Systemic CI-966, a new γ-aminobutyric acid uptake blocker, enhances γ-aminobutyric acid action in CA1 pyramidal layer in situ

1990 ◽  
Vol 68 (9) ◽  
pp. 1194-1199 ◽  
Author(s):  
U. Ebert ◽  
K. Krnjević
Keyword(s):  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Sprague Dawley ◽  
Nipecotic Acid ◽  
Ca1 Region ◽  
Stratum Pyramidale ◽  
Sprague Dawley Rats ◽  
Pyramidal Layer ◽  
Urethane Anaesthesia

A new potent, blood–brain barrier permeable γ-aminobutyric acid (GABA) uptake blocker, 1-[2-[bis[4-(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) was administered systemically by i.p. injection (5 mg/kg) in Sprague–Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there was a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region. Like the effect of nipecotic acid (applied locally by iontophoresis), the potentiation by CI-966 was clearest when GABA was applied in or near the stratum pyramidale where its action normally is weakest and shows the most pronounced fading. This change in GABA potency is most simply explained by a reduction in GABA uptake.Key words: GABA, muscimol, nipecotic acid, GABA-uptake blocker, epilepsy.

Structure–activity studies on the inhibition of γ-aminobutyric acid uptake in brain slices by compounds related to nipecotic acid

1979 ◽  
Vol 57 (6) ◽  
pp. 581-585 ◽  
Author(s):  
J. D. Wood ◽  
D. Tsui ◽  
J. W. Phillis
Keyword(s):  
Cortical Neurons ◽  
Therapeutic Potential ◽  
Brain Slices ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Nipecotic Acid ◽  
Depressant Action ◽  
Methyl Derivatives ◽  
Derivatives Of

Various N-methyl derivatives of nipecotic acid and related compounds were tested as inhibitors of γ-aminobutyric acid (GABA) uptake into mini slices. N-Methylnipecotic acid, N,N-dimethyinipecotic acid, N-methylguvacine, and N-methylnicotinic acid were effective inhibitors. None of them, however, were as potent as nipecotic acid itself. All the effective inhibitors, including nipecotic acid, also inhibited the uptake of L-proline, but to a much lesser extent. Four of the test compounds produced a depressant action on cerebral cortical neurons, but even N-methylisoguvacine, the most potent in this respect, was considerably less active than GABA. None of the test compounds caused any clearly discernible changes in the gross behaviour or appearance of mice in the 1-h period following intramuscular injection. It was concluded that methylation of the N atom of nipecotic acid and its derivatives was unlikely to lead to the development of agents with greater experimental or therapeutic potential than that of nipecotic acid itself, if the action of the agent was dependent on its effects on GABA uptake.

scholarly journals Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

Drug Research ◽  
2020 ◽  
Author(s):  
Meenakshi Dhanawat ◽  
Sumeet Gupta ◽  
Dinesh Kumar Mehta ◽  
Rina Das
Keyword(s):  
Epileptic Activity ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Design Synthesis ◽  
Hydrophilic Nature ◽  
Carrier Mediated Transport ◽  
Ester Prodrug ◽  
Hplc Data

Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

Neurotransmitter Levels in Brains of Chronically Jiawey Siwu-Treated Rats

2002 ◽  
Vol 30 (04) ◽  
pp. 507-519
Author(s):  
Sue Yu ◽  
Yee-Yung Ng ◽  
Zhi-Hong Jian ◽  
Chien-Chih Chen ◽  
Mei-Shiun Lu ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Medulla Oblongata ◽  
Excitatory Amino Acids ◽  
Aminobutyric Acid ◽  
Vanillylmandelic Acid ◽  
Dose Dependency ◽  
Sprague Dawley ◽  
Brain Areas ◽  
Sprague Dawley Rats ◽  
Body Weights

Levels of monoamines and metabolites, excitatory amino acids, and γ-aminobutyric acid (GABA) were investigated in discrete brain areas of chronic Jiawey Siwu (JS)-treated rats. Male Sprague-Dawley rats were dosed orally for 3 months with normal saline or JS at 0.21, 1.05 or 4.2 g/kg/day. Body weights of these four groups were similar over 3 months. Most effects of JS revealed a dose dependency with levels of neurotransmitters. Levels of norepinephrine (NE) and epinephrine (EPI) in cerebral cortex; EPI, vanillylmandelic acid (VMA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in medulla oblongata; DA in midbrain; NE and 5-HT in amygdala; and 5-HT in hypothalamus had decreased in JS-treated rats. 3-Methoxytyramine (3-MT) in cerebral cortex; 5-hydroxyindole-3-acetic acid (5-HIAA) in medulla oblongata; NE, 3-MT and homovanillic acid (HVA) in pons; EPI and 3-MT in midbrain; 3-MT and HVA in amygdala; 3-MT, 3,4-dihydroxyphenylacetic acid (DOPAC), HVA and 5-HIAA in cerebellum; HVA in hypothalamus; and DOPAC and HVA in hippocampus had all increased in JS-treated rats. In pons, 5-HT increased with low and decreased with high JS doses. Ratios of DA/3-MT in pons and midbrain; DA/HVA in pons and cerebellum; and 5-HT/5-HIAA in medulla oblongata, cerebellum and hypothalamus had decreased. Furthermore, aspartate (ASP) and glutamate (GLU) levels had decreased in cerebral cortex, midbrain, hypothalamus and hippocampus or amygdala, and increased in pons. GABA levels were reduced in cerebral cortex, and higher in medulla oblongata, pons, amygdala, cerebellum, hippocampus and striatum of JS-treated rats. These results indicate that the synthesis and (or) metabolism of NE, DA, EPI and 5-HT, and the levels of ASP, GLU and GABA in rat brains were differentially regionally altered by JS, which may contribute to the central manifestations of JS treatment.

