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Fulltext Molecular identification and phylogenetic analysis of GABA-producing lactic acid bacteria isolated from indigenous dadih of West Sumatera, Indonesia

Anggraini L, Marlida Y, Wizna W, Jamsari J, Mirzah M, Adzitey F, et al.

F1000Res, 2018 10 19;7:1663.
PMID: 32201563 DOI: 10.12688/f1000research.16224.3

Background: Dadih (fermented buffalo milk) is a traditional Indonesian food originating from West Sumatra province. The fermentation process is carried out by lactic acid bacteria (LAB), which are naturally present in buffalo milk. Lactic acid bacteria have been reported as one of potential producers of γ-aminobutyric acid (GABA). GABA acts as a neurotransmitter inhibitor of the central nervous system. Methods: In this study, molecular identification and phylogenetic analysis of GABA producing LAB isolated from indigenous dadih of West Sumatera were determined. Identification of the GABA-producing LAB DS15 was based on conventional polymerase chain reaction. 16S rRNA gene sequence analysis was used to identify LAB DS15. Results: PCR of the 16S rRNA gene sequence of LAB DS15 gave an approximately 1400 bp amplicon. Phylogenetic analysis showed that LAB DS15 was Pediococcusacidilactici, with high similarity of 99% at 100% query coverage to Pediococcusacidilactici strain DSM 20284. Conclusions: It can be concluded that GABA producing LAB isolated from indigenous dadih was Pediococcus acidilactici.

Matched MeSH terms: gamma-Aminobutyric Acid*
Glutamate application maintains quality and antioxidant capacity of fresh-cut carrots by modulating GABA shunt, phenylpropanoid and ROS metabolism

Zhang J, Zhao J, Zuo X, You W, Ru X, Xu F, et al.

Food Chem, 2024 Jun 15;443:138545.
PMID: 38306904 DOI: 10.1016/j.foodchem.2024.138545

The effects of exogenous glutamate treatment on the quality attributes, γ-aminobutyric acid (GABA) shunt, phenylpropanoid pathway, and antioxidant capacity of fresh-cut carrots were investigated. Results showed that glutamate treatment suppressed the increases in lightness and whiteness values, inhibited the degradation of total carotenoids and maintained better flavor and taste in fresh-cut carrots. Moreover, glutamate treatment rapidly promoted the activities of glutamate decarboxylase and GABA transaminase, thus improving the GABA content. It also significantly enhanced the activities of phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, and 4-coumarate coenzyme A ligase and promoted the accumulation of total phenolics as well as the main individual phenolic compounds, including chlorogenic and caffeic acid. In addition, glutamate application activated the reactive oxygen system-related enzyme including peroxidase, superoxide dismutase, ascorbate peroxidase, and catalase activities to maintain higher antioxidant capacity in fresh-cut carrots. These results demonstrated that exogenous glutamate treatment maintained better nutritional quality and alleviated color deterioration by accelerating the accumulation of GABA and phenolics and enhancing the antioxidant capacity in fresh-cut carrots.

Matched MeSH terms: gamma-Aminobutyric Acid/metabolism
Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies

Mohamad FH, Mohamad Jamali MA, Che Has AT

J Mol Neurosci, 2023 Oct;73(9-10):804-817.
PMID: 37750966 DOI: 10.1007/s12031-023-02158-3

The γ-aminobutyric acid type A receptor (GABA (A) receptor) is a membrane protein activated by the neurotransmitter GABA. Structurally, this major inhibitory neurotransmitter receptor in the human central nervous system is a pentamer that can be built from a selection of 19 subunits consisting of α(1,2,3,4,5 or 6), β (1,2 or 3), γ (1,2 or 3), ρ (1,2 or 3), and δ, π, θ, and ε. This creates several possible pentameric arrangements, which also influence the pharmacological and physiological properties of the receptor. The complexity and heterogeneity of the receptors are further increased by the addition of short and long splice variants in several subunits and the existence of multiple allosteric binding sites and expansive ligands that can bind to the receptors. Therefore, a comprehensive understanding of the structure and function of the receptors is required to gain novel insights into the consequences of receptor dysfunction and subsequent drug development studies. Notably, advancements in computational-aided studies have facilitated the elucidation of residual interactions and exploring energy binding, which may otherwise be challenging to investigate. In this review, we aim to summarize the current understanding of the structure and function of GABA (A) receptors obtained from advancements in computational-aided applications.

