Galantamine inhibits slowly inactivating K+ currents with a dual dose–response relationship in differentiated N1E-115 cells and in CA1 neurones

Vicente, M. Inês; Costa, Patrícia; Lima, Pedro U.

doi:10.1016/j.ejphar.2010.02.021

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…But the drug also inhibits the activity of cholinesterase and other esterases at higher concentrations (Darvesh et al, 2003; Nordberg and Svensson, 1998), possibly limiting its ability to provide definitive proof for the involvement of α7 receptors in the actions of kynurenic acid. Moreover, galantamine blocks some potassium channels (Vicente et al, 2010; Vigneault et al, 2012), which may be sufficient to explain its facilitatory effect on neuronal transmission and its apparent reversal of the effects of kynurenate.…”

Section: Molecular Sites Of Actionmentioning

confidence: 99%

The kynurenine pathway and the brain: Challenges, controversies and promises

2017

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Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter.

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Section: Molecular Sites Of Actionmentioning

confidence: 99%

The kynurenine pathway and the brain: Challenges, controversies and promises

2017

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“…Since kynurenic acid tends to reduce neuronal excitability, irrespective of whether it is blocking NMDA, AMPA or kainate receptors, the depolarisation induced by blocking potassium conductances will appear to reverse those effects – another example of ‘physiological antagonism’ or ‘signal cancellation’ (see above). This effect is sufficiently potent to contribute to the pro‐cognitive actions of galantamine (Vicente et al ).…”

Section: Galantamine As a Pharmacological Toolmentioning

confidence: 99%

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Stone

2019

Journal of Neurochemistry

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As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.

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“…To study steady-state inactivation, a single-command step was preceded by incremental prepulses. 23 l-Glutamate-induced currents were obtained by continuous recording under variable resting potentials. Glutamate was administered with a handmade adaptation of the perfusion system using gravity.…”

Section: Electrophysiology Recordingmentioning

confidence: 99%

“…Outward currents were measured as illustrated previously. 23 Peak current was taken for current amplitude of the faster current component; for each experiment, current decay was best fit with a sum of two exponentials (Eq. 3).…”

Section: Electrophysiology Recordingmentioning

confidence: 99%

Modeling Human Neural FunctionalityIn Vitro: Three-Dimensional Culture for Dopaminergic Differentiation

Simão

Pinto

Piersanti

et al. 2015

Tissue Engineering Part A

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Advances in mechanistic knowledge of human neurological disorders have been hindered by the lack of adequate human in vitro models. Three-dimensional (3D) cellular models displaying higher biological relevance are gaining momentum; however, their lack of robustness and scarcity of analytical tools adapted to three dimensions hampers their widespread implementation. Herein we show that human midbrain-derived neural progenitor cells, cultured as 3D neurospheres in stirred culture systems, reproducibly differentiate into complex tissue-like structures containing functional dopaminergic neurons, as well as astrocytes and oligodendrocytes. Moreover, an extensive toolbox of analytical methodologies has been adapted to 3D neural cell models, allowing molecular and phenotypic profiling and interrogation. The generated neurons underwent synaptogenesis and elicit spontaneous Ca(2+) transients. Synaptic vesicle trafficking and release of dopamine in response to depolarizing stimuli was also observed. Under whole-cell current-and-voltage clamp, recordings showed polarized neurons (Vm=-70 mV) and voltage-dependent potassium currents, which included A-type-like currents. Glutamate-induced currents sensitive to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate antagonists revealed the existence of functional glutamate receptors. Molecular and phenotypic profiling showed recapitulation of midbrain patterning events, and remodeling toward increased similarity to human brain features, such as extracellular matrix composition and metabolic signature. We have developed a robust and reproducible human 3D neural cell model, which may be extended to patient-derived induced pluripotent stem cells, broadening the applicability of this model.

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Galantamine inhibits slowly inactivating K+ currents with a dual dose–response relationship in differentiated N1E-115 cells and in CA1 neurones

Cited by 8 publications

References 45 publications

The kynurenine pathway and the brain: Challenges, controversies and promises

The kynurenine pathway and the brain: Challenges, controversies and promises

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Modeling Human Neural FunctionalityIn Vitro: Three-Dimensional Culture for Dopaminergic Differentiation

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