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At least 361 records · Page 20Linked to original sources
PubMed1996

GABA, glutamate and substance P-like immunoreactivity release: effects of novel GABAB antagonists.

1. The effects of various GABA receptor ligands on the electrically-evoked release of endogenous GABA, glutamate and substance P-like immunoreactivity from the dorsal horn of rat isolated spinal cord were examined. 2. Exogenous GABA (10-300 microM) significantly decreased the evoked, but not basal, release of endogenous glutamate in a concentration-dependent manner. The GABAA agonist, isoguvacine (1-100 microM), failed to decrease the release of glutamate although it did reduce the release of GABA. Baclofen (0.1-1000 microM), the GABAB agonist, reduced the release of GABA and glutamate in a stereospecific and concentration-dependent manner. 3. The actions of five GABAB antagonists on these release systems were compared. CGP36742, CGP52432, CGP55845A and CGP57250A significantly increased the evoked release of GABA and glutamate. They also reversed the effects of (-)-baclofen in a concentration-dependent manner. On the other hand, while CGP56999A had no effect on glutamate release, it was an effective antagonist of the baclofen-induced inhibition of GABA and substance P release. 4. These results suggest that GABAB receptors on nerve terminals within the dorsal horn spinal cord may be heterogeneous. However, this is based solely on the data obtained with CGP56999A which affected only GABA and substance P, but not glutamate, release.

Animals↗
PubMed2001

Design of NAALADase inhibitors: a novel neuroprotective strategy.

Excessive glutamatergic transmission is thought to be responsible for the injury observed in a variety of neurological disorders such as stroke. N-acetylaspartylglutamate (NAAG), a major peptidic component of the brain, has been suggested to serve as a potential storage form of glutamate. N-acetylated-a-linked acidic dipeptidase (NAALADase, EC 3.4.17.21) is responsible for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of NAALADase should be neuroprotective in diseases in which excess glutamatergic transmission is detrimental. In addition, NAAG has been demonstrated to be an agonist at group II metabotropic glutamate receptors and functions as a mixed agonist/antagonist at N-methyl-D-aspartate receptors. Therefore, inhibition of NAALADase would also function to increase NAAG levels which, in turn, should provide neuroprotection via the interaction of NAAG with these receptors. Recently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of NAALADase is neuroprotective in animal models of neurodegeneration. As such, NAALADase inhibition represents a novel method of regulating extracellular glutamate levels and provides a new avenue for the treatment of neurological disorders.

Animals↗
PubMed2006

Determination of pK(a) values of diastereomers of phosphinic pseudopeptides by CZE.

A CE method was used for the determination of acidity constants (pK(a)) of a series of ten phosphinic pseudopeptides, which varied in number and type of ionogenic groups. Effective electrophoretic mobilities were measured in the 1.8-12.0 pH range in the BGEs of constant ionic strength of 25 mM. Effective electrophoretic mobilities, corrected to standard temperature of 25 degrees C, were subjected to non-linear regression analysis and the obtained apparent pK(a) values were recalculated to thermodynamic pK(a)'s by extrapolation to zero ionic strength according to the extended Debye-Hückel model. The pK(a) values of the phosphinic acid group fell typically in the 1.5-2.25 interval, C-terminal carboxylic groups in the 2.94-3.50 interval, carboxylic groups of the lateral chain of glutamate and aspartate in the 4.68-4.97 interval, imidazolyl moiety of histidine in the 6.55-8.32 interval, N-terminal amino groups in the 7.65-8.28 interval and epsilon-amino group of the lateral chain of lysine in the 10.46-10.61 interval. Further, separation of diastereomers of the phosphinic pseudopeptides was investigated in achiral BGEs. Evaluation of the resolution of the diastereomers as a function of pH of the BGE revealed that most suitable pH region for separation of the diastereomers is around the pK(a) values of the central phosphinic acid group of the pseudopeptides. Successful separation of some diastereomers was, however, achieved in the neutral and alkaline BGEs as well.

Electrophoresis, Capillary↗
PubMed2002

Early induction of secretoneurin expression following kainic acid administration at convulsant doses in the rat and gerbil hippocampus.

