Available via license: CC BY
Content may be subject to copyright.
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 different 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 diffuse 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 different 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 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 1and 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 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 effect
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 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]
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 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.
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
Effect 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 Effect
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 different experimental models (Table 3). Kimura et al. [
35
] have investigated the effect 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 effect 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
effect 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 effective 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 effect in normotensive rats [
38
]. Likewise, the significant
anti-hypertensive activity and the serum cholesterol-lowering effect of Gaba-rich brown rice were
shown in spontaneously hypertensive rats as compared to the control [
39
,
40
]. In the clinical trial,
the effects 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 effect 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
effective 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 effect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Effect 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 Effect
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
effect of pharmacological drugs is accompanied with various disadvantages such as drug resistance,
side effects, 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 effective 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 offspring [
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 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,
Molecules 2019,24, 2678 8 of 23
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.
Table 4. Anti-diabetic effect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
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]
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 offspring 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
Effect 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 Effect
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 effects. 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 effects 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 effect of Gaba.
STT Source Dose/Model
Time of
Treatment/
Administration
Effect 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 Effect
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 effect 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 effect 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 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 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 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 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 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).
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 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 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 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.
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 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
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 effect
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 effect 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 effects of Gaba on
cholesterol-metabolism-associated molecules in human monocyte-derived macrophages (HMDMs).
It was found that Gaba was effective 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 effect 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 effects 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 effective 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 effects, and prevention of disease pathogenesis [
139
]. As a result, the antioxidant activity of
Gaba may partly contribute to its biological effects 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 effects. Thus, the functional foods produced from
Gaba are believed to be able to prevent and/or treat different 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 efficacy 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.
References
1.
Olsen, R.W.; Betz, H. GABA and glycine. In Basic Neurochemistry, 7th ed.; Siegel, G.J., Albers, R.W., Brady, S.T.,
Price, D.L., Eds.; Elsevier Academic Press: Boston, MA, USA, 2006.
2.
Martin, D.L.; Olsen, R.W. (Eds.) GABA in the Nervous System: The View at 50 Years; Lippincott Williams &
Wilkins: Philadelphia, PA, USA, 2000.
3.
Madsen, K.K.; Clausen, R.P.; Larsson, O.M.; Krogsgaard-Larsen, P.; Schousboe, A.; White, H.S. Synaptic
and extrasynaptic GABA transporters as targets for anti-epileptic drugs. J. Neurochem.
2009
,109, 139–144.
[CrossRef] [PubMed]
4.
Mann, E.O.; Kohl, M.M.; Paulsen, O. Distinct roles of GABA(A) and GABA(B) receptors in balancing and
terminating persistent cortical activity. J. Neurosci. 2009,29, 7513–7518. [CrossRef] [PubMed]
5. Stagg, C.J.; Bachtiar, V.; Johansen-Berg, H. The role of GABA in human motor learning. Curr. Biol. 2011,21,
480–484. [CrossRef] [PubMed]
6.
Nuss, P. Anxiety disorders and GABA neurotransmission: A disturbance of modulation. Neuropsychiatr. Dis.
Treat. 2015,11, 165–175. [PubMed]
7.
Wagner, S.; Castel, M.; Gainer, H.; Yarom, Y. GABA in the mammalian suprachiasmatic nucleus and its role
in diurnal rhythmicity. Nature 1997,387, 598–603. [CrossRef] [PubMed]
8. Gottesmann, C. GABA mechanisms and sleep. Neuroscience 2002,111, 231–239. [CrossRef]
9.
Plante, D.T.; Jensen, J.E.; Schoerning, L.; Winkelman, J.W. Reduced
γ
-aminobutyric acid in occipital and
anterior cingulate cortices in primary insomnia: A link to major depressive disorder? Neuropsychopharmacology
2012,37, 1548–1557. [CrossRef] [PubMed]
10.
Rashmi, D.; Zanan, R.; John, S.; Khandagale, K.; Nadaf, A.
γ
-aminobutyric acid (GABA): Biosynthesis, role,
commercial production, and application. In Study in Natural Products Chemistry, 1st ed.; Rahman, A., Ed.;
Elsevier: 1000 AE Amsterdam, The Netherlands, 2018; Volume 57, pp. 413–452.
11.
Kaminsky, N.; Bihari, O.; Kanner, S.; Barzilai, A. Connecting malfunctioning glial cells and brain degenerative
disorders. Genom. Proteom. Bioinform. 2016,14, 155–165. [CrossRef] [PubMed]
12.
Bagli, E.; Goussia, A.; Moschos, M.M.; Agnantis, N.; Kitsos, G. Natural compounds and neuroprotection:
Mechanisms of action and novel delivery systems. In Vivo 2016,30, 535–547.
Molecules 2019,24, 2678 17 of 23
13.
Cho, Y.R.; Chang, J.Y.; Chang, H.C. Production of gamma-aminobutyric acid (GABA) by Lactobacillus buchneri
isolated from kimchi and its neuroprotective effect on neuronal cells. J. Microbiol. Biotechnol.
2007
,17,
104–109. [PubMed]
14.
Li, W.; Wei, M.; Wu, J.; Rui, X.; Dong, M. Novel fermented chickpea milk with enhanced level of
γ
-aminobutyric
acid and neuroprotective effect on PC12 cells. Peer J 2016,4, e2292. [CrossRef] [PubMed]
15.
Zhou, C.; Li, C.; Yu, H.M.; Zhang, F.; Han, D.; Zhang, G.Y. Neuroprotection of gamma-aminobutyric acid
receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased
neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral
ischemia. J. Neurosci. Res. 2008,86, 2973–2983. [PubMed]
16.
