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Abstract

GABA orally administered has several beneficial effects on health, including the regulation of hyperglycaemic states in humans. Those effects are similar to the effects reported for camel milk (CMk); however, it is not known whether compounds with GABAergic activity are present in milk from camels or other species. We determined CMk free-GABA concentration by LS/MS and its bioactivity on human GABA receptors. We found that camel and goat milks have significantly more bioavailable GABA than cow and human milks and are able to activate GABAρ receptors. The relationship between GABA and taurine concentrations suggests that whole camel milk may be more efficient to activate GABAρ1 receptors than goat milk. Because GABAρ receptors are normally found in enteroendocrine cells in the lumen of the digestive tract, these results suggest that GABA in camel and goat milk may participate in GABA-modulated functions of enteroendocrine cells in the GI lumen.

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... For metabolic disorders, we mention that GABA tea (a tea product that contains a high level of GABA), may have potential anti-diabetic properties (Cherng et al., 2014;Huang et al., 2014) especially that orally administered GABA has the beneficial effects of regulating the hyperglycaemic states in humans (Limon et al., 2014) indicating the new area of targeting GABA system in non-neurological disorders. ...
... On the other hand, GABA has natural sources such as camel, goat, cow and human milks (Limon et al., 2014). Moreover, literature is describing natural products that contain neuroactive substances that interact with GABA system (Waye et al., 2014;Johnston et al., 2006;Johnston et al., 2009;Alexeev et al., 2012) which is a source of new laboratory compounds for both experimental usage and therapeutic researches. ...
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GABAnergic system is among the most important neural systems due to its physiological, pathological and pharmacological properties. Recent advances regarding its functions have raised theories in terms of new aspects toward future therapeutic approaches. With hope that the data described within this paper, together with the selected references, will inspire both researchers and clinicians to develop new pharmacological methods and treatment methodologies.
... Fractionation of raw CM was achieved through a combination of recent and traditional fractionation procedures (Limon et al., 2014;Oursel et al., 2017;Robinson et al., 2018) and developing innovative extraction methods (Ward, 2009;Hamed et al., 2014Hamed et al., , 2016. Raw milk was obtained from a primiparous camel (C. ...
... After 24 h, it was thawed and then centrifuged at 3,500 × g for 60 min at 4°C (K3 series, Benchtop Centrifuge, Centurion Scientific Ltd., Chichester, UK) to separate hydrophobic portion (lipids) from the hydrophilic one. A sequential filtration was carried out through gauze pads to remove lipids (Limon et al., 2014). Two volumes of pure cold methanol were added to the filtrated portion and incubated at −30°C for 2 h to precipitate proteins, and subsequently, centrifuged at 3,500 × g and 4°C for 30 min. ...
... Fractionation of raw CM was achieved through a combination of recent and traditional fractionation procedures (Limon et al., 2014;Oursel et al., 2017;Robinson et al., 2018) and developing innovative extraction methods (Ward, 2009;Hamed et al., 2014Hamed et al., , 2016. Raw milk was obtained from a primiparous camel (C. ...
... After 24 h, it was thawed and then centrifuged at 3,500 × g for 60 min at 4°C (K3 series, Benchtop Centrifuge, Centurion Scientific Ltd., Chichester, UK) to separate hydrophobic portion (lipids) from the hydrophilic one. A sequential filtration was carried out through gauze pads to remove lipids (Limon et al., 2014). Two volumes of pure cold methanol were added to the filtrated portion and incubated at −30°C for 2 h to precipitate proteins, and subsequently, centrifuged at 3,500 × g and 4°C for 30 min. ...
Article
The aim of this study is to characterize minor lipids in methanol fraction extracted from raw camel milk. The C18 column showed high fractionation efficiency of minor lipids, such as glycosphingolipids, lipopolysaccharides or oligosaccharides when compared to other constituents, in particular polysaccharides, proteins and free fatty acids. LC-ESIMS/ MS in negative ion mode was used to identify 21 new glycosphingolipids, lipopolysaccharides and oligosaccharides. The obtained results showed that the tested fraction is a rich source of glycosphingolipids, lipopolysaccharides and oligosaccharides with antioxidant activity
... Results suggested that in vitro digestion of CM decreases the therapeutic activity of CM insuline. It was also supposed that several antioxidant compounds naturally present in CM might be involved in antidiabetic activities in human population consuming CM. 141 Furthermore, CM also helpful for the treatment of pathological disorders assosiated with diabetes melittus for example enhance antioxidant defense, reduce liver inflamatory coditions, restore injuries and decrease blood chlestrole level. 142 According to the study of Khan et al. 143 dietary supplimentation of CM significatly normalized the elevated level of circulating liver enzymes inculding asparate aminotransferase and alanine aminotransferase (ALT). ...
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Camel milk (CM) is the key component of human diet specially for the population belongs to the arid and semi-arid regions of the world. CM possess unique composition as compare to the cow milk with abundant amount of medium chain fatty acids in fat low lactose and higher concentration of whey protein and vitamin C. Besides the nutritional significance of CM, it also contains higher concentration of bioactive compounds including bioactive pepti-des, lactic acid bacteria (LAB), lactoferrin (LF), lactoperoxidase, lysozyme casein and immuno-globulin. Recently, CM and their bioactive compounds gaining more attention toward scientific community owing to their multiple health benefits, especially in the current era of emerging drug resistance and untold side effects of synthetic medicines. Consumption of fresh or fermented CM and its products presumed exceptional nutraceutical and medicinal properties, including antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, hepatopro-tective, nephroprotective, anticancer and immunomodulatory activities. Moreover, CM isolated LAB exhibit antioxidant and probiotic effects leading to enhance the innate and adaptive immune response against both gram-negative and gram-positive pathogenic bacteria. The main objective of this review is to highlight the nutritional significance, pharmaceutical potential, medicinal value and salient beneficial health aspect of CM for human and animals.