Matched MeSH terms: gamma-Aminobutyric Acid
α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials

Sieghart W, Chiou LC, Ernst M, Fabjan J, M Savić M, Lee MT

Pharmacol Rev, 2022 Jan;74(1):238-270.
PMID: 35017178 DOI: 10.1124/pharmrev.121.000293

GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors. SIGNIFICANCE STATEMENT: α6-Containing GABAA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABAA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.

Matched MeSH terms: gamma-Aminobutyric Acid
Evaluation of commercial soy sauce koji strains of Aspergillus oryzae for γ-aminobutyric acid (GABA) production

Ab Kadir S, Wan-Mohtar WA, Mohammad R, Abdul Halim Lim S, Sabo Mohammed A, Saari N

J Ind Microbiol Biotechnol, 2016 Oct;43(10):1387-95.
PMID: 27541157 DOI: 10.1007/s10295-016-1828-5

In this study, four selected commercial strains of Aspergillus oryzae were collected from soy sauce koji. These A. oryzae strains designated as NSK, NSZ, NSJ and NST shared similar morphological characteristics with the reference strain (A. oryzae FRR 1675) which confirmed them as A. oryzae species. They were further evaluated for their ability to produce γ-aminobutyric acid (GABA) by cultivating the spore suspension in a broth medium containing 0.4 % (w/v) of glutamic acid as a substrate for GABA production. The results showed that these strains were capable of producing GABA; however, the concentrations differed significantly (P

Matched MeSH terms: gamma-Aminobutyric Acid/biosynthesis*
CmCML11 interacts with CmCAMTA5 to enhance γ-aminobutyric acid (GABA) accumulation by regulating GABA shunt in fresh-cut cantaloupe

You W, Zhang J, Ru X, Xu F, Wu Z, Jin P, et al.

Plant Physiol Biochem, 2024 Jan;206:108217.
PMID: 38039581 DOI: 10.1016/j.plaphy.2023.108217

The effect of calcium chloride (CaCl2) treatment on γ-aminobutyric acid (GABA) accumulation in fresh-cut cantaloupe and the involved mechanisms were investigated. The result showed that 1% (w/v) CaCl2 treatment increased GABA content and activities of glutamate decarboxylase (GAD) and succinate semialdehyde dehydrogenase (SSADH), while decreased glutamate (Glu) content and GABA transaminase (GABA-T) activities in fresh-cut cantaloupe. CmCML11 and CmCAMTA5 expressions of CaCl2-treated fruit increased by 187.4% and 165.6% than control fruit in the initial 6 h. Besides, expressions of GABA shunt genes, including CmGAD1, CmGAD2, CmGABA-T and CmSSADH were also up-regulated by CaCl2 treatment during early storage. Moreover, acting as a transcriptional activator, CmCAMTA5 could bind to the CG-box in promoters of CmGAD1, CmGABA-T and CmSSADH and activate their transcription. Furthermore, the interaction between CmCML11 and CmCAMTA5 could enhance the transcriptional activation on GABA shunt genes which were regulated by CmCAMTA5. Collectively, our findings revealed that CaCl2 treatment promoted GABA accumulation in fresh-cut cantaloupe via the combined effect of CmCML11 and CmCAMTA5 in the regulation of expressions of CmGAD1, CmGABA-T, and CmSSADH in GABA shunt.

Matched MeSH terms: gamma-Aminobutyric Acid/metabolism
Enhancing food preservation with postbiotic metabolites γ-aminobutyric acid (GABA) and bacteriocin-like inhibitory substances (BLIS) produced by Lactobacillus brevis C23 co-cultures in plant-based medium

Chuah WW, Tan JS, Hazwani Oslan SN, Bothi Raja P

Prep Biochem Biotechnol, 2024 Apr;54(4):514-525.
PMID: 37694843 DOI: 10.1080/10826068.2023.2252047