Liu, L.; Li, C.J.; Lu, Y.; Zong, X.G.; Luo, C.; Sun, J.; Guo, L.J. Baclofen mediates neuroprotection on hippocampal
CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion. Sci. Rep.
2015,5, 14474. [CrossRef] [PubMed]
17.
Wei, X.W.; Yan, H.; Xu, B.; Wu, Y.P.; Li, C.; Zhang, G.Y. Neuroprotection of co-activation of GABA receptors by
preventing caspase-3 denitrosylation in KA-induced seizures. Brain. Res. Bull.
2012
,88, 617–623. [CrossRef]
[PubMed]
18.
Parvez, M.K. Natural or plant products for the treatment of neurological disorders: Current knowledge.
Curr. Drug. Metab. 2018,19, 424–428. [CrossRef] [PubMed]
19.
Okada, T.; Sugishita, T.; Murakami, T.; Murai, H.; Saikusa, T.; Horino, T.; Onoda, A.; Kajimoto, O.;
Takahashi, R.; Takahashi, T. Effect of the defatted rice germ enriched with GABA for sleeplessness, depression,
autonomic disorder by oral administration. J. Jpn. Soc. Food Sci. 2000,47, 596–603. [CrossRef]
20.
Chuang, C.Y.; Shi, Y.C.; You, H.P.; Lo, Y.H.; Pan, T.M. Antidepressant effect of GABA-rich monascus-fermented
product on forced swimming rat model. J. Agric. Food Chem. 2011,59, 3027–3034. [CrossRef]
21.
Yamatsu, A.; Yamashita, Y.; Pandharipande, T.; Maru, I.; Kim, M. Effect of oral
γ
-aminobutyric acid (GABA)
administration on sleep and its absorption in humans. Food Sci. Biotechnol. 2016,25, 547–551. [CrossRef]
22.
Kim, S.; Jo, K.; Hong, K.B.; Han, S.H.; Suh, H.J. GABA and l-theanine mixture decreases sleep latency and
improves NREM sleep. Pharm. Biol. 2019,57, 65–73. [CrossRef]
23.
Abdou, A.M.; Higashiguchi, S.; Horie, K.; Kim, M.; Hatta, H.; Yokogoshi, H. Relaxation and immunity
enhancement effect of gamma-aminobutyric acid (GABA) administration in humans. BioFactors
2006
,26,
201–208. [CrossRef]
24.
Seo, Y.C.; Choi, W.Y.; Kim, J.S.; Lee, C.G.; Ahn, J.H.; Cho, H.Y.; Lee, S.H.; Cho, J.S.; Joo, S.J.; Lee, H.Y.
Enhancement of the cognitive effects of GABA from monosodium glutamate fermentation by Lactobacillus
sakei B2-16. Food Biotechnol. 2012,26, 29–44. [CrossRef]
25.
Reid, S.N.S.; Ryu, J.K.; Kim, Y.; Jeon, B.H. The effects of fermented Laminaria japonica on short-term working
memory and physical fitness in the elderly. Evid. Based Complement. Altern. Med. 2018,2018, 8109621.
26.
Reid, S.N.S.; Ryu, J.K.; Kim, Y.S.; Jeon, B.H. GABA-enriched fermented Laminaria japonica improves cognitive
impairment and neuroplasticity in scopolamine- and ethanol-induced dementia model mice. Nutr. Res.
Pract. 2018,12, 199–207. [CrossRef] [PubMed]
27.
Choi, W.C.; Reid, S.N.S.; Ryu, J.K.; Kim, Y.; Jo, Y.H.; Jeon, B.H. Effects of
γ
-aminobutyric acid-enriched
fermented sea tangle (Laminaria japonica) on brain derived neurotrophic factor-related muscle growth and
lipolysis in middle aged women. Algae 2016,31, 175–187. [CrossRef]
28.
Schellack, N.; Naicker, P. Hypertension: A review of antihypertensive medication, past and present. S. Afr.
Pharm. J. 2015,82, 17–25.
29.
Murray, B.A.; FitzGerald, R.J. Angiotensin converting enzyme inhibitory peptides derived from food proteins:
Biochemistry, bioactivity and production. Curr. Pharm. Des. 2007,13, 773–791. [CrossRef]
30.
Nejati, F.; Rizzello, C.G.; Cagno, R.D.; Sheikh-Zeinoddin, M.; Diviccaro, A.; Minervini, F.; Gobbetti, M.
Manufacture of a functional fermented milk enriched of angiotensin-I converting enzyme (ACE)-inhibitory
peptides and γ-amino butyric acid (GABA). Food Sci. Technol. 2013,51, 183–189. [CrossRef]
31.
Tung, Y.T.; Lee, B.H.; Liu, C.F.; Pan, T.M. Optimization of culture condition for ACEI and GABA production
by lactic acid bacteria. J. Food Sci. 2011,76, M585–M591. [CrossRef]
32.
Jang, E.K.; Kim, N.Y.; Ahn, H.J.; Ji, G.E.
γ
-Aminobutyric acid (GABA) production and angiotensin-I converting
enzyme (ACE) inhibitory activity of fermented soybean containing sea tangle by the co-culture of Lactobacillus
brevis with Aspergillus oryzae.J. Microbiol. Biotechnol. 2015,25, 1315–1320. [CrossRef]
Molecules 2019,24, 2678 18 of 23
33.
Sang, V.T.; Uyen, L.P.; Hung, N.D. The increased gamma-aminobutyric acid content by optimizing
fermentation conditions of bacteria from kimchi and investigation of its biological activities. EurAsian J.
Biosci. 2018,12, 369–376.
34.
Torino, M.I.; Lim
ó
n, R.I.; Mart
í
nez-Villaluenga, C.; Mäkinen, S.; Pihlanto, A.; Vidal-Valverde, C.; Frias, J.