... It is an inhibitory neurotransmitter and produce parasympathetic activity to provide several beneficial effects, for instance, anti-stress (19). Although in the present study, this biomarker increased in stomach and cortex tissue in response to the presence of oseltamivir and salmonella, and decreased with indomethacin plus salmonella in striatum and cerebellum/medulla oblongata, it may participate in GABA-modulated functions of enteroendocrine cells of the gastrointestinal lumen (20). Probably, GABA is differentially involved in the locomotor hyperactivity by manipulations of oseltamivir or indomethacin drugs. ...
Article
The aim of this study was to determine the effect of oseltamivir and indomethacin on lipid peroxidation (LP), GABA levels, and ATPase activity in brain and stomach of normal and infected rats (IR), as novel inflammation model. Female Sprague Dawley rats grouped five each, either in the absence or presence of a live culture of Salmonella typhimurium (S. typh), were treated as follows: group 1 (control), PBS buffer; group 2, oseltamivir (100 mg/kg); group 3, indomethacin (67 μg/rat); group 4, oseltamivir (100 mg/kg) + indomethacin (67 μg/rat). All drugs were given intraperitoneally for 5 days. IR received the same treatments and the brain and stomach of the rats were removed in order to measure levels of GABA, LP, and total ATPase, using validated methods. Levels of GABA increased in stomach and cortex of IR with oseltamivir, but decreased in striatum and cerebellum/medulla oblongata of IR with indomethacin. LP decreased in the three brain regions of IR with oseltamivir. ATPase increased in stomach of IR and non-IR with oseltamivir and in striatum and cerebellum/medulla oblongata of IR with indomethacin. Results suggest that the effect of free radicals produced in an infection and inflammatory condition caused by S. typh could be less toxic by a combination of oseltamivir and indomethacin.
... The presence of high concentration of insulin/insulin-like substances in camel milk such as half-cystine (Agrawal et al., 2003), the effect of small-sized immunoglobulins of camel milk on ␤-cells (Agrawal et al., 2007) and the lack of coagulation of camel milk in the human stomach contribute to the hypoglycemic effect in type-1 diabetes (Agrawal et al., 2003), type-2 diabetes (Ejtahed et al., 2015) in human, rats (Sahani et al., 2005) and in alloxan-induced diabetic dogs (Sboui et al., 2010). The endogenous gammaaminobutyric acid (GABA) bioactivity of camel milk and its hypoglycemic effect have been explored by Limon et al. (2014) and reported that the milk of camel and goat has significantly more bioavailable GABA than that of cow and human and are able to activate GABAq receptors. ...
Article
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Purpose – Camel as a livestock plays an important role in desert ecosystem and its milk has potential contribution in human nutrition in the hot and arid regions of the world. This milk contains all the essential nutrients as found in other milk. Fresh and fermented camel milk has been used in different regions in the world including India, Russia and Sudan for human consumption as well as for treatment of a series of diseases such as dropsy, jaundice, tuberculosis, asthma and leishmaniasis or kala-azar. The present paper aims to explore the possibility of camel milk as an alternative milk for human consumption. Design/methodology/approach – Recently, camel milk and its components were also reported to have other potential therapeutic properties, such as anti-carcinogenic, anti-diabetic, anti-hypertensive and renoprotective potential; and for autism, and has been recommended to be consumed by children who are allergic to bovine milk. Findings – It has also been reported to alleviate oxidative stress and lipid peroxidation in rats. Camel milk differs from bovine milk in composition. It contains low total solids and fat; however, proteins and lactose are in equal amount but of higher quality than cow milk. Because of the high percentage of β-casein, low percentage of α-casein, deficiency of β-lactoglobulin and similarity of the immunoglobulins, it become safer for persons who are allergic to bovine milk. It contains protective proteins in higher amount which contributes to its functionality. The fermentation and enzymatic hydrolysis of camel protein produce different types of bioactive peptides which exerts different activity in in vitro and in vivo conditions. Originality/value – Because of its unique quality and functionality, this milk has potential application in management of different diseases and application in food industries.
... The presence of GABA, the natural agonist of the GABA A R, in various foods has been shown before [19][20][21]. To determine if the observed effects resulted from endogenous GABA in the plant extracts, their GABA concentrations were analysed by HPLC-FLD after derivatisation with OPA. ...
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Potentiation of γ-amino butyric acid (GABA)-induced GABAA receptor (GABAAR) activation is a common pathway to achieve sedative, sleep-enhancing, anxiolytic, and antidepressant effects. Presently, a three-component test system was established for the identification of novel GABAAR modulating food plants. In the first step, potentiation of GABA-induced response of the GABAAR was analysed by two-electrode voltage clamp (TEVC) for activity on human α1β2-GABAAR expressed in Xenopus laevis oocytes. Positively tested food plants were then subjected to quantification of GABA content by high-performance liquid chromatography with fluorescence detection (HPLC–FLD) to exclude test foods, which evoke a TEVC-response by endogenous GABA. In the third step, specificity of GABAA-modulating activity was assessed by TEVC analysis of Xenopus laevis oocytes expressing the homologous glycine receptor (GlyR). The three-component test was then applied to screen 10 aqueous extracts of food plants for their GABAAR activity. Thus, hop cones (Humulus lupulus) and Sideritis sipylea were identified as the most potent specific GABAAR modulators eliciting significant potentiation of the current by 182 ± 27 and 172 ± 19 %, respectively, at the lowest concentration of 0.5 μg/mL. The extracts can now be further evaluated by in vivo studies and by structural evaluation of the active components.