Level of satiety: GABA and pentose shunt activities in three brain sites associated with feeding

1985 ◽  
Vol 248 (4) ◽  
pp. R453-R458 ◽  
Author(s):  
T. R. Kasser ◽  
R. B. Harris ◽  
R. J. Martin
Keyword(s):  
Area Postrema ◽  
Ventromedial Hypothalamus ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Energy Status ◽  
Sprague Dawley ◽  
Brain Areas ◽  
Gastric Intubation ◽  
Glucose Flux ◽  
Sprague Dawley Rats

The hypothesis addressed was that metabolic activity within specific brain areas may be altered to depict peripheral metabolic status. Sixty-three female Sprague-Dawley rats (225 g) received 150, 100, or 50% of normal intake by gastric intubation for 7 days. The incentive for spontaneous feeding would be inhibited in 150% fed rats (anoretic), stimulated in 50% fed rats (hungry), and maintained in 100% fed rats (control). Glucose flux through the gamma-aminobutyric acid shunt of the ventrolateral hypothalamus was 32% lower in hungry rats and 35% higher in anoretic rats relative to control values. Glucose flux through the pentose shunt of the ventromedial hypothalamus was 111% lower in hungry rats and 152% higher in anoretic rats relative to control values. Pentose shunt activity in the area postrema nucleus of the solitary tract (AP NTS) was 116% lower in hungry rats and 60% higher in anoretic rats relative to control values; however, hungry and anoretic rats had AP NTS pentose shunt activities that were not different from control values but were different from each other. The data demonstrate that within selective brain sites, specific pathways for glucose oxidation are affected by energy intake and may be used by the rat to assess and respond to changes in peripheral energy status.

scholarly journals Concurrent acetylcholinesterase staining and gamma-aminobutyric acid uptake of cortical neurons in culture.

1981 ◽  
Vol 29 (2) ◽  
pp. 306-308 ◽  
Author(s):  
M M Mesulam ◽  
M Dichter
Keyword(s):  
Tissue Culture ◽  
Cortical Neurons ◽  
Gabaergic Neurons ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Gamma Aminobutyric Acid ◽  
Acetylcholinesterase Staining ◽  
Culture Positive

Gamma-aminobutyric acid (GABA) uptake and acetylcholinesterase (AChE) content were demonstrated concurrently in cortical neurons grown in tissue culture. Positive reactions either for GABA uptake or for AChE content were encountered in pyramidal and stellate, as well as spindle-shaped neurons. Neither reaction was confined to a specific morphological subtype. Nearly half the neurons were negative for either reaction. Most of the remaining neurons were positive only for GABA or only for AChE. However, a subpopulation of neurons showed not only a high AChE content, but also an avid GABA uptake. Thus, four types of neurons could be identified on the basis of these two reactions. The high AChE content in some of the cortical neurons that also showed GABA uptake indicates that there are at least two distinct types of GABAergic neurons.

Changes in respiratory timing induced by hypercapnia in maturing rats

1999 ◽  
Vol 87 (2) ◽  
pp. 484-490 ◽  
Author(s):  
Jalal M. Abu-Shaweesh ◽  
Ismail A. Dreshaj ◽  
Agnes J. Thomas ◽  
Musa A. Haxhiu ◽  
Kingman P. Strohl ◽  
...  
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Aminobutyric Acid ◽  
Whole Body ◽  
Sprague Dawley ◽  
Newborn Rat ◽  
Rat Pups ◽  
Significant Prolongation ◽  
Sprague Dawley Rats ◽  
Central Origin