Antioxidant and antihypertensive properties of liquid and solid state fermented lentils. Food Chem.
2013
,
136, 1030–1037. [CrossRef]
35.
Kimura, M.; Hayakawa, K.; Sansawa, H. Involvement of gamma-aminobutyric acid (GABA) B receptors
in the hypotensive effect of systemically administered GABA in spontaneously hypertensive rats. Jpn. J.
Pharmacol. 2002,89, 388–394. [CrossRef] [PubMed]
36.
Hayakawa, K.; Kimura, M.; Kasaha, K.; Matsumoto, K.; Sansawa, H.; Yamori, Y. Effect of a
gamma-aminobutyric acid-enriched dairy product on the blood pressure of spontaneously hypertensive and
normotensive Wistar-Kyoto rats. Br. J. Nutr. 2004,92, 411–417. [CrossRef] [PubMed]
37.
Matsubara, F.; Ueno, H.; Kentaro, T.; Tadano, K.; Suyama, T.; Imaizumi, K.; Suzuki, T.; Magata, K.; Kikuchi, N.
Effects of GABA supplementation on blood pressure and safety in adults with mild hypertension. Jpn.
Pharmacol. Ther. 2002,30, 963–972.
38.
Akama, K.; Kanetou, J.; Shimosaki, S.; Kawakami, K.; Tsuchikura, S.; Takaiwa, F. Seed-specific expression
of truncated OsGAD2 produces GABA-enriched rice grains that influence a decrease in blood pressure in
spontaneously hypertensive rats. Transgenic Res. 2009,18, 865–876. [CrossRef]
39.
Ebizuka, H.; Ihara, M.; Arita, M. Antihypertensive effect of pre-germinated brown rice in spontaneously
hypertensive rats. Food Sci. Technol. Res. 2009,15, 625–630. [CrossRef]
40.
Kawakami, K.; Yamada, K.; Yamada, T.; Nabika, T.; Nomura, M. Antihypertensive effect of
γ
-aminobutyric
acid-enriched brown rice on spontaneously hypertensive rats. J. Nutr. Sci. Vitaminol. (Tokyo)
2018
,64, 56–62.
[CrossRef]
41.
Nishimura, M.; Yoshida, S.; Haramoto, M.; Mizuno, H.; Fukuda, T.; Kagami-Katsuyama, H.; Tanaka, A.;
Ohkawara, T.; Sato, Y.; Nishihira, J. Effects of white rice containing enriched gamma-aminobutyric acid on
blood pressure. J. Tradit. Complement. Med. 2016,6, 66–71. [CrossRef]
42.
Tsai, C.C.; Chiu, T.H.; Ho, C.Y.; Lin, P.P.; Wu, T.Y. Effects of anti-hypertension and intestinal microflora of
spontaneously hypertensive rats fed gammaaminobutyric acid-enriched Chingshey purple sweet potato
fermented milk by lactic acid bacteria. Afr. J. Microbiol. Res. 2013,7, 932–940.
43.
Lin, P.P.; Hsieh, Y.M.; Kuo, W.W.; Lin, C.C.; Tsai, F.J.; Tsai, C.H.; Huang, C.Y.; Tsai, C.C. Inhibition of cardiac
hypertrophy by probiotic-fermented purple sweet potato yogurt in spontaneously hypertensive rat hearts.
Int. J. Mol. Med. 2012,30, 1365–1375. [CrossRef]
44.
Suwanmanon, K.; Hsieh, P.C. Effect of
γ
-aminobutyric acid and nattokinase-enriched fermented beans on
the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats. J. Food Drug. Anal.
2014,22, 485–491. [CrossRef] [PubMed]
45.
Aoki, H.; Furuya, Y.; Endo, Y.; Fujimoto, K. Effect of gamma-aminobutyric acid-enriched tempeh-like
fermented soybean (GABA-Tempeh) on the blood pressure of spontaneously hypertensive rats. Biosci.
Biotechnol. Biochem. 2003,67, 1806–1808. [CrossRef] [PubMed]
46.
Yoshimura, M.; Toyoshi, T.; Sano, A.; Izumi, T.; Fujii, T.; Konishi, C.; Inai, S.; Matsukura, C.; Fukuda, N.;
Ezura, H.; et al. Antihypertensive effect of a gamma-aminobutyric acid rich tomato cultivar ‘DG03-9’ in
spontaneously hypertensive rats. J. Agric. Food Chem. 2010,58, 615–619. [CrossRef] [PubMed]
47.
Becerra-Tom
á
s, N.; Guasch-Ferr
é
, M.; Quilez, J.; Merino, J.; Ferr
é
, R.; D
í
az-L
ó
pez, A.; Bull
ó
, M.;
Hern
á
ndez-Alonso, P.; Palau-Galindo, A.; Salas-Salvad
ó
, J. Effect of functional bread rich in potassium,
γ
-aminobutyric acid and angiotensin-converting enzyme inhibitors on blood pressure, glucose metabolism
and endothelial function: A double-blind randomized crossover clinical trial. Medicine (Baltimore)
2015
,
94, e1807. [CrossRef] [PubMed]
48.
Kharroubi, A.T.; Darwish, H.M. Diabetes mellitus: The epidemic of the century. World J. Diabetes
2015
,6,
850–867. [CrossRef] [PubMed]
49.
Li, G.; Zhang, P.; Wang, J.; Gregg, E.W.; Yang, W.; Gong, Q. The long-term effect of life style interventions to
prevent diabetes in the China Da Qing diabetes prevention study: A 20-year follow-up study. Lancet
2008
,
371, 1783–1789. [CrossRef]
50.
Babiker, A.; Dubayee, M.A. Anti-diabetic medications: How to make a choice? Sudan J. Paediatr.
