. Conversely, the inhibitory activities
of Gaba were lowered by the addition of CGP35348, a Gaba
B
receptor antagonist. It indicated that
Gaba inhibited degranulation from basophils and mast cells via Gaba
B
receptor on the cell surface.
On the other hand, Hokazono et al. [
110
] have evaluated the protective eect of Gaba against the
development of atopic dermatitis (AD)-like skin lesions in NC/Nga mice. It was observed that Gaba
could prevent the development of AD-like skin lesions in mice via alleviating serum immunoglobulin
E (IgE) and splenocyte IL-4 production. The combined administration of Gaba and the fermented
barley extract remarkedly increased splenic cell interferon-
γ
production, indicating the domination of
Th1/Th2 balance to Th1 response. Hence, the simultaneous intake of Gaba and the fermented barley
extract was encouraged to ameliorate allergic symptoms such as atopic dermatitis (Figure 6).
Molecules 2019,24, 2678 13 of 23
Molecules 2019, 24, x FOR PEER REVIEW 13 of 23
Figure 6. Therapeutic targets for anti-allergic activity of Gaba.
2.10. Hepatoprotective Effect
The long-term use of ethanol can cause liver damage and unfavorable lipid profiles in humans.
The toxic acetaldehyde is formed from alcohol under catalysis of alcohol dehydrogenase, causing
various adverse effects such as thirst, vomiting, fatigue, headache, and abdominal pain [111]. For the
first time, Oh and colleagues have evaluated the protective effect of Gaba-rich germinated brown
rice against the toxic consequences of chronic ethanol use [112]. Interestingly, serum low-density
lipoprotein cholesterol, liver aspartate aminotransferase, and liver alanine aminotransferase levels
were decreased in mice fed both ethanol and brown rice extract for 30 days. Furthermore, the brown
rice extract significantly increased serum and liver high-density lipoprotein cholesterol
concentrations and reduced liver triglyceride and total cholesterol concentrations. In the same trend,
Lee et al. [113] have reported that Gaba-rich fermented sea tangle (GFST) could prevent ethanol and
carbon tetrachloride-induced hepatotoxicity in rats. The oral administration of GFST decreased the
serum levels of glutamic pyruvate transaminase, gamma glutamyl transpeptidase, and
malondialdehyde levels and increased antioxidant enzyme such as superoxide dismutase, catalase,
and glutathione peroxidase [113]. Moreover, GFST increased the activities and transcript levels of
major alcohol-metabolizing enzymes, such as alcohol dehydrogenase and aldehyde dehydrogenase,
and reduced blood concentrations of alcohol and acetaldehyde [114]. In an in vitro study, the
protective effects of GFST against alcohol hepatotoxicity in ethanol-exposed HepG2 cells were
revealed by preventing intracellular glutathione depletion, decreasing gamma-glutamyl
transpeptidase activity, and suppressing cytochrome P450 2E1 enzyme expression [115]. These
results indicated that Gaba-rich foods might have a pharmaceutical role in the prevention of chronic
alcohol-related diseases (Figure 7).
Figure 7. Mechanism of the action of Gaba for hepatoprotection.
Figure 6. Therapeutic targets for anti-allergic activity of Gaba.
2.10. Hepatoprotective Eect
The long-term use of ethanol can cause liver damage and unfavorable lipid profiles in humans. The
toxic acetaldehyde is formed from alcohol under catalysis of alcohol dehydrogenase, causing various
adverse eects such as thirst, vomiting, fatigue, headache, and abdominal pain [
111
]. For the first time,
Oh and colleagues have evaluated the protective eect of Gaba-rich germinated brown rice against
the toxic consequences of chronic ethanol use [
112
]. Interestingly, serum low-density lipoprotein
cholesterol, liver aspartate aminotransferase, and liver alanine aminotransferase levels were decreased
in mice fed both ethanol and brown rice extract for 30 days. Furthermore, the brown rice extract
significantly increased serum and liver high-density lipoprotein cholesterol concentrations and reduced
liver triglyceride and total cholesterol concentrations. In the same trend, Lee et al. [
113
] have reported
that Gaba-rich fermented sea tangle (GFST) could prevent ethanol and carbon tetrachloride-induced
hepatotoxicity in rats. The oral administration of GFST decreased the serum levels of glutamic pyruvate
transaminase, gamma glutamyl transpeptidase, and malondialdehyde levels and increased antioxidant
enzyme such as superoxide dismutase, catalase, and glutathione peroxidase [
113
]. Moreover, GFST
increased the activities and transcript levels of major alcohol-metabolizing enzymes, such as alcohol
dehydrogenase and aldehyde dehydrogenase, and reduced blood concentrations of alcohol and
acetaldehyde [
114
]. In an
in vitro
study, the protective eects of GFST against alcohol hepatotoxicity
in ethanol-exposed HepG
2
cells were revealed by preventing intracellular glutathione depletion,
decreasing gamma-glutamyl transpeptidase activity, and suppressing cytochrome P450 2E1 enzyme
expression [
115
]. These results indicated that Gaba-rich foods might have a pharmaceutical role in the
prevention of chronic alcohol-related diseases (Figure 7).