Lactic acid bacteria (LAB) can produce γ-aminobutyric acid (GABA) with antioxidant properties and sedative effects when it binds to the GABA receptor in the human brain. LAB can also produce bacteriocin-like inhibitory substances (BLIS) with antimicrobial capabilities during carbohydrate fermentation. GABA and BLIS are natural compounds with potential health benefits and food preservation properties. Lactobacillus brevis C23 was co-cultured with three different LABs as inducers, which produced the highest GABA content and BLIS activity. They were cultured in various plant-based media to obtain an edible and better-tasting final product over commercially available media like MRS broth. A coconut-based medium with additives was optimized using response surface methodology (RSM) to increase GABA and BLIS production. The optimized medium for maximum GABA production (3.22 ± 0.01 mg/mL) and BLIS activity (84.40 ± 0.44%) was a 5.5% coconut medium containing 0.23% glucose, 1.44% Tween 20, 0.48% L-glutamic acid, and 0.02% pyridoxine. Due to the presence of GABA, the cell-free supernatant (CFS) as a postbiotic showed higher antioxidant activity than other food preservatives like nisin and potassium sorbate. Finally, microbiological tests on food samples showed that the postbiotic was more effective than other preservatives at combating the growth of LAB, molds and coliform bacteria, making it a possible food preservative.

Matched MeSH terms: gamma-Aminobutyric Acid
Fulltext Optimization of γ-aminobutyric acid production by Lactobacillus plantarum Taj-Apis362 from honeybees

Tajabadi N, Ebrahimpour A, Baradaran A, Rahim RA, Mahyudin NA, Manap MY, et al.

Molecules, 2015 Apr 15;20(4):6654-69.
PMID: 25884548 DOI: 10.3390/molecules20046654

Dominant strains of lactic acid bacteria (LAB) isolated from honey bees were evaluated for their γ-aminobutyric acid (GABA)-producing ability. Out of 24 strains, strain Taj-Apis362 showed the highest GABA-producing ability (1.76 mM) in MRS broth containing 50 mM initial glutamic acid cultured for 60 h. Effects of fermentation parameters, including initial glutamic acid level, culture temperature, initial pH and incubation time on GABA production were investigated via a single parameter optimization strategy. The optimal fermentation condition for GABA production was modeled using response surface methodology (RSM). The results showed that the culture temperature was the most significant factor for GABA production. The optimum conditions for maximum GABA production by Lactobacillus plantarum Taj-Apis362 were an initial glutamic acid concentration of 497.97 mM, culture temperature of 36 °C, initial pH of 5.31 and incubation time of 60 h, which produced 7.15 mM of GABA. The value is comparable with the predicted value of 7.21 mM.

Matched MeSH terms: gamma-Aminobutyric Acid/biosynthesis*; gamma-Aminobutyric Acid/chemistry
Fulltext Evaluation of a Malaysian soy sauce koji strain Aspergillus oryzae NSK for γ-aminobutyric acid (GABA) production using different native sugars

Hajar-Azhari S, Wan-Mohtar WAAQI, Ab Kadir S, Rahim MHA, Saari N

Food Sci Biotechnol, 2018 Apr;27(2):479-488.
PMID: 30263772 DOI: 10.1007/s10068-017-0289-6

In this study, a selected γ-aminobutyric acid (GABA)-rich Malaysian strain Aspergillus oryzae NSK was collected from soy sauce koji. The strain was used to explore the effect of using renewable native sugar syrup, sugarcane, nipa, and molasses as fermentable substrates for developing a novel functional GABA soy sauce. We evaluated the strain using the chosen native sugars for 7 days using shake flask fermentation at 30 °C. The results showed optimum GABA concentration was achieved using cane molasses as the fermentable substrate (354.08 mg/L), followed by sugarcane syrup (320.7 mg/L) and nipa syrup (232.07 mg/L). Cane molasses was subsequently utilized as a substrate to determine the most suitable concentration for A. oryzae NSK to enhance GABA production and was determined as 50% g/L of glucose standard cane molasses. Our findings indicate that cane molasses can be used as a GABA-rich ingredient to develop a new starter culture for A. oryzae NSK soy sauce production.

