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Role of central GABA in the regulation of blood pressure and the development of hypertension in the SHR
Published in H. Saito, Y. Yamori, M. Minami, S.H. Parvez, New Advances in SHR Research –, 2020
Maarten Van Den Buuse, Geoffrey A. Head
While the above mentioned experiments indicate a role of GABA-A receptors in the NTS, other workers observed that micro-injection of the GABA-B receptor agonist baclofen into the NTS caused an increase in blood pressure (Sved and Sved, 1989; Florentino et al., 1990). Furthermore, the effects of intra-NTS injections of nipecotic acid could be blocked by phaclofen (Sved and Sved, 1990), but not bicuculline (Sved and Sved, 1989), indicating that it was mediated by activation of GABA-B receptors.
The Use of Brain Slices in the Study of Free Radical Actions
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Depletion of neurotransmitter available for release through failure of reuptake mechanisms for the amino acids is a possible mechanism for decreasing synaptic potentials. In glial cell cultures, Volterra et al.65 has reported that free radicals can reduce glutamate uptake. This is consistent with the increase in basal release of glutamate from the synaptosomes observed by Gilman et al.,66 as well as the increase in release of excitatory amino acid from hippocampal slices.67 The electrophysiological consequences of inhibition of glutamate uptake alone are inconsistent with free radical actions. Uptake blockers, dihydrokainate and threo-hydroxy aspartate elicit a transient hyperexcitability in field potential recordings (Pellmar and Lee, unpublished observations) never seen with peroxide, radiation, or DHF. However, concurrent inhibition of GABA uptake with nipecotic acid prevents this activity. Together they reversibly decrease the population synaptic potential and E/S coupling (Pellmar and Lee, unpublished observations). While it is improbable that blockade of GABA and glutamate uptake fully explains the changes in synaptic efficacy caused by free radicals, this is likely to contribute to the free radical effects.
From Motivation to Action: A Review of Dopaminergic Regulation of Limbic → Nucleus Accumbens → Ventral Pallidum → Pedunculopontine Nucleus Circuitries Involved in Limbic-Motor Integration
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Gordon J. Mogenson, Stefan M. Brudzynski, Michael Wu, Charles R. Yang, Conrad C.Y. Yim
Behaviorally, the hippocampal → accumbens → subpallidal → MLR pathway was shown to contribute to locomotion in animals adapted to an open-field apparatus. Microinjecting NMDA into the ventral subiculum of the hippocampus increased locomotor activity which was markedly attenuated by DA D2 agonist injected into the accumbens. As mentioned above, mutual DA-glutamate interaction was documented in the striatum. The action of the DA D2 agonist on the glutamatergic terminals of the hippocampal-accumbens neurons,33,47 or on the autoreceptors on the dopaminergic afferent terminals, which had been activated by the NMDA-stimulated glutamatergic hippocampal-accumbens neuron,67,68 mediated this interaction. The NMDA-induced locomotor activity was reduced when a) nipecotic acid, a GABA uptake inhibitor, was injected into the subpallidal region, or b) when procaine was injected into the MLR.47 Nonetheless, since a mixture of excitatory and inhibitory responses were recorded in the PPN region upon electrical stimulation of the subpallidal region, it is still not possible to predict what kind of signals MLR will receive when the hippocampus or amygdala is stimulated.160
Mono- and di-thiocarbamate inhibition studies of the δ-carbonic anhydrase TweCAδ from the marine diatom Thalassiosira weissflogii
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Silvia Bua, Murat Bozdag, Sonia Del Prete, Fabrizio Carta, William A. Donald, Clemente Capasso, Claudiu T. Supuran
The first inhibition study of a δ-CA with mono- and di-thiocarbamates, classes of CAIs recently discovered, was reported. TweCAδ from the marine diatom T. weissflogii was not particularly sensitive to inhibition by these classes of compounds. Many of the mono- and di-thiocarbamates did not show inhibitory action up to 20 µM, whereas some aliphatic, heterocyclic, and aromatic inhibited this enzyme in the low micromolar range. Several MTCs/DTCs incorporating the piperazine ring effectively inhibited TweCAδ with KIs in the range of 129–791 nM. The most effective inhibitors identified were 3,4-dimethoxyphenyl-ethyl-mono-thiocarbamate (KI of 67.7 nM) and the R-enantiomer of the nipecotic acid DTC (KI of 93.6 nM). Such inhibitors can now be used as molecular probes to investigate the role of this enzyme in the carbon fixation processes in diatom marine organisms that are responsible for removing large amounts of CO2 from the atmosphere.
Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5)
Published in Expert Opinion on Therapeutic Targets, 2018
Longfa Kou, Rui Sun, Vadivel Ganapathy, Qing Yao, Ruijie Chen
L-Carnitine by itself also has therapeutic effects; therefore, it can be utilized not only as a carrier for the design of prodrugs but also as a drug. Prodrugs could be designed with L-carnitine to elicit synergistic therapeutic effect between the drug and L-carnitine. Butyryl-L-carnitine (BC) is a good example. BC could be taken into cells at the sites of inflammation via OCTN2 and ATB°,+, and butyrate and L-carnitine released after hydrolysis could work synergistically to provide therapeutic efficacy against inflammation. A similar strategy is for nipecotic acid prodrug design for anticonvulsant therapy.
Have there been improvements in Alzheimer’s disease drug discovery over the past 5 years?
Published in Expert Opinion on Drug Discovery, 2018
Only seven GABAergic modulators were identified, including MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide), a selective positive allosteric modulator of GABA-A receptors; 3α-hydroxy-neurosteroids (allopregnanolone and tetrahydrodeoxycorticosterone) which potentiate GABA-A; N-substituted nipecotic acid derivatives; tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators; and classical GABA-A and GABA-B receptor agonists (muscimol and baclofen, respectively).