Premature infants respond to hypercapnia by an attenuated ventilatory response that is characterized by a decrease in respiratory frequency. We hypothesized that this impaired hypercapnic ventilatory response is of central origin and is mediated via γ-aminobutyric acid-ergic (GABAergic) pathways. We therefore studied two groups of maturing Sprague-Dawley rats: unrestrained rats in a whole body plethysmograph at four postnatal ages (5, 16–17, 22–23, and 41–42 days); and ventilated, decerebrate, vagotomized, paralyzed rats in which phrenic nerve responses to hypercapnia were measured at 4–6 and 37–39 days of age. In the unrestrained group, the increase in minute ventilation induced by hypercapnia was significantly lower at 5 days vs. beyond 16 days. Although there was an increase in tidal volume at all ages, frequency decreased significantly from baseline at 5 days, whereas it increased significantly at 16–17, 22–23, and 41–42 days. The decrease in frequency at 5 days of age was mainly due to a significant prolongation in expiratory duration (Te). In the ventilated group, hypercapnia also caused prolongation in Te at 4–6 days but not at 37–39 days of age. Intravenous administration of bicuculline (GABAA-receptor blocker) abolished the prolongation of Te in response to hypercapnia in the newborn rats. We conclude that newborn rat pups exhibit a characteristic ventilatory response to CO2 expressed as a centrally mediated prolongation of Te that appears to be mediated by GABAergic mechanisms.

Abstract 211: Delayed Cell Death in CA1 Region in a Cardiac Arrest Rat Model: Continuing After 2 Weeks of Survival?

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sandra Högler ◽  
Ursula Teubenbacher ◽  
Wolfgang Weihs ◽  
Fritz Sterz ◽  
Ingrid A M Magnet ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Arrest ◽  
Brain Regions ◽  
Spontaneous Circulation ◽  
Sprague Dawley ◽  
Ca1 Region ◽  
Delayed Cell Death ◽  
Time Period ◽  
Sprague Dawley Rats ◽  
Hematoxylin Eosin

Background: Evolution of histological lesions in selectively vulnerable brain regions in animal models of cardiac arrest (CA)give evidence of potential therapeutic windows. Delayed cell death is of special interest in this regard. Methods: In male Sprague-Dawley rats (350g) ventricular fibrillation (VF) CA was induced for 6 min followed by chest compressions, ventilation and drugs for 2 min. To achieve return of spontaneous circulation animals were defibrillated every 2 min. Animals were sacrificed after one week (n=5) or two weeks (n=7) of survival and compared to four sham animals. Brains were fixed in formalin, embedded in paraffin wax and cut into 3 μm thick coronary sections for histological examination. Viable neurons with nucleolus were counted in Hematoxylin-Eosin (HE)-stained sections in a 250 μm sector of the medial CA1 region. FluoroJade B staining was applied to count dying neurons in the same sector. Results: In HE-staining sham animals had 31±4 viable neurons. In one week survivors 11±9 viable neurons (p=0.003) and in two week survivors 7±7 viable neurons (p=0.001 vs sham, p=0.49 vs one week survivors) were counted. Furthermore, a lot of degenerated hypereosinophilic neurons were present in HE-staining in both CA-groups. FluoroJade B-staining was negative in sham animals. In one week survivors 29±8 dying neurons (p=0.006) and in two week survivors 33±13 dying neurons (p= 0.016 vs sham, p=0.343 vs one week survivors) were detectable. Conclusions: Consistent damage in the medial CA1 region was present after 6 min VFCA in both survival time groups. Lesions seemed to be constant, with no significant differences between time points. Contrary to expectations, FluoroJade B-staining was still positive after two weeks of survival, suggesting that delayed cell death might go on for a longer time period than assumed so far.

scholarly journals Identification and Characterization of γ-Aminobutyric Acid Uptake System GabPCg(NCgl0464) in Corynebacterium glutamicum

2012 ◽  
Vol 78 (8) ◽  
pp. 2596-2601 ◽  
Author(s):  
Zhi Zhao ◽  
Jiu-Yuan Ding ◽  
Wen-hua Ma ◽  
Ning-Yi Zhou ◽  
Shuang-Jiang Liu
Keyword(s):  
Amino Acid ◽  
Corynebacterium Glutamicum ◽  
Dry Weight ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Uptake System ◽  
Content Type ◽  
Gaba Transporters ◽  
New Type

ABSTRACTCorynebacterium glutamicumis widely used for industrial production of various amino acids and vitamins, and there is growing interest in engineering this bacterium for more commercial bioproducts such as γ-aminobutyric acid (GABA). In this study, aC. glutamicumGABA-specific transporter (GabPCg) encoded byncgl0464was identified and characterized. GabPCgplays a major role in GABA uptake and is essential toC. glutamicumgrowing on GABA. GABA uptake by GabPCgwas weakly competed byl-Asn andl-Gln and stimulated by sodium ion (Na+). TheKmandVmaxvalues were determined to be 41.1 ± 4.5 μM and 36.8 ± 2.6 nmol min−1(mg dry weight [DW])−1, respectively, at pH 6.5 and 34.2 ± 1.1 μM and 67.3 ± 1.0 nmol min−1(mg DW)−1, respectively, at pH 7.5. GabPCghas 29% amino acid sequence identity to a previously and functionally identified aromatic amino acid transporter (TyrP) ofEscherichia colibut low identities to the currently known GABA transporters (17% and 15% toE. coliGabP andBacillus subtilisGabP, respectively). The mutant RES167 Δncgl0464/pGXKZ9 with the GabPCgdeletion showed 12.5% higher productivity of GABA than RES167/pGXKZ9. It is concluded that GabPCgrepresents a new type of GABA transporter and is potentially important for engineering GABA-producingC. glutamicumstrains.