... CM has been reported to exhibit protective properties against diabetes, including type I and II, by reducing demand for insulin in patients and improving residual b-cell function in the pancreas, considering its immunomodulatory influence. The anti-inflammatory effect and high concentration of antioxidants probably possess positive roles in curing diabetes too (Limon et al., 2014). CM with high amount of insulin can resist against coagulum formation in the stomach, and therefore becomes available for absorption in the small intestine . ...
Article
Drinking non-bovine milk has been reported to possess bio-functionality for regular consumers. Camel milk is a traditional product that has been used for many years in arid rural communities of Asia and Africa as a biomedicine to cure several health issues such as asthma, oedema, and diabetes. The product consists of appropriate amounts of bioactive compounds. In addition, it contains low amounts of fatty acids and cholesterol, whilst it does not contain β-lactoglobulin. The latter, which is present in bovine milk, causes allergic symptoms in some people. The similarity of the formula to human milk suggests this superfood as an alternative for bovine milk with complete nutrition for infants. In this review, the biomolecules present in camel milk and their positive roles on the health of consumers are extensively discussed.
... Also, it was found that some compounds may be positively modulating GABA responses, for example, taurine potentiates GABA receptors at concentrations below 30 μM but inhibits them at concentrations higher than 300 μM. Limon et al. (2014) evaluated endogenous GABA bioactivity of camel, bovine, goat, and human milk by GABA ρ receptors as sensors for GABA in milk. The authors found that camel and goat milk have significantly more bioavailable GABA than cow and human milk and are capable to activate GABA ρ receptors. ...
Chapter
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Camel milk is known for its medicinal properties, which have been widely exploited for human health since ancient times. Many studies have reported that camel milk has potential therapeutic properties such as antidiabetic, wound healing in diabetic patients, hepatitis C infection curing, treatment of autism, hypoallergenic effect, and antihypertensive. It has also been proven as a good alternative for people with cow milk allergy and as a therapeutic agent to reduce the harmful effects of exposure to toxins. Most of these properties are attributed to the unique characteristics of camel milk proteins, especially whey protein. Therefore in this chapter, the health-promoting activities of camel milk and their protein hydrolysates as well as their potential as an alternative for people with cow milk allergy was discussed.
... Lactase persistence or lactose tolerance occurs due to mutation in the human genome leading to adults being able to consume milk thereby increasing the demand for milk, and increasing the price of milk required to sustain the young generation to adulthood (18). Efforts to provide a solution for these problems have led to the production and consumption of milk from other animals including cow, buffalo, and goats (16,20,21). Recent findings have implicated that the consumption of milk from these animals led to the development of health complications such as body pains, deformed body structure in both adult male and female, early breast development among under-aged children due to hormonal imbalance generated by interference of other hormones meant for these lower animals, in humans (22). ...
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A new plant milk was discovered from the seed of Adenanthera pavonina. The physicochemical and nutritional properties of the new pro-milk extract were assessed, and their biochemical effects were compared with those of soy bean extracts. Eleven groups of three albino rats each were used to assess the health benefits of the pro-milk. Groups were separately administered 3.1, 6.1, and 9.2 µl/g animal wt. pro-milk extract from A. pavonina seed, 6.1 µl/g animal wt. milk extract from soybean, and 6.1 µl/g animal wt. normal saline for 7 or 14 days. The “baseline” group consisted of those sacrificed on day 0. Among the physical properties considered, the pro-milk from A. pavonina had significantly higher (P < 0.05) hue color value and significantly lower (P < 0.05) L* than that from soy bean did. The pro-milk from A. pavonina had a significantly higher (P < 0.05) level of protein (36.14 ± 0.12%), Ca (440.99 ± 0.93 mg/l), Mg (96.69 ± 0.03 mg/l), K (190.41 ± 0.11 mg/l), Na (64.24 ± 0.24 mg/l), and Cu (0.55 ± 0.24 mg/l), and a significantly lower (P < 0.05) level of Mn (0.04 ± 0.01 mg/l) and vitamins A (undetectable), C (1.87 ± 0.01 mg/100 g), and E (0.12 ± 0.01 mg/100 g) compared to those of soy milk. The daily consumption of the pro-milk extract from A. pavonina for 14 days significantly reduced (P < 0.05) Ca2+-adenosine triphosphate synthase (Ca2+-ATPase) at low dose (3.1 µl/g animal wt.), but significantly increased (P < 0.05) Mg2+-ATPase at high dose (9.2 µl/g animal wt.). Daily administration of the A. pavonina extract for 14 days caused a significant reduction (P < 0.05) in acetylcholinesterase activity in the liver, intestine, heart, and kidney, suggesting that the pro-milk may facilitate ions transportation across the membrane. The pro-milk offers promising beneficial effects for patients with neurological diseases, as well as supporting general health owing to the high protein and mineral content. Vitamins fortification is recommended during production.
... The results are in the same line as previous studies that show CAM induced GABA biogenic activity. 56 It is well known that GABA acts as a negative regulator of dopamine, thus CAM reduces the level of dopamine and serotonin. CAM showed anti-inflammatory and anti-apoptotic effects indicated by significant reduction of expression of TNF-α, BAX and caspase 3. ...