Matched MeSH terms: gamma-Aminobutyric Acid
Fulltext Vital parameters for high gamma-aminobutyric acid (GABA) production by an industrial soy sauce koji Aspergillus oryzae NSK in submerged-liquid fermentation

Wan-Mohtar WAAQI, Ab Kadir S, Halim-Lim SA, Ilham Z, Hajar-Azhari S, Saari N

Food Sci Biotechnol, 2019 Dec;28(6):1747-1757.
PMID: 31807347 DOI: 10.1007/s10068-019-00602-y

In submerged-liquid fermentation, seven key parameters were assessed using one-factor-at-a-time to obtain the highest GABA yield using an industrial soy sauce koji Aspergillus oryzae strain NSK (AOSNSK). AOSNSK generated maximum GABA at 30 °C (194 mg/L) and initial pH 5 (231 mg/L), thus was able to utilize sucrose (327 mg/L of GABA) for carbon source. Sucrose at 100 g/L, improved GABA production at 646 mg/L. Single nitrogen sources failed to improve GABA production, however a combination of yeast extract (YE) and glutamic acid (GA) improved GABA at 646.78 mg/L. Carbon-to-nitrogen ratio (C8:N3) produced the highest cell (24.01 g/L) and GABA at a minimal time of 216 h. The key parameters of 30 °C, initial pH 5, 100 g/L of sucrose, combination YE and GA, and C8:N3 generated the highest GABA (3278.31 mg/L) in a koji fermentation. AOSNSK promisingly showed for the development of a new GABA-rich soy sauce.

Matched MeSH terms: gamma-Aminobutyric Acid
Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents

Partap S, Yar MS, Hassan MZ, Akhtar MJ, Siddiqui AA

Arch Pharm (Weinheim), 2017 Oct;350(10).
PMID: 28863231 DOI: 10.1002/ardp.201700135

A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor.

Matched MeSH terms: gamma-Aminobutyric Acid
Fulltext Dorsal root ganglia control nociceptive input to the central nervous system

Hao H, Ramli R, Wang C, Liu C, Shah S, Mullen P, et al.

PLoS Biol, 2023 Jan;21(1):e3001958.
PMID: 36603052 DOI: 10.1371/journal.pbio.3001958

Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here, in experiments on rats and mice, we show that the peripheral afferent nociceptive information undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics, we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG. Filtering induced by focal application of GABA or optogenetic GABA release from the DRG-transplanted GABAergic progenitor cells was specific to nociceptive fibers. Light-sheet imaging and computer modeling demonstrated that, compared to other somatosensory fiber types, nociceptors have shorter stem axons, making somatic control over t-junctional filtering more efficient. Optogenetically induced GABA release within DRG from the transplanted GABAergic cells enhanced filtering and alleviated hypersensitivity to noxious stimulation produced by chronic inflammation and neuropathic injury in vivo. These findings support "gating" of pain information by DRGs and suggest new therapeutic approaches for pain relief.

Matched MeSH terms: gamma-Aminobutyric Acid
Fulltext The Effect of 4-hydroxybenzaldehyde on the γ-aminobutyric Acid Type A Receptor

Zhang J, Mohamad H, Wong JH, Bilal M, Ismail AHB, Lloyd AJ, et al.

Malays J Med Sci, 2017 Mar;24(2):94-99.
PMID: 28894409 DOI: 10.21315/mjms2017.24.2.12

The α1β2γ2 subtype of GABAA receptors is the most commonly found GABAA receptor subtype in the mammalian cortex and hippocampus. It is expressed heterologously in the Xenopus laevis oocyte as a α1β2γ2S/L subtype for application as an in vitro model for the screening of compounds that modulate receptor activities. In fact, 4-hydroxybenzaldehyde (4-HB) has been identified as one of the major components in Dendrocalamus asper bamboo shoots in our previous study, and the current study showed that at 101.7 μM, 4-HB significantly reduced the GABA-induced chloride current of GABAA receptors expressed on Xenopus oocytes, indicating a possible GABAergic antagonistic effect at high concentrations.

Matched MeSH terms: gamma-Aminobutyric Acid
Revisiting the role of neurotransmitters in epilepsy: An updated review