2017
,17,
11–20. [CrossRef] [PubMed]
Molecules 2019,24, 2678 19 of 23
51.
Soltani, N.; Qiu, H.; Aleksic, M.; Glinka, Y.; Zhao, F.; Liu, R.; Li, Y.; Zhang, N.; Chakrabarti, R.; Ng, T.; et al.
GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc. Natl. Acad.
Sci. USA 2011,108, 11692–11697. [CrossRef] [PubMed]
52.
Untereiner, A.; Abdo, S.; Bhattacharjee, A.; Gohil, H.; Pourasgari, F.; Ibeh, N.; Lai, M.; Batchuluun, B.;
Wong, A.; Khuu, N.; et al. GABA promotes
β
-cell proliferation, but does not overcome impaired glucose
homeostasis associated with diet-induced obesity. FASEB J. 2019,33, 3968–3984. [CrossRef]
53.
Liu, W.; Son, D.O.; Lau, H.K.; Zhou, Y.; Prud’homme, G.J.; Jin, T.; Wang, Q. Combined oral administration of
GABA and DPP-4 inhibitor prevents beta cell damage and promotes beta cell regeneration in mice. Front.
Pharmacol. 2017,8, 362. [CrossRef]
54.
Bansal, P.; Wang, S.; Liu, S.; Xiang, Y.Y.; Lu, W.Y.; Wang, Q. GABA coordinates with insulin in regulating
secretory function in pancreatic INS-1 β-cells. PLoS ONE 2011,6, e26225. [CrossRef] [PubMed]
55.
Tian, J.; Dang, H.N.; Yong, J.; Chui, W.S.; Dizon, M.P.; Yaw, C.K.; Kaufman, D.L. Oral treatment with
γ
-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high
fat diet-fed mice. PLoS ONE 2011,6, e25338. [CrossRef] [PubMed]
56.
Huang, C.Y.; Kuo, W.W.; Wang, H.F.; Lin, C.J.; Lin, Y.M.; Chen, J.L.; Kuo, C.H.; Chen, P.K.; Lin, J.Y. GABA tea
ameliorates cerebral cortex apoptosis and autophagy in streptozotocin-induced diabetic rats. J. Funct. Foods
2014,6, 534–544. [CrossRef]
57.
Imam, M.U.; Azmi, N.H.; Bhanger, M.I.; Ismail, N.; Ismail, M. Antidiabetic properties of germinated brown
rice: A systematic review. J. Evid. Based Complement. Altern. Med. 2012,2012, 816501.
58.
Sivamaruthi, B.S.; Kesika, P.; Prasanth, M.I.; Chaiyasut, C. A mini review on antidiabetic properties of
fermented foods. Nutrients 2018,10, 1973. [CrossRef] [PubMed]
59.
Hagiwara, H.; Seki, T.; Ariga, T. The effect of pre-germinated brown rice intake on blood glucose and PAI-1
levels in streptozotocin-induced diabetic rats. Biosci. Biotechnol. Biochem.
2004
,68, 444–447. [CrossRef]
[PubMed]
60.
Torimitsu, M.; Nagase, R.; Yanagi, M.; Homma, M.; Sasai, Y.; Ito, Y.; Hayamizu, K.; Nonaka, S.; Hosono, T.;
Kise, M.; et al. Replacing white rice with pre-germinated brown rice mildly ameliorates hyperglycemia and
imbalance of adipocytokine levels in type 2 diabetes model rats. J. Nutr. Sci. Vitaminol. (Tokyo)
2010
,56,
287–292. [CrossRef]
61.
Adamu, H.A.; Imam, M.U.; Ooi, D.J.; Esa, N.M.; Rosli, R.; Ismail, M. Perinatal exposure to germinated brown
rice and its gamma amino-butyric acid-rich extract prevents high fat diet-induced insulin resistance in first
generation rat offspring. Food Nutr. Res. 2016,60, 30209. [CrossRef]
62.
Chung, S.I.; Jin, X.; Kang, M.Y. Enhancement of glucose and bone metabolism in ovariectomized rats fed with
germinated pigmented rice with giant embryo (Oryza sativa L. cv. Keunnunjami). Food Nutr. Res.
2019
,63.
[CrossRef]
63.
Shang, W.; Si, X.; Zhou, Z.; Strappe, P.; Blanchard, C. Wheat bran with enriched gamma-aminobutyric
acid attenuates glucose intolerance and hyperinsulinemia induced by a high-fat diet. Food Funct.
2018
,9,
2820–2828. [CrossRef]
64.
Si, X.; Shang, W.; Zhou, Z.; Shui, G.; Lam, S.M.; Blanchard, C.; Strappe, P. Gamma-aminobutyric acid
enriched rice bran diet attenuates insulin resistance and balances energy expenditure via modification of gut
microbiota and short-chain fatty acids. J. Agric. Food Chem. 2018,66, 881–890. [CrossRef] [PubMed]
65.
Ito, Y.; Mizukuchi, A.; Kise, M.; Aoto, H.; Yamamoto, S.; Yoshihara, R.; Yokoyama, J. Postprandial blood
glucose and insulin responses to pre-germinated brown rice in healthy subjects. J. Med. Investig.
2005
,52,
159–164. [CrossRef]
66.
Hsu, T.F.; Kise, M.; Wang, M.F.; Ito, Y.; Yang, M.D.; Aoto, H.; Yoshihara, R.; Yokoyama, J.; Kunii, D.;
Yamamoto, S. Effects of pre-germinated brown rice on blood glucose and lipid levels in free-living patients
with impaired fasting glucose or type 2 diabetes. J. Nutr. Sci. Vitaminol. (Tokyo)
2008
,54, 163–168. [CrossRef]
[PubMed]
67.