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The aspect of treatment of autistic behaviour was investigated using valproic acid rat model of pregnant female rats. Two main groups (10 male rats/group) were treated for 6 days and then divided into six subgroups. The first group of normal rats was divided into three subgroups: (A) – control group, (B) – treated with camel milk (CAM; 2 mL/p.o) and (C) – treated with leptin (1000 µg/kg i.p) twice daily. The second group of autistic rats was randomly distributed into four subgroups as follows: (D) – positive control (autistics rats), (E) – treated with CAM, (F) – treated with a moderate dose of leptin and (G) – treated with a higher dose of leptin. Autistic behaviours of male offspring were checked by grooming and elevated pulz maze tests. Valproic acid (VPA)-induced autistic rats showed severe changes in oxidative stress markers, neurotransmitters and inflammatory cytokines, besides genotoxic manifestation of expression of tumour necrosis factor (TNF)-α, Bax and caspase-3. Leptin or CAM alone showed no signs of toxicity. CAM showed pronounced improvement in control rats than control itself. Leptin or CAM treatment of autistic animals showed a significant improvement of all measured parameters and genetic expression values. The improvement was pronounced in animals treated with CAM. These results suggest that CAM is a potential therapeutic candidate for autism via regulation of inflammatory and apoptotic pathways. Leptin plays an essential role in alleviation of autistic behaviour through antioxidant effects.
... Camel milk has been known for its ability to promote bone formation in infants, and its curative properties against many internal diseases [22]. Nowadays, these medicinal virtues have been scientifically supported, in particular, the association of camel milk with a decreased prevalence of diabetes type I and II by reducing the demand for insulin in patients and improving residual β-cell function in the pancreas, due to its immunomodulatory influence [23]. This hypoglycemic potential is either due to the presence of insulin-like small molecules that are easily absorbed into circulation compared to insulin from other sources or to the existence of insulin in camel milk in indigestible form, i.e., encapsulated in nanoparticles (lipid vesicles) [24]. ...
... Other elements in CM may also potentially contribute to its antidiabetic activity. For example, antioxidants in CM may also be capable of regulating hyperglycaemic states in humans (Limon et al., 2014). ...
Article
Camel milk is superior to bovine milk and quite close to human milk in terms of its nutritional value. It contains high concentrations of many bioactive compounds that are essential for human health. Despite its profound nutritional and health benefits, food products produced from camel milk are still very limited compared to bovine milk. Differences in the composition of bovine and camel milk make the production processes for bovine milk products unsuitable for camel milk products. Therefore, a comprehensive understanding regarding the composition, bioactive compounds, and the heat stability of camel milk is essential to preserve the inherent nutritional value of camel milk while achieving desirable attributes in the final products. In this review, the properties and functionalities of macro-nutrients in camel milk, especially heat stability of camel milk and its proteins are described. In addition, technical aspects of the production of various camel milk products, including difficulties in their production and directions for further research to enhance their quality, are comprehensively discussed.
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Camel milk (CM) is the key component of human diet specially for the population belongs to the arid and semi-arid regions of the world. CM possess unique composition as compare to the cow milk with abundant amount of medium chain fatty acids in fat low lactose and higher concentration of whey protein and vitamin C. Besides the nutritional significance of CM, it also contains higher concentration of bioactive compounds including bioactive peptides, lactic acid bacteria (LAB), lactoferrin (LF), lactoperoxidase, lysozyme casein and immunoglobulin. Recently, CM and their bioactive compounds gaining more attention toward scientific community owing to their multiple health benefits, especially in the current era of emerging drug resistance and untold side effects of synthetic medicines. Consumption of fresh or fermented CM and its products presumed exceptional nutraceutical and medicinal properties, including antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, hepatoprotective, nephroprotective, anticancer and immunomodulatory activities. Moreover, CM isolated LAB exhibit antioxidant and probiotic effects leading to enhance the innate and adaptive immune response against both gram-negative and gram-positive pathogenic bacteria. The main objective of this review is to highlight the nutritional significance, pharmaceutical potential, medicinal value and salient beneficial health aspect of CM for human and animals
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The effect of orally administrated gamma-aminobutyric acid (GABA) on relaxation and immunity during stress has been investigated in humans. Two studies were conducted. The first evaluated the effect of GABA intake by 13 subjects on their brain waves. Electroencephalograms (EEG) were obtained after 3 tests on each volunteer as follows: intake only water, GABA, or L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into 2 groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. Placebo group showed marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within 1 hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.
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Anatomical visualization of neurotransmitter receptor localization is facilitated by tagging receptors, but this process can alter their functional properties. We have evaluated the distribution and properties of WT glutamate receptor 3 (GluR3) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (WT GluR3) and two receptors in which GFP was tagged to the amino terminus (GFP-GluR3) or to the carboxyl terminus (GluR3-GFP). Although the fluorescence in Xenopus oocytes was stronger in the vegetal hemisphere because of localization of internal structures (probable sites of production, storage or recycling of receptors), the insertion of receptors into the plasma membrane was polarized to the animal hemisphere. The fluorescence intensity of oocytes injected with GluR3-GFP RNA was approximately double that of oocytes injected with GFP-GluR3 RNA. Accordingly, GluR3-GFP oocytes generated larger kainate-induced currents than GFP-GluR3 oocytes, with similar EC(50) values. Currents elicited by glutamate, or AMPA coapplied with cyclothiazide, were also larger in GluR3-GFP oocytes. The glutamate- to kainate-current amplitude ratios differed, with GluR3-GFP being activated more efficiently by glutamate than the WT or GFP-GluR3 receptors. This pattern correlates with the slower decay of glutamate-induced currents generated by GluR3-GFP receptors. These changes were not observed when GFP was tagged to the amino terminus, and these receptors behaved like the WT. The antagonistic effects of 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were not altered in any of the tagged receptors. We conclude that GFP is a useful and convenient tag for visualizing these proteins. However, the effects of different sites of tag insertion on receptor characteristics must be taken into account in assessing the roles played by these receptor proteins.