Akyuz E, Polat AK, Eroglu E, Kullu I, Angelopoulou E, Paudel YN

Life Sci, 2021 Jan 15;265:118826.
PMID: 33259863 DOI: 10.1016/j.lfs.2020.118826

Epilepsy is a neurologicaldisorder characterized by persistent predisposition to recurrent seizurescaused by abnormal neuronal activity in the brain. Epileptic seizures maydevelop due to a relative imbalance of excitatory and inhibitory neurotransmitters. Expressional alterations of receptors and ion channelsactivated by neurotransmitters can lead to epilepsy pathogenesis.
AIMS: In this updated comprehensive review, we discuss the emerging implication of mutations in neurotransmitter-mediated receptors and ion channels. We aim to provide critical findings of the current literature about the role of neurotransmitters in epilepsy.
MATERIALS AND METHODS: A comprehensive literature review was conducted to identify and critically evaluate studies analyzing the possible relationship between epilepsy and neurotransmitters. The PubMed database was searched for related research articles.
KEY FINDINGS: Glutamate and gamma-aminobutyric acid (GABA) are the main neurotransmitters playing a critical role in the pathophysiology of this balance, and irreversible neuronal damage may occur as a result of abnormal changes in these molecules. Acetylcholine (ACh), the main stimulant of the autonomic nervous system, mediates signal transmission through cholinergic and nicotinic receptors. Accumulating evidence indicates that dysfunction of nicotinic ACh receptors, which are widely expressed in hippocampal and cortical neurons, may be significantly implicated in the pathogenesis of epilepsy. The dopamine-norepinephrine-epinephrine cycle activates hormonal and neuronal pathways; serotonin, norepinephrine, histamine, and melatonin can act as both hormones and neurotransmitters. Recent reports have demonstrated that nitric oxide mediates cognitive and memory-related functions via stimulating neuronal transmission.
SIGNIFICANCE: The elucidation of the role of the main mediators and receptors in epilepsy is crucial for developing new diagnostic and therapeutic approaches.

Matched MeSH terms: gamma-Aminobutyric Acid/metabolism
Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors

Ayoub R, Jarrar Q, Ali D, Moshawih S, Jarrar Y, Hakim M, et al.

Eur J Pharm Sci, 2021 Aug 01;163:105865.
PMID: 33979659 DOI: 10.1016/j.ejps.2021.105865

BACKGROUND: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy.
METHOD: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations.
RESULTS: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA.
CONCLUSION: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.

Matched MeSH terms: gamma-Aminobutyric Acid/therapeutic use
Fulltext Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice

Jarrar Q, Ayoub R, Jarrar Y, Aburass H, Goh KW, Ardianto C, et al.

J Integr Neurosci, 2023 Jul 26;22(4):104.
PMID: 37519168 DOI: 10.31083/j.jin2204104

BACKGROUND: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity.
METHODS: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted.
RESULTS: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities.
CONCLUSIONS: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.

Matched MeSH terms: gamma-Aminobutyric Acid/adverse effects
Gabapentin completely attenuated the acute morphine-induced c-Fos expression in the rat nucleus accumbens

Kazi JA, Abu-Hassan MI

J Mol Neurosci, 2011 Oct;45(2):101-9.
PMID: 20734160 DOI: 10.1007/s12031-010-9435-9

A growing body of evidence suggests the existence of a functional interaction between gabapentin (GBP)-morphine system. However, the neuro-anatomical sites and molecular mechanism of action of gabapentin-morphine interaction to prevent and reverse morphine side effects as well as enhancement of the analgesic effect of morphine is not clear. Therefore, we examined the combined effects of GBP-morphine on acute morphine-induced c-Fos expression in rat nucleus accumbens. The combined effect of GBP-morphine was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of morphine (10 mg/kg), saline (control), and co-injection of GBP (150 mg/kg) with morphine (5 mg/kg) was administered under anesthesia. The deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde 2 h after drugs administration. Serial 40 μm thick sections of brain were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase-antiperoxidase detection protocol. The present study demonstrated that, administration of GBP (150 mg/kg, i.p.) in combination with morphine (5 mg/kg, i.p.) significantly (p < 0.01) attenuated the acute morphine (5 mg/kg, i.p.)-induced c-Fos expression in the rat nucleus accumbens shell. Present results showed that GBP-morphine combination action prevented the acute morphine-induced c-Fos expression in rat nucleus accumbens. Moreover, this study provides first evidence of neuro-anatomical site and that GBP neutralized the morphine-induced activation of rat nucleus accumbens shell.