Molecules 2019, 24, x FOR PEER REVIEW 13 of 23
Figure 6. Therapeutic targets for anti-allergic activity of Gaba.
2.10. Hepatoprotective Effect
The long-term use of ethanol can cause liver damage and unfavorable lipid profiles in humans.
The toxic acetaldehyde is formed from alcohol under catalysis of alcohol dehydrogenase, causing
various adverse effects such as thirst, vomiting, fatigue, headache, and abdominal pain [111]. For the
first time, Oh and colleagues have evaluated the protective effect of Gaba-rich germinated brown
rice against the toxic consequences of chronic ethanol use [112]. Interestingly, serum low-density
lipoprotein cholesterol, liver aspartate aminotransferase, and liver alanine aminotransferase levels
were decreased in mice fed both ethanol and brown rice extract for 30 days. Furthermore, the brown
rice extract significantly increased serum and liver high-density lipoprotein cholesterol
concentrations and reduced liver triglyceride and total cholesterol concentrations. In the same trend,
Lee et al. [113] have reported that Gaba-rich fermented sea tangle (GFST) could prevent ethanol and
carbon tetrachloride-induced hepatotoxicity in rats. The oral administration of GFST decreased the
serum levels of glutamic pyruvate transaminase, gamma glutamyl transpeptidase, and
malondialdehyde levels and increased antioxidant enzyme such as superoxide dismutase, catalase,
and glutathione peroxidase [113]. Moreover, GFST increased the activities and transcript levels of
major alcohol-metabolizing enzymes, such as alcohol dehydrogenase and aldehyde dehydrogenase,
and reduced blood concentrations of alcohol and acetaldehyde [114]. In an in vitro study, the
protective effects of GFST against alcohol hepatotoxicity in ethanol-exposed HepG2 cells were
revealed by preventing intracellular glutathione depletion, decreasing gamma-glutamyl
transpeptidase activity, and suppressing cytochrome P450 2E1 enzyme expression [115]. These
results indicated that Gaba-rich foods might have a pharmaceutical role in the prevention of chronic
alcohol-related diseases (Figure 7).
Figure 7. Mechanism of the action of Gaba for hepatoprotection.
Figure 7. Mechanism of the action of Gaba for hepatoprotection.
Molecules 2019,24, 2678 14 of 23
2.11. Renoprotective Eect
Acute kidney injury is involved in kidney damage and cell death, causing high morbidity and
mortality worldwide [
116
]. The renoprotective agents derived from natural products may be essential
for the prevention or treatment of kidney injury-related diseases. Indeed, numerous studies have
evidenced the protective eect of Gaba against acute kidney injury (Figure 8). According to Kim et al.
(2004), the physiological changes caused by acute renal failure such as body weight and kidney weight
gain, urea nitrogen and creatinine elevation, creatinine clearance reduction, sodium FE(Na) secretion,
and urine osmolarity decrease in rats were significantly improved by oral administration of Gaba [
117
].
Moreover, the status of serum albumin decrease, urinary protein increase, and serum lipid profile
was completely improved by Gaba. In addition, Gaba alleviated nephrectomy-induced oxidative
stress by increasing superoxide dismutase and catalase, and decreasing lipid peroxidation in rats [
118
].
Furthermore, Gaba reduced tubular fibrosis, tubular atrophy, and the transforming growth factor-beta1
and fibronectin expression [
119
]. The acute tubular necrosis was also apparently reduced to normal
proximal condition by Gaba treatment [
120
]. In another study, Talebi and colleagues have shown the
protective eect of Gaba on kidney injury induced by renal ischemia-reperfusion in ovariectomized rats
via decreasing serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue
damage [
121
]. Meanwhile, the increases in alanine amino transferase and aspartate amino transferase
activities, urea and creatinine levels, malondialdehyde and advanced oxidation protein levels, and
oxidative damage to the kidney tissues induced by
γ
-irradiated- and streptozotocin-treated rats were
markedly attenuated by Gaba administration in rats [
122
]. Especially, Gaba was observed to ameliorate
kidney injury induced by renal ischemia/reperfusion injury in a gender dependent manner [
123
]. These
results emphasized the protective eect of Gaba against the renal damage involving in renal failure.