Article
Taurine, considered a `conditionally essential amino acid' and the profile of free amino acids in milk from four different goat breeds bred in Italy (Garganica, Maltese, Saanen and Derivata di Siria) were determined by using a new physico-chemical purification system. The trial involved three different stages of lactation: beginning, middle and final. Taurine was the most representative free amino acid in goat milk, followed by glycine, glutamine and glutamic acid. Taurine was significantly the highest in the Maltese breed milk (90.90 vs. 55.21, 49.59 and 36.80μmol/100ml in Garganica, Derivata di Siria and Saanen, respectively). Also, the total amino acid content in the Maltese breed was significantly higher (252.10μmol/100ml vs. 200.62 in Derivata di Siria, 200.45 in Garganica and 174.42 in Saanen). As far as the trend during lactation was concerned, the Tau amount was the highest at the final stage, but a significant difference was found only between the second and the final stages. The multivariate analysis of variance showed a highly significant difference (P=0.0001) for breed factor, lactation stage factor and for their interaction. This investigation showed also that the milk from goats, bred in Italy, and especially from the Mediterranean breeds, had a high content of taurine in all stages of lactation, and new-borns and infants fed goat milk do not need any addition of this amino acid. Further investigations are needed to verify if Maltese milk has higher taurine contents than other breeds.
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GABAρ1 receptors are highly expressed in bipolar neurons of the retina and to a lesser extent in several areas of the central nervous system (CNS), and dopamine and serotonin are also involved in the modulation of retinal neural transmission. Whether these biogenic amines have a direct effect on ionotropic GABA receptors was not known. Here, we report that GABAρ1 receptors, expressed in X. laevis oocytes, were negatively modulated by dopamine and serotonin and less so by octopamine and tyramine. Interestingly, these molecules did not have effects on GABA(A) receptors. 5-Carboxamido-tryptamine and apomorphine did not exert evident effects on any of the receptors. Schild plot analyses of the inhibitory actions of dopamine and serotonin on currents elicited by GABA showed slopes of 2.7 ± 0.3 and 6.1 ± 1.8, respectively, indicating a noncompetitive mechanism of inhibition. The inhibition of GABAρ1 currents was independent of the membrane potential and was insensitive to picrotoxin, a GABA receptor channel blocker and to the GABAρ-specific antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl phosphinic acid (TPMPA). Dopamine and serotonin changed the sensitivity of GABAρ1 receptors to the inhibitory actions of Zn(2+). In contrast, La(3+) potentiated the amplitude of the GABA currents generated during negative modulation by dopamine (EC(50) 146 μM) and serotonin (EC(50) 196 μM). The functional role of the direct modulation of GABAρ receptors by dopamine and serotonin remains to be elucidated; however, it may represent an important modulatory pathway in the retina, where GABAρ receptors are highly expressed and where these biogenic amines are abundant.
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γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABA(A)R), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABA(A)R agonist and antagonist. The effect of GABA(A)R antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABA(A)R subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABA(A)R agonist induced an inward current and depolarized IEC-18. Both GABA and the GABA(A)R agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABA(A)R antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which upregulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea.
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GABA(A) receptors mediate both synaptic and extrasynaptic actions of GABA. In several neuronal populations, α4 and δ subunits are key components of extrasynaptic GABA(A) receptors that strongly influence neuronal excitability and could mediate the effects of neuroactive agents including neurosteroids and ethanol. However, these receptors can be difficult to study in native cells and recombinant δ subunits can be difficult to express in heterologous systems. We engineered concatemeric (fused) subunits to ensure δ and α4 subunit expression. We tested the pharmacology of the concatemeric receptors, compared with a common synaptic-like receptor subunit combination (α1 +β2 +γ2L), and with free-subunit α4/δ receptors, expressed in Xenopus oocytes. δ-β2 -α4 +β2-α4 cRNA co-injected into Xenopus oocytes resulted in GABA-gated currents with the expected pharmacological properties of α4/δ-containing receptors. Criteria included sensitivity to agonists of different efficacy, sensitivity to the allosteric activator pentobarbital, and modulation of agonist responses by DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide; a δ-selective positive modulator), furosemide, and Zn(2+) . We used the concatemers to examine neurosteroid sensitivity of extrasynaptic-like, δ-containing receptors. We found no qualitative differences between extrasynaptic-like receptors and synaptic-like receptors in the actions of either negative or positive neurosteroid modulators of receptor function. Quantitative differences were explained by the partial agonist effects of the natural agonist GABA and by a mildly increased sensitivity to low steroid concentrations. The neurosteroid structure-activity profile for α4/δ-containing extrasynaptic receptors is unlikely to differ from that of synaptic-like receptors such as α1/β2/γ2-containing receptors.
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Hypoglycemic effect of camel milk supplementation in experimental rat model and significant reduction in doses of insulin in type 1 diabetic patients have been observed in our previous studies. This long-term study was undertaken to assess the efficacy, safety and acceptability of camel milk as an adjunct to insulin therapy in type 1 diabetics. In this 2-year randomized clinical, parallel design study, 24 type 1 diabetics were enrolled and divided into two groups. Group I (n=12) received usual care, that is, diet, exercise and insulin and Group II (n=12) received 500 ml camel milk in addition to the usual care. Insulin requirement was titrated weekly by blood glucose estimation. Results were analyzed by using the regression technique. In camel milk group, there was decrease in mean blood glucose (118.58±19-93.16±17.06 mg/dl), hemoglobin A1c levels (7.81±1.39-5.44±0.81%) and insulin doses (32.50±9.99-17.50±12.09 U/day, P<0.05). Out of 12 subjects receiving camel milk, insulin requirement in 3 subjects reduced to zero. There was nonsignificant change in plasma insulin and anti-insulin antibodies in both the groups. It may be stated that camel milk is safe and efficacious in improving long-term glycemic control, with a significant reduction in the doses of insulin in type 1 diabetic patients.