The expression of secretogranin-II and its major proteolytic product secretoneurin (SN) is under the control of neuronal excitation, as demonstrated by treating rats with the excitotoxic kainic acid (KA). Differences in the structure and function of the hippocampus in rats and gerbils have been described; these suggest possible differential reactive responses to KA. In the present study, the SN immunostaining pattern in relation with cell damage is analyzed from 6 h to 4 days following KA administration in rats and gerbils. Dramatic differences in the expression of SN were found in the hippocampal complex following KA administration in gerbils and rats. A robust increase in SN immunoreactivity was detected in the pyramidal cell layer of the rat hippocampus, especially in the CA1 area. In the gerbil, however, a strong increase in SN immunostaining was detected in interneurons of the hippocampal formation, as shown by double-labeling immunohistochemistry to SN and the calcium-binding proteins parvalbumin, calbindin, and calretinin. In addition, no damage (in the hippocampal formation) or moderate damage (in the entorhinal cortex) was observed in the gerbil, in contrast to the rat. The administration of KA and the GABA-B receptor inhibitors (CGP56999A or CGP36742) to the gerbil resulted in a strong rise in SN immunoreactitivty in the CA1 pyramidal cell layer of the hippocampus, as in the rat. However, no increased cell damage was observed under these conditions. The present data provide evidence of a species-differential reactive response to KA that might be based, in part, on distinct inhibitory intrahippocampal circuitry.

Animals↗
PubMed1975

Organophosphorus esters causing delayed neurotoxic effects: mechanism of action and structure activity studies.

Evidence is reviewed that the initial biochemical event leading to delayed neurotoxicity is phosphorylation of the active site of a specific enzyme called Neurotoxic Esterase. This is followed by a bondcleavage (? hydrolytic) leading to formation of a mono-substituted phosphoric acid residue on the protein. The mechanism by which some phosphinates protect hens against neurotoxic compounds is explained. Screening Assay. Assay of effects of compounds on Neurotoxic Esterase activity of hen brain in vitro and in vivo provides a quick biochemical screen to supplement the 3-week clinical test. This test provides an estimate of safety margin for compounds which give negative results in the clinical test and are currently used as pesticides, plasticisers, etc. Simplified assay procedures are being developed. Structure/Activity Studies. Data is now available for the biochemical and neurotoxic activity of many compounds. This provides a basis for structure/activity predictions; neurotoxicity data published since 1930 has been assessed in this light.

Animals↗
PubMed1999

Inhibitory postsynaptic currents of rat substantia nigra pars reticulata neurons: role of GABA receptors and GABA uptake.

Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata neurons in midbrain slices of young rats to study the characteristics of spontaneous and evoked inhibitory postsynaptic currents and factors which govern their decay kinetics. In the presence of the glutamate receptor antagonists D, L-2-amino-5-phosphonopentanoic acid (20 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM), bicuculline-sensitive spontaneous inward inhibitory postsynaptic currents were often observed using high Cl(-) electrodes. Application of the selective GABA(B) receptor antagonist CGP55845A (2 microM) did not alter the half decay time of these inhibitory postsynaptic currents, which however was prolonged by the potent GABA uptake blocker tiagabine (1 microM). In addition, the frequencies and amplitudes of the inhibitory postsynaptic currents were significantly reduced by tiagabine but these effects were prevented by CGP55845A. Inhibitory postsynaptic currents with similar sensitivity to bicuculline could also be evoked intranigrally. Similar to the spontaneous currents, the decay time of evoked inhibitory postsynaptic currents was not affected by 2 microM CGP55845A. However, in the absence of CGP55845A, tiagabine shortened the IPSC decay time but had an opposite effect if CGP55845A was present. These data suggest that the spontaneous and evoked inhibitory postsynaptic currents recorded from substantia nigra pars reticulata neurons are mediated mainly by GABA(A) receptors. Uptake of GABA helps to terminate these currents. When the uptake mechanism is blocked, accumulation of GABA would lead to activation of presynaptic GABA(B) receptors and reduction in GABA release. The role of postsynaptic GABA(B) receptors in substantia nigra pars reticulata of young rats seems to be minimal.

Animals↗
PubMed2002

In vivo modulation of ventral tegmental area dopamine and glutamate efflux by local GABA(B) receptors is altered after repeated amphetamine treatment.

The activity of dopamine neurons in the ventral tegmental area is modulated by excitatory (glutamatergic) and inhibitory (GABAergic) afferents. GABA, released by intrinsic neurons and by projection neurons originating in the nucleus accumbens and other regions, inhibits dopamine neurons via activation of GABA(A) and GABA(B) receptor subtypes. Using in vivo microdialysis in freely moving rats, we investigated the role of ventral tegmental area GABA(B) receptors in modulating levels of dopamine and glutamate within the ventral tegmental area, both in naive rats and in rats treated repeatedly with saline or amphetamine (5 mg/kg i.p., for 5 days). In naive rats, administration of a potent and selective GABA(B) receptor antagonist (CGP 55845A) into the ventral tegmental area elicited a concentration-dependent increase in dopamine levels, but did not alter glutamate levels. In rats tested 3 days after discontinuing repeated amphetamine administration, 50 microM CGP 55845A increased dopamine levels to a greater extent than in saline controls. This difference was no longer present in rats tested 10-14 days after discontinuing repeated amphetamine injections. CGP 55845A (50 microM) had no effect on glutamate levels in the ventral tegmental area of saline-treated rats. However, it produced a robust increase in glutamate levels in rats tested 3 days, but not 10-14 days, after discontinuing repeated amphetamine injections. These results suggest that somatodendritic dopamine release is normally under strong tonic inhibitory control by GABA(B) receptors. Repeated amphetamine administration enhances GABA(B) receptor transmission in the ventral tegmental area during the early withdrawal period, increasing inhibitory tone on both dopamine and glutamate levels. This is the first demonstration, in an intact animal, that drugs of abuse alter GABA(B) receptor transmission in the ventral tegmental area.