Molecules 2019, 24, x FOR PEER REVIEW 14 of 23
2.11. Renoprotective Effect
Acute kidney injury is involved in kidney damage and cell death, causing high morbidity and
mortality worldwide [116]. The renoprotective agents derived from natural products may be
essential for the prevention or treatment of kidney injury-related diseases. Indeed, numerous studies
have evidenced the protective effect of Gaba against acute kidney injury (Figure 8). According to
Kim et al. (2004), the physiological changes caused by acute renal failure such as body weight and
kidney weight gain, urea nitrogen and creatinine elevation, creatinine clearance reduction, sodium
FE(Na) secretion, and urine osmolarity decrease in rats were significantly improved by oral
administration of Gaba [117]. Moreover, the status of serum albumin decrease, urinary protein
increase, and serum lipid profile was completely improved by Gaba. In addition, Gaba alleviated
nephrectomy-induced oxidative stress by increasing superoxide dismutase and catalase, and
decreasing lipid peroxidation in rats [118]. Furthermore, Gaba reduced tubular fibrosis, tubular
atrophy, and the transforming growth factor-beta1 and fibronectin expression [119]. The acute
tubular necrosis was also apparently reduced to normal proximal condition by Gaba treatment [120].
In another study, Talebi and colleagues have shown the protective effect of Gaba on kidney injury
induced by renal ischemia-reperfusion in ovariectomized rats via decreasing serum levels of
creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage [121]. Meanwhile, the
increases in alanine amino transferase and aspartate amino transferase activities, urea and creatinine
levels, malondialdehyde and advanced oxidation protein levels, and oxidative damage to the kidney
tissues induced by γ-irradiated- and streptozotocin-treated rats were markedly attenuated by Gaba
administration in rats [122]. Especially, Gaba was observed to ameliorate kidney injury induced by
renal ischemia/reperfusion injury in a gender dependent manner [123]. These results emphasized
the protective effect of Gaba against the renal damage involving in renal failure.
Figure 8. Mechanism of the action of Gaba for renoprotection.
2.12. Intestinal Protective Effect
Chen and colleagues have examined the beneficial roles of Gaba on intestinal mucosa in vivo
[124,125]. It was shown that heat stress-induced chicken decreased the activity of Na-K-ATPase,
maltase, sucrase, and alkaline phosphatase enzymes in intestinal mucosa [124]. Moreover, heat
stress caused the marked decline in villus length, mucosa thickness, intestinal wall thickness, and
crypt depth in the duodenum and ileum [125]. However, the treatment of Gaba administration
markedly increased the activity of maltase, sucrase, alkaline phosphatase, and Na-K-ATPase [124].
Furthermore, Gaba enhanced villus length, mucosa thickness, intestinal wall thickness, and crypt
depth in the duodenum and ileum [125]. It indicated that Gaba could effectively alleviate heat
stress-induced damages of the intestinal mucosa. In a further study, they investigated the effect of
Gaba supplementation on the growth performance, intestinal immunity, and gut microflora of the
weaned piglets [126]. Notably, Gaba supplementation improved the growth performance, inhibited
proinflammatory cytokines (IL-1 and IL-18) expression, promoted anti-inflammatory cytokines
Figure 8. Mechanism of the action of Gaba for renoprotection.
2.12. Intestinal Protective Eect
Chen and colleagues have examined the beneficial roles of Gaba on intestinal mucosa
in vivo [124,125]
. It was shown that heat stress-induced chicken decreased the activity of
Na
+
-K
+
-ATPase, maltase, sucrase, and alkaline phosphatase enzymes in intestinal mucosa [
124
].