Hayakawa, T.; Suzuki, S.; Kobayashi, S.; Fukutomi, T.; Ide, M.; Ohno, T.; Ohkouchi, M.; Taki, M.; Miyamoto, T.;
Nimura, T. Effect of pre-germinated brown rice on metabolism of glucose and lipid in patients with diabetes
mellitus type 2. J. Jpn. Assoc. Rural Med. 2009,58, 438–446. [CrossRef]
Molecules 2019,24, 2678 20 of 23
68.
Tamaya, K.; Matsui, T.; Toshima, A.; Noguchi, M.; Ju, Q.; Miyata, Y.; Tanaka, T.; Tanaka, K. Suppression of
blood glucose level by a new fermented tea obtained by tea-rolling processing of loquat (Eriobotrya japonica)
and green tea leaves in disaccharide-loaded Sprague-Dawley rats. J. Sci. Food Agric.
2010
,90, 779–783.
[CrossRef] [PubMed]
69.
Lee, S.Y.; Park, S.L.; Nam, Y.D.; Lee, S.H. Anti-diabetic effects of fermented green tea in KK-Ay diabetic mice.
Korean J. Food Sci. Technol. 2013,45, 488–494. [CrossRef]
70.
Yeap, S.K.; Ali, N.M.; Yusof, H.M.; Alitheen, N.B.; Beh, B.K.; Ho, W.Y.; Koh, S.P.; Long, K. Antihyperglycemic
effects of fermented and nonfermented mung bean extracts on alloxan-induced-diabetic mice. J. Biomed.
Biotechnol. 2012,2012, 285430. [CrossRef]
71.
Chen, L.; Zhao, H.; Zhang, C.; Lu, Y.; Zhu, X.; Lu, Z.
γ
-Aminobutyric acid-rich yogurt fermented
by Streptococcus salivarius subsp. thermophiles fmb5 apprars to have anti-diabetic effect on
streptozotocin-induced diabetic mice. J. Funct. Foods 2016,20, 267–275. [CrossRef]
72. Nam, H.; Jung, H.; Karuppasamy, S.; Park, Y.S.; Cho, Y.S.; Lee, J.Y.; Seong, S.I.; Suh, J.G. Anti-diabetic effect
of the soybean extract fermented by Bacillus subtilis MORI in db/db mice. Food Sci. Biotechnol.
2012
,21,
1669–1676. [CrossRef]
73.
Song, K.; Song, I.B.; Gu, H.J.; Na, J.; Kim, S.; Yang, H.S.; Lee, S.C.; Huh, C.; Kwon, J. Anti-diabetic effect of
fermented milk containing conjugated linoleic acid on type II diabetes mellitus. Korean J. Food Sci. Anim.
Resour. 2016,36, 170–177. [CrossRef]
74.
Ostadrahimi, A.; Taghizadeh, A.; Mobasseri, M.; Farrin, N.; Payahoo, L.; Gheshlaghi, Z.B.; Vahedjabbari, M.
Effect of probiotic fermented milk (kefir) on glycemic control and lipid profile in type 2 diabetic patients:
A randomized double-blind placebo-controlled clinical trial. Iran. J. Public Health 2015,44, 228–237.
75.
Alihosseini, N.; Moahboob, S.A.; Farrin, N.; Mobasseri, M.; Taghizadeh, A.; Ostadrahimi, A.R. Effect of
probiotic fermented milk (kefir) on serum level of insulin and homocysteine in type 2 diabetes patients. Acta
Endocrinol. 2017,13, 431–436. [CrossRef] [PubMed]
76.
Ribas, V.; Garc
í
a-Ruiz, C.; Fern
á
ndez-Checa, J.C. Mitochondria, cholesterol and cancer cell metabolism. Clin.
Transl. Med. 2016,5, 22. [CrossRef] [PubMed]
77.
Oh, C.H.; Oh, S.H. Effects of germinated brown rice extracts with enhanced levels of GABA on cancer cell
proliferation and apoptosis. J. Med. Food 2004,7, 19–23. [CrossRef] [PubMed]
78.
Schuller, H.M.; Al-Wadei, H.A.; Majidi, M. Gamma-aminobutyric acid, a potential tumor suppressor for
small airway-derived lung adenocarcinoma. Carcinogenesis 2008,29, 1979–1985. [CrossRef]
79.
Huang, Q.; Liu, C.; Wang, C.; Hu, Y.; Qiu, L.; Xu, P. Neurotransmitter
γ
-aminobutyric acid-mediated
inhibition of the invasive ability of cholangiocarcinoma cells. Oncol. Lett. 2011,2, 519–523. [CrossRef]
80.
Song, L.; Du, A.; Xiong, Y.; Jiang, J.; Zhang, Y.; Tian, Z.; Yan, H.
γ
-Aminobutyric acid inhibits the proliferation
and increases oxaliplatin sensitivity in human colon cancer cells. Tumour. Biol.
2016
,37, 14885–14894.
[CrossRef]
81.
Al-Wadei, H.A.; Al-Wadei, M.H.; Ullah, M.F.; Schuller, H.M. Celecoxib and GABA cooperatively prevent
the progression of pancreatic cancer
in vitro
and in xenograft models of stress-free and stress-exposed mice.
PLoS ONE 2012,7, e43376. [CrossRef]
82.
Tatsuta, M.; Iishi, H.; Baba, M.; Nakaizumi, A.; Ichii, M.; Taniguchi, H. Inhibition by gamma-amino-n-butyric
acid and baclofen of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats.
Cancer Res. 1990,50, 4931–4934.
83.
Chen, Z.A.; Bao, M.Y.; Xu, Y.F.; Zha, R.P.; Shi, H.B.; Chen, T.Y.; He, X.H. Suppression of human liver cancer
cell migration and invasion via the GABAA receptor. Cancer Biol. Med. 2012,9, 90–98. [PubMed]
84.