Article
Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals: glial-like (type I) cells, receptor (type II) cells, and presynaptic (type III) cells. Using a combination of Ca2+ imaging, single-cell reverse transcriptase-PCR and immunostaining, we show that GABA is an inhibitory transmitter in mouse taste buds, acting on GABA(A) and GABA(B) receptors to suppress transmitter (ATP) secretion from receptor cells during taste stimulation. Specifically, receptor cells express GABA(A) receptor subunits β2, δ, and π, as well as GABA(B) receptors. In contrast, presynaptic cells express the GABA(A) β3 subunit and only occasionally GABA(B) receptors. In keeping with the distinct expression pattern of GABA receptors in presynaptic cells, we detected no GABAergic suppression of transmitter release from presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in type I taste cells as well as by GAD67 in presynaptic (type III) taste cells and is stored in both those two cell types. We conclude that GABA is an inhibitory transmitter released during taste stimulation and possibly also during growth and differentiation of taste buds.
Article
Kaitocephalin is the first discovered natural toxin with protective properties against excitotoxic-death of cultured neurons induced by N-methyl-d-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainic acid (kainate, KA) receptors. Nevertheless, the effects of kaitocephalin on the function of these receptors were unknown. In this work we report some pharmacological properties of synthetic (-)-kaitocephalin on rat brain glutamate receptors expressed in Xenopus laevis oocytes and, on the homomeric AMPA-type GluR3 and KA-type GluR6 receptors. Kaitocephalin was found to be a more potent antagonist of NMDA receptors (IC(50) = 75 +/- 9 nM) than of AMPA receptors from cerebral cortex (IC(50) = 242 +/- 37 nM) and from homomeric GluR3 subunits (IC(50) = 502 +/- 55 nM). Moreover, kaitocephalin is a weak antagonist of the KA-type receptor GluR6 (IC(50) ~ 100 muM) and of metabotropic (IC(50) > 100 muM) glutamate receptors expressed by rat brain mRNA.
Article
GABArho1 receptors are formed by homopentameric assemblies that gate a chloride ion-channel upon activation by the neurotransmitter. Very little is known about the structural and functional roles played by the different domains that form each subunit; but one of them, the fourth transmembrane segment (TM4), is known to form a hydrophobic bundle together with three other TM segments that are necessary to stabilize the structure of the receptor. In this study we progressively removed amino acid residues from the C-terminus of the human GABArho1 and studied the functional properties of the receptor mutants expressed in X. laevis oocytes. We found that deletions of up to the last four residues gave rise to receptors that were still functional, generating currents of 3.92 microA for the wt, 5.75 microA for S479X, 1.82 microA for F478X, 0.52 microA for I477X and 0.27 microA for S476X when exposed to 5 microM GABA; surprisingly, the mutant with one residue removed resulted more sensitive to the agonists. Further deletions, up to residue W475, resulted in receptors that did not gate an ion-channel. In addition, deleting the signal sequence, from R2-A15, in the N-terminus produced non-functional receptors. This study reveals that GABArho1 can tolerate removal of several residues that form the fourth transmembrane segment up to a critical point, signaled by W475, beyond which the mutant protein is translated but does not form functional receptors. A comparative study is presented of some electrophysiological and pharmacological properties of the deletion mutants that were able to generate GABA currents.
Article
There is a traditional belief in the Middle East that regular consumption of camel milk may aid in prevention and control of diabetes. The aim of this work was to evaluate the efficacy of camel milk as an adjuvant therapy in young type 1 diabetics. This 16-week randomized study enrolled 54 type 1 diabetic patients (average age 20 years) selected from those attending the outpatient diabetes clinic of the Menofia University Hospital, affiliated with Egypt's National Cancer Institute. Subjects were randomly divided into two groups of 27 patients: one received usual management (diet, exercise, and insulin), whereas the other received 500 mL of camel milk daily in addition to standard management. A control group of 10 healthy subjects was also assessed. The following parameters were evaluated at baseline and at 4 and 16 weeks: hemoglobin A1c (HbA1c), human C-peptide, lipid profile, serum insulin, anti-insulin antibodies, creatinine clearance, albumin in 24-hour urine, body mass index, and Diabetes Quality of Life score. The following parameters were significantly different between the usual-management group versus the camel milk group after 16 weeks: fasting blood sugar (227.2 +/- 17.7 vs. 98.9 +/- 16.2 mg/dL), HbA1c (9.59 +/- 2.05[%] vs. 7.16 +/- 1.84[%]), serum anti-insulin antibodies (26.20 +/- 7.69 vs. 20.92 +/- 5.45 microU/mL), urinary albumin excretion (25.17 +/- 5.43 vs. 14.54 +/- 5.62 mg/dL/24 hours), daily insulin dose (48.1 +/- 6.95 vs. 23 +/- 4.05 units), and body mass index (18.43 +/- 3.59 vs. 24.3 +/- 2.95 kg/m(2)). Most notably, C-peptide levels were markedly higher in the camel milk group (0.28 +/- 0.6 vs. 2.30 +/- 0.51 pmol/mL). These results suggest that, as an adjunct to standard management, daily ingestion of camel milk can aid metabolic control in young type 1 diabetics, at least in part by boosting endogenous insulin secretion.
Article
In this review we attempt to summarize experimental evidence on the existence of defined native GABA(A) receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA(A) receptors (Pharmacol Rev 50:291-313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA(A) receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. GABA(A) receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA(A) receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."