Moreover, heat stress caused the marked decline in villus length, mucosa thickness, intestinal
wall thickness, and crypt depth in the duodenum and ileum [
125
]. However, the treatment of
Gaba administration markedly increased the activity of maltase, sucrase, alkaline phosphatase, and
Na
+
-K
+
-ATPase [
124
]. Furthermore, Gaba enhanced villus length, mucosa thickness, intestinal wall
thickness, and crypt depth in the duodenum and ileum [
125
]. It indicated that Gaba could eectively
alleviate heat stress-induced damages of the intestinal mucosa. In a further study, they investigated the
eect of Gaba supplementation on the growth performance, intestinal immunity, and gut microflora of
the weaned piglets [
126
]. Notably, Gaba supplementation improved the growth performance, inhibited
Molecules 2019,24, 2678 15 of 23
proinflammatory cytokines (IL-1 and IL-18) expression, promoted anti-inflammatory cytokines (IFN-
γ
,
IL-4, and IL-10) expression, and increased the dominant microbial populations, the community richness,
and diversity of the ileal microbiota. On the other hand, Xie and colleagues also investigated the eect
of Gaba on colon health in mice [
127
]. It was observed that the female Kunming mice administrated
with Gaba at doses of 40 mg/kg/d for 14 days could increase the concentrations of acetate, propionate,
butyrate, and total short chain fatty acids, and decreased pH value in colonic and cecal contents.
Recently, Kubota and colleagues have revealed that Gaba attenuated ischemia reperfusion-induced
alterations in intestinal immunity via increasing IgA secretion, alpha-defensin-5 expression, and
superoxide dismutase activity in the rat small intestine [
128
]. Besides, Jiang and colleagues also
showed the protective eect of Gaba against intestinal mucosal barrier injury of colitis induced by
2,4,6-trinitrobenzene sulfonic acid and alcohol [
129
]. These results have evidenced the physiological
function of Gaba in improvement and promotion of intestinal health.
2.13. Other Pharmaceutical Properties
Yang et al. [
130
] have examined the modulatory eects of Gaba on
cholesterol-metabolism-associated molecules in human monocyte-derived macrophages (HMDMs).
It was found that Gaba was eective in the reduction of cholesterol ester in lipid-laden HMDMs
via suppressing the expression of scavenger receptor class A, lectin-like oxidized low-density
lipoprotein receptor-1, and CD36, and promoting the expression of ATP-binding cassette transporter 1,
ATP-binding cassette sub-family G member 1, and scavenger receptor class B type I. Moreover, the
production of TNF-
α
was decreased and the activation of signaling pathways (p38MAPK and NF-
κ
B)
was repressed in the presence of Gaba. The inhibitory eect of Gaba on the formation of human
macrophage-derived foam cells suggests its role in the prevention of atherosclerotic lesions.
Yang et al. [
131
] have investigated whether Gaba ameliorate fluoride-induced a thyroid injury
in vivo
. The model of hypothyroidism was conducted by exposing NaF (50 mg/kg) to adult male mice
for 30 days. Thereafter, thyroid hormone production, oxidative stress, thyroid function-associated
genes, and side eects during therapy were measured. Interestingly, Gaba supplementation remarkedly
promoted the expression of thyroid thyroglobulin, thyroid peroxidase, and sodium/iodide symporter.
Moreover, it improved the thyroid redox state, the expression of thyroid function-associated genes,
and liver metabolic protection. These findings indicate that Gaba has a therapeutic potential
in hypothyroidism.
In regarding to the growth hormone, the oral administration of Gaba was reported to elevate the
resting and post-exercise immunoreactive growth hormone and immunofunctional growth hormone
concentrations in humans [
132
]. Moreover, the administration of Gaba is likely to increase the
concentrations of plasma growth hormone and the rate of protein synthesis in the rat brain [
133
,
134
].
Recently, the role of Gaba in the enhancement of muscular hypertrophy in men after progressive
resistance training was also evaluated by Sakashita and colleagues [
135
]. They found that the
combination of Gaba and whey protein was eective in increasing whole body fat-free mass, thus
enhancing exercise-induced muscle hypertrophy.
Indeed, the excessive production of free radicals and oxidants causes oxidative stress that damages
cell membranes and other structures such as DNA, lipids, and proteins [
136
]. Particularly, the damage
of cell membranes and lipoproteins by hydroxyl and peroxynitrite radicals causes lipid peroxidation
and formation of cytotoxic and mutagenic agents such as malondialdehyde and conjugated diene
compounds [
137
]. Moreover, the free radicals and oxidants can change protein structure and lose enzyme
activity. Various mutations may also result from oxidants-induced DNA damages. Therefore, oxidative
stress can induce a variety of chronic and degenerative diseases such as cancer, cardiovascular disease,
neurological disease, pulmonary disease, rheumatoid arthritis, nephropathy, and ocular disease [
138
]. In
this sense, antioxidants play an important role in the neutralization of free radicals, protection of the cells
from toxic eects, and prevention of disease pathogenesis [
139
]. As a result, the antioxidant activity of
Gaba may partly contribute to its biological eects such as anti-hypertension, anti-diabetes, anti-cancer,
Molecules 2019,24, 2678 16 of 23
antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and
intestinal protection.