Zhang, M.; Gong, Y.; Assy, N.; Minuk, Y. Increased GABAergic activity inhibits a-fetoprotein mRNA
expression and the proliferation activity of the HepG2 human hepatocellular carcinoma cell line. J. Hepatol.
2000,32, 85–91. [CrossRef]
85.
Phaniendra, A.; Jestadi, D.B.; Periyasamy, L. Free radicals: Properties, sources, targets, and their implication
in various diseases. Indian J. Clin. Biochem. 2015,30, 11–26. [CrossRef] [PubMed]
86.
Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on
human health. Pharmacogn. Rev. 2010,4, 118–126. [CrossRef] [PubMed]
87.
Deng, Y.; Xu, L.; Zeng, X.; Li, Z.; Qin, B.; He, N. New perspective of GABA as an inhibitor of formation of
advanced lipoxidation end-products: it’s interaction with malondiadehyde. J. Biomed. Nanotechnol.
2010
,6,
318–324. [CrossRef] [PubMed]
Molecules 2019,24, 2678 21 of 23
88.
Deng, Y.; Wang, W.; Yu, P.; Xi, Z.; Xu, L.; Li, X.; He, N. Comparison of taurine, GABA, Glu, and Asp as
scavengers of malondialdehyde
in vitro
and
in vivo
.Nanoscale Res. Lett.
2013
,8, 190. [CrossRef] [PubMed]
89.
Tang, X.; Yu, R.; Zhou, Q.; Jiang, S.; Le, G. Protective effects of
γ
-aminobutyric acid against H
2
O
2
-induced
oxidative stress in RIN-m5F pancreatic cells. Nutr. Metab. (Lond.) 2018,15, 60. [CrossRef]
90.
Zhu, Z.; Shi, Z.; Xie, C.; Gong, W.; Hu, Z.; Peng, Y. A novel mechanism of gamma-aminobutyric acid (GABA)
protecting human umbilical vein endothelial cells (HUVECs) against H
2
O
2
-induced oxidative injury. Comp.
Biochem. Physiol. C Toxicol. Pharmacol. 2019,217, 68–75. [CrossRef]
91.
El-Hady, A.M.A.; Gewefel, H.S.; Badawi, M.A.; Eltahawy, N.A. Gamma-aminobutyric acid ameliorates
gamma rays-induced oxidative stress in the small intestine of rats. J. Basic Appl. Zool.
2017
,78, 2. [CrossRef]
92.
Eltahawy, N.A.; Saada, H.N.; Hammad, A.S. Gamma amino butyric acid attenuates brain oxidative damage
associated with insulin alteration in streptozotocin-treated rats. Indian J. Clin. Biochem.
2017
,32, 207–213.
[CrossRef]
93.
Lee, B.J.; Kim, J.S.; Kang, Y.M.; Lim, J.H.; Kim, Y.M.; Lee, M.S.; Jeong, M.H.; Ahn, C.B.; Je, J.Y. Antioxidant
activity and
γ
-aminobutyric acid (GABA) content in sea tangle fermented by Lactobacillus brevis BJ20 isolated
from traditional fermented foods. Food Chem. 2010,122, 271–276. [CrossRef]
94.
Md Zamri, N.D.; Imam, M.U.; Abd Ghafar, S.A.; Ismail, M. Antioxidative effects of germinated brown
rice-derived extracts on H
2
O
2
-induced oxidative stress in HepG2 cells. Evid. Based Complement. Altern. Med.
2014,2014, 371907. [CrossRef] [PubMed]
95.
Phuapaiboon, P. Gamma-aminobutyric acid, total anthocyanin content and antioxidant activity of vinegar
brewed from germinated pigmented rice. Pakistan J. Nutr. 2017,16, 109–118.
96.
Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and
inflammation-associated diseases in organs. Oncotarget 2017,9, 7204–7218. [CrossRef] [PubMed]
97.
Abdulkhaleq, L.A.; Assi, M.A.; Abdullah, R.; Zamri-Saad, M.; Taufiq-Yap, Y.H.; Hezmee, M. The crucial roles
of inflammatory mediators in inflammation: A review. Vet. World 2018,11, 627–635. [CrossRef] [PubMed]
98.
Han, D.; Kim, H.Y.; Lee, H.J.; Shim, I.; Hahm, D.H. Wound healing activity of gamma-aminobutyric acid
(GABA) in rats. J. Microbiol. Biotechnol. 2007,17, 1661–1669. [PubMed]
99.
Prud’homme, G.; Glinka, Y.; Wang, Q. GABA exerts anti-inflammatory and immunosuppressive effects
(P5175). J. Immunol. 2013,190, 68.
100.
Choi, J.I.; Yun, I.H.; Jung, Y.J.; Lee, E.H.; Nam, T.J.; Kim, Y.M. Effects of
γ
-aminobutyric acid (gaba)-enriched
sea tangle Laminaria japonica extract on lipopolysaccharide-induced inflammation in mouse macrophage
(RAW 264.7) cells. Fish Aquat. Sci. 2012,15, 293–297. [CrossRef]
101.
Tuntipopipat, S.; Muangnoi, C.; Thiyajai, P.; Srichamnong, W.; Charoenkiatkul, S.; Praengam, K. A
bioaccessible fraction of parboiled germinated brown rice exhibits a higher anti-inflammatory activity
than that of brown rice. Food Funct. 2015,6, 1480–1488. [CrossRef]
102.