Article
Taurine and other free amino acids have been determined in human milk of a number of other species. Taurine is the most abundant free amino acid in the milk of the gerbil, mouse, cat, dog and rhesus monkey. Taurine is the second most abundant amino acid in the milk of the rat, baboon, chimpanzee, sheep, Java monkey and man. Taurine is not a major constituent in the milk of the guinea pig, rabbit, cow and horse. The milk of each species has a characteristic free amino acid pattern which may be an indication of the relative nutritional importance of these compounds during early postnatal development.
Membrane currents were investigated in Xenopus laevis oocytes under voltage clamp. Depolarizing pulses, given from a holding potential of about-100 mV, elicited a transient outward current when the membrane potential was made more positive than about-20 mV. As the potential was made increasingly positive the transient outward current first increased and then decreased. The amplitude of the transient current increased when the external Ca2+ concentration was raised; and the current was abolished by Mn2+. It appears that when the membrane is depolarized Ca2+ ions enter the oocyte and trigger an outward current, possibly by opening C1- channels.
Article
The high concentrations of gamma aminobutyric acid (GABA) in the pancreatic islets and the neurotransmitter role played by this amino acid in the central nervous system, make it plausible that GABA also intervenes in the control of endocrine pancreatic function. In 12 normal subjects, a single oral dose of 5 or 10 g GABA, as compared to placebo, caused a significant (p less than 0.01) and dose-dependent (p less than 0.01) increase of plasma levels of immunoreactive insulin, C peptide and glucagon, without affecting plasma glucose concentration. By contrast, in 15 additional subjects, a single oral dose of 5 mg muscimol, a specific GABA receptor agonist, did not consistently influence the above parameters. Although the lack of effects of muscimol might indicate that the action of GABA is not mediated through specific receptors, the results with GABA suggest that this amino acid plays a specific role in the regulation of endocrine pancreatic function.
Article
Poly(A)+ RNA from mammalian retina expresses bicuculline/baclofen-insensitive gamma-aminobutyric acid (GABA) receptors in Xenopus oocytes with properties similar to those of homooligomeric GABA rho 1 receptors. The pharmacological profile of these rho-like receptors was extended by measuring sensitivities to various GABAA and GABAB receptor ligands. For direct comparison the same compounds were also assayed with GABAA receptors expressed by rat brain RNA. The potency sequence for heterocyclic GABA analogues at the GABA rho-like receptors was GABA (1.3) > muscimol (2.3) > isoguvacine (100) (approximate EC50 in parentheses; all EC50 and Kb values given in microM). Both muscimol and isoguvacine were partial agonists at the rho-like receptors. 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (Kb congruent to 32), piperidine-4-sulfonic acid (Kb congruent to 85), and isonipecotic acid (Kb congruent to 1000) acted primarily as competitive antagonists, showing little or no activity as agonists. The sulfonic acid GABA analogue 3-aminopropanesulfonic acid was also a competitive antagonist (Kb congruent to 20). Conformationally restricted GABA analogues trans- and cis-4-aminocrotonic acid (TACA and CACA) were agonists at the rho-like receptors. TACA (EC50 congruent to 0.6) had twice the potency of GABA and was 125 times more potent than CACA (EC50 congruent to 75). Z-3-(Amidinothio)propenoic acid, an isothiouronium analogue of GABA, had little activity as an agonist but instead acted as a competitive antagonist (Kb congruent to 20). At concentrations of > 100 microM, bicuculline did have some weak competitive inhibitory effects on the GABA rho-like receptors (Kb congruent to 6000), but it was at least 5000 times more potent at GABAA receptors. Strychnine (Kb congruent to 70) and SR-95531 (Kb congruent to 35) also were competitive inhibitors of the rho-like receptors but were, respectively, 20 and 240 times more potent at GABAA receptors. The GABAB receptor ligands baclofen, phaclofen, and saclofen (1-100 microM) had no appreciable effects on the rho-like receptors. In contrast, 3-aminopropylphosphonic acid, the phosphonic acid analogue of GABA, acted as a competitive antagonist (Kb congruent to 10), and 3-aminopropylphosphinic acid and 3-aminopropyl(methyl)-phosphinic acid were moderately potent antagonists (Kb congruent to 1.7 and 0.8, respectively). delta-Aminovaleric acid was also an antagonist (Kb congruent to 20), whereas 4-aminobutylphosphonic acid, the phosphonic acid analogue of delta-aminovaleric acid, was only a weak inhibitor (Kb congruent to 600).(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Although GABA(C) receptors play a crucial role in the mammalian central nervous system, their functional expression in peripheral tissues has not yet been studied. Using the gut neuroendocrine tumor cell line STC-1 as a model, we provide first evidence for the functional expression of GABA(C) receptors in the gut: mRNAs of the GABA(C) receptor subunits rho1 and rho2 were detected in STC-1 cells by reverse transcription polymerase chain reaction (RT-PCR). Applying anti-rho-antibodies, specific immunostaining for GABA(C) receptors was observed. For functional characterization, the effects of GABA(C) receptor activation on [Ca2+]i and hormone secretion were studied. The selective GABA(C) receptor agonist cis-4-aminocrotonic acid (CACA) induced dose-dependent increases both of [Ca2+]i and of hormone (cholecystokinin) secretion. The stimulatory effects of CACA were antagonized by the GABA(C) receptor blockers (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and 3-aminopropyl(methyl)phosphinic acid (3-APMPA). These results demonstrate that GABA(C) receptors play an important role in neuroendocrine gastrointestinal secretion.