3. Conclusions
The fact that consumers have paid much attention to natural products in order to promote and
maintain their health. Simultaneously, various functional foods derived from natural products have
been developed along with the tendency of consumers. Herein, Gaba has been evidenced as a powerful
bioactive compound with numerous health beneficial eects. Thus, the functional foods produced from
Gaba are believed to be able to prevent and/or treat dierent diseases, especially hypertension, diabetes,
and neurological disorders. Whereby, the researches into large-scale production, biotechnological
techniques, and high Gaba-producing strains will be remarkedly increased in food industry. However,
the further testing and validation due to the safety and ecacy of Gaba consumption are necessary in
clinical trials.
Author Contributions:
We declare that this review was done by the authors named in this article. The review was
conceived and designed by D.-H.N. The data were collected and analyzed by D.-H.N. and T.S.V. The manuscript
was written by T.S.V. All authors read and approved the manuscript for publication.
Funding:
This research is funded by Vietnam National Foundation for Science and Technology Development
(NAFOSTED) under grant number 106.02-2018.304.
Acknowledgments:
This review is also supported by Nguyen Tat Thanh University, Ho Chi Minh city, Vietnam
and Thu Dau Mot University, Binh Duong province, Vietnam.
Conflicts of Interest: There are no conflicts to declare.
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... In humans, it is a major inhibitory neurotransmitter in the central nervous system that regulates internal neuronal communication but also acts as a muscle relaxant during sleep and in setting overall muscle tone (23). It is also an antioxidant and anti-in ammatory amino acid (24). Our previous studies have shown that GABA has potential for early prevention of post-menopausal osteoporosis (15). ...
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Background: Physical activity maintains musculoskeletal and general overall health. Declining physical performance is the most obvious indicator of declining health with aging. Early identification of declining physical performance using biomarkers would be useful in predicting treatment outcomes and identifying potential therapeutics. Method: As γ-aminobutyric acid (GABA), a muscle autocrine factor, can function as muscle relaxant and L-α-aminobutyric acid (L-AABA), is a biomarker for malnutrition, and depression, we sought to determine if they may also be useful for monitoring physical performance during aging. Serum levels were quantified in 120 individuals divided by age, gender, and physical capacity into low (LP), average (AP), and high (HP) performers and correlated with physical parameters and performance. Results: Both GABA and the ratio of GABA/AABA (G/A), but not AABA, were highly positively associated with age (Pearson correlations r=0.35, p=0.0001 for GABA, and r=0.31, p=0.0007 for G/A, n=120). GABA showed negative associations in the whole cohort with physical performance (fast gait speed, 6 minute walking test (6MWT), PROMIS score, and SF36 PFS raw score) and with subtotal and femoral neck bone mineral density (BMD). L-AABA was positively associated with usual gait speed, 6MWT, total SPPB score, and SF36 PFS raw score in total 120 human subjects, also with 6MWT and SF36 PFS raw score in the 60 male subjects, but no associations were observed in the 60 females. As both GABA and L-AABA appear to be indicative of physical performance, but in opposite directions, we examined the G/A ratio. Unlike GABA, the G/A ratio showed a more distinct association with mobility tests such as total SPPB score, usual and fast gait speed, 6MWT, and SF36 PFS raw score in the males, regardless of age and metabolic status. Serum G/A ratio could be potentially linked to physical performance in the male population. Conclusions: All these findings strongly suggest that GABA, L-AABA, and the G/A ratio in human serum may be useful markers to link with age and physical function. Taking these aminobutyric acids into consideration may significantly enhance the goal of identifying universal biomarkers to accurately predict physical performance and the beneficial effects of exercise on aging.
... It is the main inhibitory neurotransmitter in the brain and plays an important role in brain metabolism (9). In recent years, with the deepening of research, many physiological functions such as anti-anxiety, calming nerves and lowering blood pressure of γ-aminobutyric acid (GABA) have been revealed continuously, and GABA has good thermal stability and safety, which has become a potential new food functional factor and plays an irreplaceable role in the regulation of life activities (10). However, the content of GABA in higher plants is very low, only 0.03-2.00 ...