Scandolera, A.; Hubert, J.; Humeau, A.; Lambert, C.; De Bizemont, A.; Winkel, C.; Kaouas, A.; Renault, J.H.;
Nuzillard, J.M.; Reynaud, R. GABA and GABA-alanine from the red microalgae Rhodosorus marinus exhibit
a significant neuro-soothing activity through inhibition of neuro-inflammation mediators and positive
regulation of TRPV1-related skin sensitization. Mar. Drugs 2018,16, 96. [CrossRef]
103.
Sokovic Bajic, S.; Djokic, J.; Dinic, M.; Veljovic, K.; Golic, N.; Mihajlovic, S.; Tolinacki, M. GABA-producing
natural dairy isolate from artisanal zlatar cheese attenuates gut inflammation and strengthens gut epithelial
barrier in vitro. Front. Microbiol. 2019,10, 527. [CrossRef]
104.
Mau, J.L.; Chiou, S.Y.; Hsu, C.A.; Tsai, H.L.; Lin, S.D. Antimutagenic and antimicrobial activities of
γ-aminobutyric acid (Gaba) tea extract. Int. Conf. Nutr. Food Sci. 2012,39, 178–182.
105.
Dagorn, A.; Hillion, M.; Chapalain, A.; Lesouhaitier, O.; Duclairoir Poc, C.; Vieillard, J.; Chevalier, S.;
Taupin, L.; Le Derf, F.; Feuilloley, M.G. Gamma-aminobutyric acid acts as a specific virulence regulator in
Pseudomonas aeruginosa.Microbiology 2013,159, 339–351. [CrossRef] [PubMed]
106.
Kim, J.K.; Kim, Y.S.; Lee, H.M.; Jin, H.S.; Neupane, C.; Kim, S.; Lee, S.H.; Min, J.J.; Sasai, M.; Jeong, J.H.; et al.
GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections.
Nat. Commun. 2018,9, 4184. [CrossRef] [PubMed]
107. Galli, S.J.; Tsai, M. IgE and mast cells in allergic disease. Nat. Med. 2012,18, 693–704. [CrossRef] [PubMed]
108.
Hori, A.; Hara, T.; Honma, K.; Joh, T. Suppressive effect of
γ
-aminobutyric acid (GABA) on histamine release
in rat basophilic RBL-2H3 cells. Bull. Fac. Agric. Niigata Univ. 2008,61, 47–51.
Molecules 2019,24, 2678 22 of 23
109.
Kawasaki, A.; Hara, T.; Joh, T. Inhibitory effect of
γ
-aminobutyric acid (GABA) on histamine release from rat
basophilic leukemia RBL-2H3 cells and rat peritoneal exudate cells. Nippon Shokuhin Kagaku Kogaku Kaishi
2014,61, 362–366. [CrossRef]
110.
Hokazono, H.; Omori, T.; Ono, K. Effects of single and combined administration of fermented barley extract
and
γ
-aminobutyric acid on the development of atopic dermatitis in NC/Nga mice. Biosci. Biotechnol.
Biochem. 2010,74, 135–139. [CrossRef] [PubMed]
111.
Nagy, L.E. Molecular aspects of alcohol metabolism: Transcription factors involved in early ethanol-induced
liver injury. Annu. Rev. Nutr. 2004,24, 55–78. [CrossRef]
112.
Oh, S.H.; Soh, J.R.; Cha, Y.S. Germinated brown rice extract shows a nutraceutical effect in the recovery of
chronic alcohol-related symptoms. J. Med. Food 2003,6, 115–121. [CrossRef]
113.
Lee, B.J.; Senevirathne, M.; Kim, J.S.; Kim, Y.M.; Lee, M.S.; Jeong, M.H.; Kang, Y.M.; Kim, J.I.; Nam, B.H.;
Ahn, C.B.; et al. Protective effect of fermented sea tangle against ethanol and carbon tetrachloride-induced
hepatic damage in Sprague-Dawley rats. Food Chem. Toxicol. 2010,48, 1123–1128. [CrossRef]
114.
Cha, J.Y.; Lee, B.J.; Je, J.Y.; Kang, Y.M.; Kim, Y.M.; Cho, Y.S. GABA-enriched fermented Laminaria japonica
protects against alcoholic hepatotoxicity in Sprague-Dawley rats. Fish Aquat. Sci.
2011
,14, 79–88. [CrossRef]
115.
Kang, Y.M.; Qian, Z.J.; Lee, B.J.; Kim, Y.M. Protective effect of GABA-enriched fermented sea tangle against
ethanol-induced cytotoxicity in HepG2 Cells. Biotechnol. Bioprocess E 2011,16, 966. [CrossRef]
116.
Makris, K.; Spanou, L. Acute kidney injury: Definition, pathophysiology and clinical phenotypes. Clin.
Biochem. Rev. 2016,37, 85–98. [PubMed]
117.
Kim, H.Y.; Yokozawa, T.; Nakagawa, T.; Sasaki, S. Protective effect of gamma-aminobutyric acid against
glycerol-induced acute renal failure in rats. Food Chem. Toxicol. 2004,42, 2009–2014. [CrossRef] [PubMed]
118.
Sasaki, S.; Yokozawa, T.; Cho, E.J.; Oowada, S.; Kim, M. Protective role of gamma-aminobutyric acid against
chronic renal failure in rats. J. Pharm. Pharmacol. 2006,58, 1515–1525. [CrossRef]
119.
Sasaki, S.; Tohda, C.; Kim, M.; Yokozawa, T. Gamma-aminobutyric acid specifically inhibits progression
of tubular fibrosis and atrophy in nephrectomized rats. Biol. Pharm. Bull.
2007
,30, 687–691. [CrossRef]
[PubMed]
120.