Matched MeSH terms: gamma-Aminobutyric Acid/metabolism; gamma-Aminobutyric Acid/pharmacology*
Analytical solution of reaction-diffusion equations for calcium wave propagation in a starburst amacrine cell

Poznanski RR

J Integr Neurosci, 2010 Sep;9(3):283-97.
PMID: 21064219

A reaction-diffusion model is presented to encapsulate calcium-induced calcium release (CICR) as a potential mechanism for somatofugal bias of dendritic calcium movement in starburst amacrine cells. Calcium dynamics involves a simple calcium extrusion (pump) and a buffering mechanism of calcium binding proteins homogeneously distributed over the plasma membrane of the endoplasmic reticulum within starburst amacrine cells. The system of reaction-diffusion equations in the excess buffer (or low calcium concentration) approximation are reformulated as a nonlinear Volterra integral equation which is solved analytically via a regular perturbation series expansion in response to calcium feedback from a continuously and uniformly distributed calcium sources. Calculation of luminal calcium diffusion in the absence of buffering enables a wave to travel at distances of 120 μm from the soma to distal tips of a starburst amacrine cell dendrite in 100 msec, yet in the presence of discretely distributed calcium-binding proteins it is unknown whether the propagating calcium wave-front in the somatofugal direction is further impeded by endogenous buffers. If so, this would indicate CICR to be an unlikely mechanism of retinal direction selectivity in starburst amacrine cells.

Matched MeSH terms: gamma-Aminobutyric Acid/metabolism; gamma-Aminobutyric Acid/pharmacology
Fulltext Gabapentin Differentially Modulate c-Fos Expression in Hypothalamus and Spinal Trigeminal Nucleus in Surgical Molar Extraction

Kazi JA, Ibrahim BK

Braz Dent J, 2016 Oct-Dec;27(6):744-750.
PMID: 27982189 DOI: 10.1590/0103-6440201600207

The study on the efficacy of oral analgesics reported that no single class of drug is effective in post-surgical dental pain. Pain following removal of third molar is most commonly used and widely accepted acute pain model for assessing the analgesic effect of drugs in humans. Reports demonstrated that analgesic efficacy in the human dental model is highly predictive. The high incidence of false-negative findings in analgesic investigations hinders the process of molecular discovery. Molecular mechanism of post-surgical pain is not known. More importantly, the animal model for postoperative dental pain is not well established. In an attempt to discover an effective post-surgical dental pain blocker with acceptable side effects, it is essential to elucidate the molecular mechanism of post-operative dental pain. The present study investigated mandibular molars extraction in rat as an animal model for the post-operative dental pain in central nervous system. Using c-Fos immunohistochemistry, we demonstrated that pre administration of GBP (150 mg/kg. i.p) significantly (p< 0.01) neutralized the surgical molar extraction induced c-Fos expression bilaterally in rat hypothalamus. Present results indicate that pain after surgical molar extraction might follow novel neural pathways therefore difficult to treat with existing anti-nociceptive drugs.

Matched MeSH terms: gamma-Aminobutyric Acid/pharmacology*; gamma-Aminobutyric Acid/therapeutic use
Fulltext Potentiality of Self-Cloned Lactobacillus plantarum Taj-Apis362 for Enhancing GABA Production in Yogurt under Glucose Induction: Optimization and Its Cardiovascular Effect on Spontaneous Hypertensive Rats

Hussin FS, Chay SY, Zarei M, Meor Hussin AS, Ibadullah WZW, Zaharuddin ND, et al.

Foods, 2020 Dec 09;9(12).
PMID: 33316941 DOI: 10.3390/foods9121826

The current study evaluated the γ-aminobutyric acid (GABA) producing ability from three novel strains of lactic acid bacteria (L. plantarum Taj-Apis362, assigned as UPMC90, UPMC91, and UPMC1065) co-cultured with starter culture in a yogurt. A combination of UPMC90 + UPMC91 with starter culture symbiotically revealed the most prominent GABA-producing effect. Response surface methodology revealed the optimized fermentation conditions at 39.0 °C, 7.25 h, and 11.5 mM glutamate substrate concentration to produce GABA-rich yogurt (29.96 mg/100 g) with desirable pH (3.93) and water-holding capacity (63.06%). At 2% glucose to replace pyridoxal-5-phosphate (PLP), a cofactor typically needed during GABA production, GABA content was further enhanced to 59.00 mg/100 g. In vivo study using this sample revealed a blood pressure-lowering efficacy at 0.1 mg/kg GABA dosage (equivalent to 30 mg/kg GABA-rich yogurt) in spontaneously hypertensive rats. An improved method to produce GABA-rich yogurt has been established, involving shorter fermentation time and lower glutamate concentration than previous work, along with glucose induction that omits the use of costly PLP, fostering the potential of developing a GABA-rich functional dairy product through natural fermentation with desirable product quality and antihypertensive property.

Matched MeSH terms: gamma-Aminobutyric Acid

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