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In order to study the nutritional changes of γ-aminobutyric acid (GABA) enrichment in adzuki bean germination, vacuum combined with monosodium glutamate (MSG) was used as the germination stress of adzuki bean. The nutrient transfer before and after GABA enrichment in adzuki bean germination under vacuum combined with MSG stress were studied by means of chromatography and scanning electron microscope (SEM). The antioxidant activity and hypoglycemic effect of different solvent extracts before and after germination of adzuki bean were evaluated by experiments in vitro. The results showed that the nutritional characteristics of adzuki bean rich in GABA changed significantly ( P < 0.05), the total fatty acids decreased significantly ( P < 0.05), and the 21 amino acids detected increased significantly. After germination, the starch granules of adzuki bean became smaller and the surface was rough Germination stress significantly increased the antioxidant and hypoglycemic activities of the extracts from different solvents ( P < 0.05), and the water extracts had the best effect on DPPH and ⋅OH radical scavenging rates of 88.52 and 83.56%, respectively. The results indicated that the germinated adzuki bean rich in GABA was more nutritious than the raw adzuki bean and had good antioxidant activity. It hoped to provide technical reference for rich food containing GABA.
... Based on current strategies for the importance of functional-fermented foods, fermented CM could serve as a potential source of bioactive nutrients for the management of various diseases [32]. Our previous work highlighted the modulatory effects of CM enriched with Bacillus amyloliquefaciens (BA) on proinflammatory cytokines including interleukin-1β (IL1β), interleukin 6 (IL6), interleukin 8 (IL8), and tumor necrosis factor alpha (TNF-α) in induced IBS in a mice model [28]. It is thus of interest to study CM fortified with BA, as an example of a probiotic that could offer a complementary approach for the management of MS. ...
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Multiple sclerosis (MS), a distinct autoimmune neuroinflammatory disorder, affects millions of people worldwide, including Saudi Arabia. Changes in the gut microbiome are linked to the development of neuroinflammation via mechanisms that are not fully understood. Prebiotics and probiotics in camel milk that has been fermented have a variety of health benefits. In this study, Bacillus amyloliquefaciens-supplemented camel milk (BASY) was used to assess its preventive effect on MS symptoms in a myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL6J mice model. To this end, MOG-induced experimental autoimmune encephalomyelitis (EAE) was established and the level of disease index, pathological scores, and anti-inflammatory markers of BASY-treated mice using macroscopic and microscopic examinations, qPCR and immunoblot were investigated. The results demonstrate that BASY significantly reduced the EAE disease index, increased total microbial load (2.5 fold), and improved the levels of the short-chain fatty acids propionic, butyric and caproic acids in the diseased mice group. Additionally, myeloperoxidase (MPO) proinflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α) and anti-inflammatory cytokines (TGF-β) were regulated by BASY treatment. Significant suppression of MPO and VCAM levels were noticed in the BASY-treated group (from 168 to 111 µM and from 34 to 27 pg/mL, respectively), in comparison to the EAE group. BASY treatment significantly reduced the expression of inflammatory cytokines, inflammatory progression related transcripts, and inflammatory progression protein markers. In conclusion, BASY significantly reduced the symptoms of EAE mice and may be used to develop a probiotic-based diet to promote host gut health. The cumulative findings of this study confirm the significant neuroprotection of BASY in the MOG-induced mice model. They could also suggest a novel approach to the treatment of MS-associated disorders.
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Epileptic seizures are frequently referred to as a brief development of a number of signs and symptoms resulting from extreme or synchronized activity in the brain. An interruption to the normal function of the sensory, motor, and autonomic systems and emotional state, behavior, cognition, or memory typically results from seizures. A persistent inclination toward having seizures falls under the umbrella term of epilepsy and the range of neurological disorders that it entails. Given the association between neurotransmitters and the brain, it can be deduced that neurotransmitters play a crucial role in epilepsy. Some examples of neurotransmitters are known to play a role in epilepsy. Of the many neurotransmitters, two that stand out are GABA and glutamate. GABA is a major inhibitory neurotransmitter, and glutamate is a major excitatory neurotransmitter. A key idea underlying epileptogenesis is a disturbance in the balance between excitation and inhibition in a given neuron or neuronal system, leading to runway excitation and hence epileptic seizures. Glutamatergic dysfunction leading to epileptogenesis can result from an increase in glutamate levels in the brain. Glutamate levels are known to be elevated in epilepsy patients. Being the primary neurotransmitters for inhibition/excitation of neurons, GABA and glutamate will remain popular targets for seizure management.