Amphetamine↗
PubMed2002

New Pd-catalyzed selective reduction of carboxylic acids to aldehydes.

A catalyst generated in situ from palladium acetate and tricyclohexylphosphine efficiently catalyzes the reduction of carboxylic acids with sodium hypophosphite in the presence of pivalic anhydride to give aldehydes with high selectivity. The low cost and convenient handling of the reagents makes this process a valuable alternative to hydrogenations and metal hydride reductions.

Aldehydes↗
PubMed2006

Evidence for a functional role of GABA receptors in the rat mature hippocampus.

Both gamma-aminobutyric acid (GABA)(C) receptor subunit mRNA and protein are expressed in the stratum pyramidale in the CA1 area of the adult rat hippocampus, but so far no conclusive evidence about functional hippocampal GABA(C) receptors has been presented. Here, the contribution of GABA(C) receptors to stimulus-evoked postsynaptic potentials was studied in the hippocampal CA1 area with extracellular and intracellular recordings at the age range of 21-47 postnatal days. Activation of GABA(C) receptors with the specific agonist cis-4-aminocrotonic acid (CACA) suppressed postsynaptic excitability and increased the membrane conductance. The GABA(C) receptor antagonist 1,2,5,6-tetrahydropyridine-4-ylmethylphosphinic acid (TPMPA), but not the GABA(A) receptor antagonist bicuculline, inhibited the effects of CACA. GABA-mediated long-lasting depolarizing responses evoked by high-frequency stimulation of local inhibitory interneurons in the CA1 area in the presence of ionotropic glutamate receptor and GABA(B) receptor blockers were prolonged by TPMPA, indicating that GABA(C) receptors are activated under these conditions. For weaker stimulation, the effect of TPMPA was enhanced after GABA uptake was inhibited. Our data demonstrate that GABA(C) receptors can be activated by endogenous synaptic transmitter release following strong stimulation or under conditions of reduced GABA uptake. The lack of GABA(C) receptor activation by less intensive stimulation under control conditions suggests that these receptors are extrasynaptic and activated via spillover of synaptically released GABA.

Action Potentials↗
PubMed1996

Phosphatase inhibitors--III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase.

Further investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has led to the highly potent series of alpha-aminobenzylphosphonic acids. The alpha-benzylaminobenzylphosphonic acid, with an IC50 = 4 nM, exhibited a 3500-fold improvement in potency over the carbon analogue, alpha-phenylethyl. The enhanced potency may be due to a combination of four favorable interactions including those with the phosphate binding region, the presence the hydrophobic moieties of the benzylamino and phenylphosphonic acid, and a rigid conformer produced by an internal salt bridge between the phosphonate and the alpha-amino group. Replacement of the phosphonic acid moiety with a phosphinic or carboxylic acid as well as deletion of the benzyl substitution of the alpha-amino group led to great reductions in potency.

Acid Phosphatase↗
PubMed2001

Paradoxical reduction of synaptic inhibition by vigabatrin.

GABAergic inhibition, a primary target for pharmacological modulation of excitability in the CNS, can be altered by multiple mechanisms including alteration of GABA metabolism. Gamma-vinyl GABA (vigabatrin, GVG) is an irreversible inhibitor of the GABA catabolic enzyme GABA transaminase, thus its anticonvulsant properties are thought to result from an elevation of brain GABA levels. We examined the effects of GVG on GABAergic synaptic transmission in hippocampal slices. GVG unexpectedly reduced miniature and evoked inhibitory postsynaptic currents (IPSCs) in dentate granule cells. The reduction in synaptic events was accompanied by an increase in tonic GABA(A) receptor-mediated current. These effects developed slowly and persisted following wash out of GVG. The GVG pretreatment reduced sucrose-evoked GABA release as well as postsynaptic sensitivity to exogenous GABA, indicating that both pre- and postsynaptic mechanisms contributed to the reduction in synaptic currents. These results suggest that tonic rather than phasic increases in GABA underlie the anticonvulsant properties of GVG, and that mechanisms that elevate brain neurotransmitter levels do not necessarily correlate with enhanced synaptic release.

4-Aminobutyrate Transaminase↗