scholarly journals Gamma Aminobutyric Acid-Enriched Fermented Oyster (Crassostrea gigas) Increases the Length of the Growth Plate on the Proximal Tibia Bone in Sprague-Dawley Rats

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4375
Author(s):  
Hyesook Lee ◽  
Hyun Hwangbo ◽  
Seon Yeong Ji ◽  
Min Yeong Kim ◽  
So Young Kim ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Oral Administration ◽  
Growth Plate ◽  
Bone Health ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tibial Growth Plate ◽  
Igfbp 3

Bone growth during childhood and puberty determines an adult’s final stature. Although several prior studies have reported that fermented oyster (FO) consisting of a high amount of gamma aminobutyric acid can be attributed to bone health, there is no research on the efficacy of FO on growth regulation and the proximal tibial growth plate. Therefore, in this study, we investigated the effect of FO oral administration on hepatic and serum growth regulator levels and the development of the proximal tibial growth plate in young Sprague-Dawley rats. Both oral administration of FO (FO 100, 100 mg/kg FO and FO 200, 200 mg/kg FO) and subcutaneous injection of recombinant human growth hormone (rhGH, 200 μg/kg of rhGH) for two weeks showed no toxicity. Circulating levels of growth hormone (GH) significantly increased in the FO 200 group. The expression and secretion of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) were enhanced by FO administration. FO administration promoted the expression of bone morphogenic proteins IGF-1 and IGFBP-3 in the proximal tibial growth plate. This positive effect of FO resulted in incremental growth of the entire plate length by expanding the proliferating and hypertrophic zones in the proximal tibial growth plate. Collectively, our results suggested that oral administration of FO is beneficial for bone health, which may ultimately result in increased height.

scholarly journals Rat gastroduodenal motility in vivo: interaction of GABA and VIP in control of spontaneous relaxations

1998 ◽  
Vol 275 (5) ◽  
pp. G897-G903 ◽  
Author(s):  
Anthony Krantis ◽  
Kamal Mattar ◽  
Ian Glasgow
Keyword(s):  
Circular Muscle ◽  
Aminobutyric Acid ◽  
Strain Gauges ◽  
Sprague Dawley ◽  
Circular Smooth Muscle ◽  
Sprague Dawley Rats ◽  
Gastroduodenal Motility ◽  
Synthase Inhibitor ◽  
Related Pathway

Spontaneous relaxations occurring within motor activity in the rat gastroduodenum in vivo can be distinguished by their dependence on either nitric oxide (NO) or ATP. We examined the interaction of γ-aminobutyric acid (GABA) and vasoactive intestinal peptide (VIP) within pathways controlling this activity in the antrum (S) and duodenum (D) of anesthetized Sprague-Dawley rats, using miniaturized extraluminal foil strain gauges oriented perpendicular to (S1, D1) or in the axis of (S2) the circular smooth muscle. The NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME; 10 mg/kg iv) attenuated ( P < 0.05) antral relaxations and, in the duodenum, nonpropagating “intergroup” relaxations. The GABAA receptor antagonist bicuculline (350 μg/kg sc) had similar effects. The GABAA agonist 3-amino-1-propanesulfonic acid stimulatedl-NAME-sensitive relaxations at S1 and D1. Propagating “grouped” responses were unchanged. VIP (6 μg/kg iv) always induced a relaxation of the duodenum, which was attenuated by bicuculline andl-NAME. VIP caused simultaneous responses at S1 and S2; however, the antrum displayed either contraction or relaxation in response to VIP. All antral relaxations in response to VIP were attenuated ( P < 0.05) byl-NAME; however, only VIP-induced relaxations at S1 were sensitive to bicuculline. VIP-induced contractions were also unaffected. GABAA receptors mediate the pathway(s) controlling NO-related spontaneous relaxations of the antrum and duodenal circular muscle. All VIP-induced relaxations are mediated by NO. Spontaneous relaxations of the rat gastroduodenum include responses that involve a GABAAergic NO-related pathway, which is targeted by VIP. In addition, VIP can target NO relaxations of the antrum via other pathways.

Sign in / Sign up

Export Citation Format

Share Document