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Gamma aminobutyric acid (GABA) is a four-C, nonprotein amino acid that plays a significant role in human nervous system. Research on GABA in medical and pharmaceutical fields has uncovered some of the exciting physiological benefits of GABA to humans. This mini review reports three main biosynthetic pathways of GABA in plants, that involved either decarboxylation of glutamate, degradation of polyamine or non-enzymatic conversion of proline into GABA. GABA is naturally present in foods, as part of the essential metabolic processes or interaction between the organism with the environment. In comparison, plant-based foods contain relatively lower amount of GABA than the animal-based foods. Generally, dietary GABA intake through plant-based diet is insignificance due to the trace amount present, except for materials that have been manipulated via germination and/or fermentation. However, data on GABA stability post-processing and during storage, its bioavailability and clinical implications upon consumption is relatively scarce in the literature, and therefore this warrant further investigation.
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Background Oral gamma-aminobutyric acid (GABA) supplementation increases growth hormone (GH) serum levels and protein synthesis. Therefore, post-exercise supplementation using GABA and protein may help enhance training-induced muscle hypertrophy. We evaluated whether GABA with whey protein enhanced muscular hypertrophy in men after progressive resistance training. Methods Twenty-one healthy men (26 - 48 years) were randomized to receive whey protein (WP; 10 g) or whey protein + GABA (WP + GABA; 10 g + 100 mg) daily for 12 weeks. Both groups performed resistance training twice per week (three sets of 12 repetitions at 60% of maximal strength; leg press, leg extension, leg curl, chest press, and pull down). Body composition was assessed using dual-energy X-ray absorptiometry. Results In the WP + GABA group, resting plasma GH concentrations were significantly elevated at 4 and 8 weeks, compared to baseline. However, resting plasma GH concentrations in the WP group were only significantly elevated at 8 weeks. After 12 weeks, the WP + GABA group exhibited significantly greater increase in whole body fat-free mass than the WP group. Conclusions The GABA and whey protein combination was more effective for increasing whole body fat-free mass; daily GABA supplementation may help enhance exercise-induced muscle hypertrophy.
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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.
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Context: Compounds to treat hypothyroidism in the absence of cardiac side effects are urgently required. In this regard, γ-aminobutyric acid (GABA) has gained interest due to its anti-anxiolytic, antihypertensive and antioxidant properties, and reported benefits to the thyroid system. Objective: We investigated the ability of GABA to ameliorate fluoride-induced thyroid injury in mice, and investigated the mechanism(s) associated with GABA-induced protection. Materials and methods: Adult male Kumning mice (N = 90) were exposed to NaF (50 mg/kg) for 30 days as a model of hypothyroidism. To evaluate the effects of GABA administration, fluoride-exposed mice received either thyroid tablets, or low (25 mg/kg), medium (50 mg/kg) or high (75 mg/kg) concentrations of pure GABA orally for 14 days groups (N = 10 each). The effects of low (50 mg/kg); medium (75 mg/kg) and high (100 mg/kg) concentrations of laboratory-separated GABA were assessed for comparison. Effects on thyroid hormone production, oxidative stress, thyroid function-associated genes, and side-effects during therapy were measured. Results: GABA supplementation in fluoride-exposed mice significantly increased the expression of thyroid TG, TPO, and NIS (P < 0.05), significantly improved the thyroid redox state (P < 0.05), modulated the expression of thyroid function-associated genes, conferred liver metabolic protection, and prevented changes to myocardial morphology, thus reducing side effects. Both pure and laboratory-separated GABA displayed comparative protective effects. Discussion and conclusion: Our findings support the assertion that GABA exerts therapeutic potential in hypothyroidism. The design and use of human GABA trials to improve therapeutic outcomes in hypothyroidism are now warranted.
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This study aims to investigate the effect of dietary gamma-aminobutyric acid (GABA) supplementation on growth performance, intestinal immunity, intestinal GABAergic system, amino acid profiles and gut microflora of weaned piglets. Totally sixteen healthy piglets were randomly assigned into two groups to feed the basal diet (Con group) or basal diet with GABA (20mg/kg) supplementation. Body weight and feed intake were monitored weekly. Piglets were sacrificed after 3 weeks of GABA supplementation to collect the samples of the blood, ileum, ileal mucosa and luminal content. Immune-associated genes, GABAergic system, amino acid profiles, and microbiota in the small intestine and serum amino acid profiles were explored. The results showed that GABA supplementation improved the growth performance and modulated intestinal immunity by inhibiting gene expression of IL-22, proinflammatory cytokines (IL-1 and IL-18), and Muc1, but promoting anti-inflammatory cytokines (IFN-γ, IL-4, and IL-10), TLR6 and MyD88. Dietary GABA regulated a few components of the intestinal GABAergic system, increased levels of most amino acids in the ileal mucosa but reduced serum amino acid profiles. GABA regulated the intestinal microbiota population and diversity, such as the abundance of the dominative microbial population, community richness, and diversity of ileal microbiota. In conclusion, GABA supplementation modulates intestinal functions, including intestinal immunity, intestinal amino acid profiles and gut microbiota in piglets, and the results would helpful for understanding the function of GABA in the intestine.