Article
The gamma-aminobutyric acid (GABA(B)) receptor has been shown to be a heterodimer consisting of two receptor subunits, GABA(B1) and GABA(B2). We have stably co-expressed these two subunits in a CHO cell line, characterised its pharmacology and compared it to the native receptor in rat brain membranes. Radioligand binding using [3H]CGP54626A demonstrated a similar rank order of potency between recombinant and native receptors: CGP62349>CGP54626A>SCH 50911>3-aminopropylphosphinicacid(3-APPA)>GABA>baclofen>saclofen>phaclofen. However, differences were observed in the affinity of agonists, which were higher at the native receptor, suggesting that in the recombinant system a large number of the receptors were in the low agonist affinity state. In contrast, [35S]GTPgammaS binding studies did not show any differences between recombinant and native receptors with the full agonists GABA and 3-APPA. Measurement of cAMP accumulation in the cells revealed a degree of endogenous coupling of the receptors to G-proteins. This is most likely to be due to the high expression levels of receptors (B(max)=22.5+/-2.5pmol/mg protein) in this experimental system. There was no evidence of GABA(B2) receptors, when expressed alone, binding [3H]CGP54626A, [3H]GABA, [3H]3-APPA nor of GABA having any effect on basal [35S]GTPgammaS binding or cAMP levels.
Article
The free amino acids of native milk from human beings, cows and goats at different periods of lactation were measured by ion-exchange column chromatography. Heat-treated milk (pasteurized, evaporated and powdered) and a milk substitute made from soybeans were screened by two-dimensional paper chromatography for free amino acids. A representative of each type of heat-treated milk was analyzed by ion-exchange chromatography. Marked differences were observed between human native milk, heat-treated animal milk and soybean milk substitutes. Soybean milk substitute and colostrum were found to be rich in their free amino acid content.
Article
The incretin hormone, glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells following food ingestion. Its secretion is triggered by a range of nutrients, including fats, carbohydrates and proteins. We reported previously that Na(+)-dependent glutamine uptake triggered electrical activity and GLP-1 release from the L-cell model line GLUTag. However, whereas alanine also triggered membrane depolarization and GLP-1 secretion, the response was Na+ independent. A range of alanine analogues, including d-alanine, beta-alanine, glycine and l-serine, but not d-serine, triggered similar depolarizing currents and elevation of intracellular [Ca2+], a sensitivity profile suggesting the involvement of glycine receptors. In support of this idea, glycine-induced currents and GLP-1 release were blocked by strychnine, and currents showed a 58.5 mV shift in reversal potential per 10-fold change in [Cl-], consistent with the activation of a Cl(-)-selective current. GABA, an agonist of related Cl- channels, also triggered Cl- currents and secretion, which were sensitive to picrotoxin. GABA-triggered [Ca2+]i increments were abolished by bicuculline and partially impaired by (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), suggesting the involvement of both GABA(A) and GABA(C) receptors. Expression of GABA(A), GABA(C) and glycine receptor subunits was confirmed by RT-PCR. Glycine-triggered GLP-1 secretion was impaired by bumetanide but not bendrofluazide, suggesting that a high intracellular [Cl-] maintained by Na(+)-K(+)-2Cl- cotransporters is necessary for the depolarizing response to glycine receptor ligands. Our results suggest that GABA and glycine stimulate electrical activity and GLP-1 release from GLUTag cells by ligand-gated ion channel activation, a mechanism that might be important in responses to endogenous ligands from the enteric nervous system or dietary sources.
Article
Preliminary trials reflected the low prevalence of diabetes in Raica community consuming camel milk habitually. Our objective was to describe the prevalence and clinical factors associated with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes (DM) among adults (>or=20 years) in large population group. Population based, cross sectional study 2099 participants from different villages of north-west Rajasthan were selected using stratified sampling of a representative Raica and non-Raica Community, consuming or not consuming camel milk. Demographic, clinical, anthropometric parameters were obtained and oral glucose tolerance tests were performed in all individuals to diagnose IFG, IGT and DM. Associations were investigated using multivariate logistic regression using SPSS Version 10.0. In the present study, the prevalence of diabetes in Raica community consuming camel milk (RCCM, n=501) was 0%; Raica community not consuming camel milk (RCNCM, n=554) was 0.7%; non-Raica community consuming milk (NRCCM, n=515) was 0.4% and non-Raica community not consuming camel milk (NRCNCM, n=529) was 5.5%. Stepwise logistic regression analysis showed that consumption of camel milk was statistically highly significant as protective factor for diabetes. Multiple logistic regression analysis revealed that camel milk consumption and community factor were associated with decreased prevalence of diabetes. Camel milk consumption and lifestyle have definite influence on prevalence of diabetes. Hence, adopting such life pattern may play protective role in preventing diabetes to some extent.
Properties of GluR3 receptors tagged with GFP at the amino or carboxyl terminus. Proceeding of the National Academy of Science of the United States of America
  • A Limon
  • J M Reyes-Ruiz
  • F Eusebi
  • R Miledi
Limon, A., Reyes-Ruiz, J. M., Eusebi, F., & Miledi, R. (2007). Properties of GluR3 receptors tagged with GFP at the amino or carboxyl terminus. Proceeding of the National Academy of Science of the United States of America, 104(39), 15526-15530.
International union of pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: Classification on the basis of subunit composition, pharmacology, and function
  • R W Olsen
  • W Sieghart
Olsen, R. W., & Sieghart, W. (2008). International union of pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: Classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacological Reviews, 60(3), 243-260.
GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes
  • N Soltani
  • H Qiu
  • M Aleksic
  • Y Glinka
  • F Zhao
  • R Liu
Soltani, N., Qiu, H., Aleksic, M., Glinka, Y., Zhao, F., Liu, R., et al. (2011). GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proceedings of the National Academy of Sciences of the United States of America, 108(28), 11692-11697.