Ali, B.H.; Al-Salam, S.; Al Za’abi, M.; Al Balushi, K.A.; AlMahruqi, A.S.; Beegam, S.; Al-Lawatia, I.; Waly, M.I.;
Nemmar, A. Renoprotective effects of gamma-aminobutyric acid on cisplatin-induced acute renal injury in
rats. Basic Clin. Pharmacol. Toxicol. 2015,116, 62–68. [CrossRef] [PubMed]
121.
Talebi, N.; Nematbakhsh, M.; Monajemi, R.; Mazaheri, S.; Talebi, A.; Vafapour, M. The protective
effect of
γ
-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in ovariectomized
estradiol-treated rats. Int. J. Prev. Med. 2016,7, 6.
122.
Saada, H.N.; Eltahawy, N.A.; Hammad, A.S.; Morcos, N.Y.S. Gamma amino butyric acid attenuates liver and
kidney damage associated with insulin alteration in
γ
-irradiated and streptozotocin-treated rats. Arab. J.
Nucl. Sci. Appl. 2016,49, 138–150.
123.
Vafapour, M.; Nematbakhsh, M.; Monajemi, R.; Mazaheri, S.; Talebi, A.; Talebi, N.; Shirdavani, S. Effect
of
γ
-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats:
Gender-related difference. Adv. Biomed. Res. 2015,4, 158.
124.
Chen, Z.; Xie, J.; Wang, B.; Tang, J. Effect of
γ
-aminobutyric acid on digestive enzymes, absorption function,
and immune function of intestinal mucosa in heat-stressed chicken. Poult. Sci.
2014
,93, 2490–2500. [CrossRef]
[PubMed]
125.
Chen, Z.; Xie, J.; Hu, M.Y.; Tang, J.; Shao, Z.F.; Li, M.H. Protective effects of
γ
-aminobutyric acid (gaba) on the
small intestinal mucosa in heat-stressed wenchang chicken. J. Anim. Plant Sci. 2015,25, 78–87.
126. Chen, S.; Tan, B.; Xia, Y.; Liao, S.; Wang, M.; Yin, J.; Wang, J.; Xiao, H.; Qi, M.; Bin, P.; et al. Effects of dietary
gamma-aminobutyric acid supplementation on the intestinal functions in weaning piglets. Food Funct.
2019
,
10, 366–378. [CrossRef] [PubMed]
127.
Xie, M.; Chen, H.H.; Nie, S.P.; Yin, J.Y.; Xie, M.Y. Gamma-aminobutyric acid increases the production of
short-chain fatty acids and decreases pH values in mouse colon. Molecules 2017,22, 653.
128.
Kubota, A.; Kobayashi, M.; Sarashina, S.; Takeno, R.; Yasuda, G.; Narumi, K.; Furugen, A.;
Takahashi-Suzuki, N.; Iseki, K. Gamma-aminobutyric acid (GABA) attenuates ischemia reperfusion-induced
alterations in intestinal immunity. Biol. Pharm. Bull. 2018,41, 1874–1878. [CrossRef] [PubMed]
129.
Jiang, T.; Yue, Y.; Li, F. Improvement of gamma-aminobutyric acid on intestinal mucosalbarrier injury of
colitis induced by 2,4,6-trinitrobenzene sulfonic acid and alcohol. Herald Med. 2018,37, 931–938.
Molecules 2019,24, 2678 23 of 23
130.
Yang, Y.; Lian, Y.T.; Huang, S.Y.; Yang, Y.; Cheng, L.X.; Liu, K. GABA and topiramate inhibit the formation of
human macrophage-derived foam cells by modulating cholesterol-metabolism-associated molecules. Cell.
Physiol. Biochem. 2014,33, 1117–1129. [CrossRef] [PubMed]
131.
Yang, H.; Xing, R.; Liu, S.; Yu, H.; Li, P. Analysis of the protective effects of
γ
-aminobutyric acid during
fluoride-induced hypothyroidism in male Kunming mice. Pharm. Biol.
2019
,57, 29–37. [CrossRef] [PubMed]
132.
Powers, M.E.; Borst, S.E.; McCoy, S.C.; Conway, R.; Yarrow, J.F. The effects of gamma aminobutyric acid on
growth hormone secretion at rest and following exercise. Med. Sci. Sports Exerc. 2003,35, S271. [CrossRef]
133.
Tujioka, K.; Okuyama, S.; Yokogoshi, H.; Fukaya, Y.; Hayase, K.; Horie, K.; Kim, M. Dietary
gamma-aminobutyric acid affects the brain protein synthesis rate in young rats. Amino Acids
2007
,32,
255–260. [CrossRef] [PubMed]
134.
Tujioka, K.; Ohsumi, M.; Horie, K.; Kim, M.; Hayase, K.; Yokogoshi, H. Dietary gamma-aminobutyric acid
affects the brain protein synthesis rate in ovariectomized female rats. J. Nutr. Sci. Vitaminol. (Tokyo)
2009
,55,
75–80. [CrossRef] [PubMed]
135.
Sakashita, M.; Nakamura, U.; Horie, N.; Yokoyama, Y.; Kim, M.; Fujita, S. Oral supplementation using
gamma-aminobutyric acid and whey protein improves whole body fat-free mass in men after resistance
training. J. Clin. Med. Res. 2019,11, 428–434. [CrossRef] [PubMed]
136.
Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev.
2002
,82, 47–95. [CrossRef]
[PubMed]
137.
Pacher, P.; Beckman, J.S.; Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev.
2007
,
87, 315–424. [CrossRef] [PubMed]
138. Pham-Huy, L.A.; He, H.; Pham-Huy, C. Free radicals, antioxidants in disease and health. Int. J. Biomed. Sci.
2008,4, 89–96. [PubMed]
139.
Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and prevention of chronic disease. Crit. Rev. Food. Sci.
Nutr. 2004,44, 275–295. [CrossRef] [PubMed]
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