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In general, fermented foods (FFs) are considered as functional foods. Since the awareness about the health benefits of FFs has increased, the consumption of FF also improved significantly in recent decades. Diabetes is one of the leading threats of the health span of an individual. The present manuscript details the general methods of the production of FFs, and the results of various studies (in vitro, in vivo, and clinical studies) on the antidiabetic properties of FFs. The fermentation method and the active microbes involved in the process play a crucial role in the functional properties of FFs. Several in vitro and in vivo studies have been reported on the health-promoting properties of FFs, such as anti-inflammation, anticancer, antioxidant properties, improved cognitive function and gastrointestinal health, and the reduced presence of metabolic disorders. The studies on the functional properties of FFs by randomized controlled clinical trials using human volunteers are very limited for several reasons, including ethical reasons, safety concerns, approval from the government, etc. Several scientific teams are working on the development of complementary and alternative medicines to improve the treatment strategies for hyperglycemia.
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The aims of this study were to determine the effects of gamma-aminobutyric acid (GABA) on immunoglobulin A (IgA) secretion from Peyer’s patch (PP) cells; to assess rat alpha-defensin-5 (RD-5) expression in the rat small intestine; and to determine the effect of GABA on intestinal ischemia reperfusion (I/R) injury-induced intestinal innate immunity. We found that GABA caused an increase in IgA secretion in the presence and absence of lipopolysaccharide (LPS). Moreover, GABA also significantly increased the mRNA levels of RD-5 and superoxide dismutase (Sod) 1, 3. Intestinal I/R was induced by a 30-min occlusion of the superior mesenteric artery followed by a reperfusion for 60-min. This led to a significant decrease in IgA secretion, and mRNA levels of RD-5 and Sod 1-3 in the ileum. On the other hand, administration of GABA before I/R induction had a significant protective effect against oxidative injury and attenuated the effects on intestinal immunity. Graphical Abstract Fullsize Image
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Background: Gamma-aminobutyric acid (Gaba) is a non-protein amino acid that plays important role in inhibition of neurotransmission. Gaba has been associated with various health benefit effects in human due to its biological activities. In this study, the optimal fermentation conditions for Gaba production from soybean solution fermented by Kimchi bacteria and its biological activities were investigated. Material and Methods: Kimchi from market was diluted in 10 mL of 0.85% NaCl solution for bacterial collection. Gaba contents were determined by using colorimetry via mixing sample with phenol 6% and sodium hypochlorite 9%. Anti-oxidant assay was conducted via DPPH and ABTS scavenging ability. The ACE inhibitory assay was performed via measuring absorbance of hippuric acid formation and Dockingserve. Results: The results showed that high Gaba content (13169 µg/10g soybean seeds) was found in the fermented product at pH value of 6.0 under temperature of 30 ⁰ C for 12h. Moreover, the antioxidant activity of Gaba-enriched soybean solution (1317 µg/mL) was observed due to scavenging 67% DPPH and 55% ABTS ⁺ radicals. Notably, the Gaba-enriched soybean solution was showed to inhibit 43% ACE activity. Conclusion: Accordingly, Gaba-enriched soybean solution was indicated as potential anti-oxidant and ACE inhibitory agent. It suggested that Gaba-enriched soybean solution was able to apply as health benefit foods with potential anti-oxidant and anti-hypertensive activities.
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γ-Aminobutyric acid (GABA) administration has been shown to increase β-cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on β cells of healthy and prediabetic/glucose-intolerant obese mice remains unknown. In the present study, we show that oral GABA administration ( ad libitum) to mice indeed increased pancreatic β-cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin-positive islet area in high fat diet-fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro, GABA treatment increased β-cell proliferation. In vitro, the effect was shown to be mediated via the GABAA receptor. Single-cell RNA sequencing analysis revealed that GABA preferentially up-regulated pathways linked to β-cell proliferation and simultaneously down-regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single-cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of β cells with a unique transcriptional signature, including urocortin 3 ( ucn3), wnt4, and hepacam2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that β-cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.-Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes β-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity.