Study on the possible involvement of protein kinases in the modulation of brain presynaptic sodium channels; comparison with calcium channels

Sitges, Marı́a; Peña, Fernando; Chiu, Luz María; Guarneros, Araceli

doi:10.1016/s0197-0186(97)00065-x

Cited by 21 publications

(10 citation statements)

References 45 publications

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“…Consistent with our findings, PKC modulates transient (Astman et al, 1998;Sitges et al, 1998;Schreibmayer, 1999) and persistent sodium currents (Astman et al, 1998;Franceschetti et al, 2000), and it has been proposed that these effects on sodium currents increase the neuronal excitability (Astman et al, 1998;Franceschetti et al, 2000). The activation of 5-HT 2A receptors has been associated with the induction of a tonic inward current (Lindsay and Feldman, 1993) that is Na ϩ dependent (Lee et al, 1999).…”

Section: Role Of Endogenous Activation Of 5-ht 2a In the Maintenance supporting

confidence: 91%

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

2002

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Endogenous amines and peptides continuously modulate the activity of neuronal networks and are required even for their normal operation. The respiratory rhythm generator, localized in the pre-Bö tzinger complex, is not an exception. This network is modulated by various neurotransmitters, including serotonin (5-HT). In this study, we isolated the respiratory network in brainstem slices and demonstrate that the endogenous activation of 5-HT 2A is required for the generation of the respiratory rhythm in vitro. At the network level, activation of 5-HT 2A receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake blocker alaproclate increased the frequency of respiratory activity. Blockade of endogenously activated 5-HT 2A receptors with three different antagonists decreased the frequency, amplitude, and regularity of respiratory population activity, an effect that was blocked by protein kinase C (PKC) activators. At the cellular level, blockade of 5-HT 2A receptors reduced the action potential discharge in all examined respiratory neurons, which was associated with a reduction in the fast and the persistent sodium current. Continuous application of 5-HT 2A -receptor antagonists differentially affected pacemaker neurons. Pacemaker activity was eliminated in cadmiuminsensitive pacemaker neurons. In cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that cadmium-insensitive pacemakers rely on the persistent sodium current, whereas cadmium-sensitive pacemakers depend on the activation of calcium currents. We conclude that endogenously activated 5-HT 2A receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.

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Section: Role Of Endogenous Activation Of 5-ht 2a In the Maintenance supporting

confidence: 91%

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

2002

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“…After oral administration, the maximal average brain uptake of vinpocetine was 0.7% of the total administered radioactivity. Though this uptake is smaller than that previously demonstrated after intravenous administration (3.7%), the data indicate that when the drug is administered in usual therapeutic doses, a considerable amount of drug molecules is present in the brain, which may be pharmacologically relevant [17,18].…”

Section: Discussioncontrasting

confidence: 61%

Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine

et al. 2002

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Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [(11)C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [(11)C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [(11)C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally administered labelled CNS drugs in the living human body.

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“…The method used to load synaptosomes with SBFI and to monitor its fluorescence was previously reported (Sitges et al. 1998, 2006).…”

Section: Methodsmentioning

confidence: 99%

Sertraline inhibits pre‐synaptic Na⁺ channel‐mediated responses in hippocampus‐isolated nerve endings

Aldana

Sitges

2012

Journal of Neurochemistry

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+. In summary, present findings demonstrate that besides the inhibition of 5-HT reuptake, sertraline is an effective inhibitor of presynaptic Na + channels controlling neurotransmitter release.Keywords: 5-HT, GABA, Glu, neurotransmitter release, sodium channels, veratridine. makes difficult to use conventional electrophysiological techniques to depolarize them. However, the rate of Na + entry in cerebral isolated nerve endings can be increased using the naturally occurring toxin veratridine that binds to the voltage sensor (site 2) of the Na + channel impeding its inactivation. However, with the aid of the Na + selective indicator dye, sodium-binding benzofuran isophthalate (SBFI) which changes its emission fluorescence in response to changes in Na + in its vicinity, the change in the internal concentration of Na + can be monitored in cerebral isolated nerve endings. As judged by the changes in SBFI fluorescence, the increase in Na + channels permeability induced by veratridine in cerebral isolated nerve endings is: inhibited by the Na + channel blocker tetrodotoxin, independent of external Ca 2+ and insensitive to the blockade of P/Q type Ca 2+ channels with the x-agatoxins: IVA and TK (Sitges et al. 1998;Sitges and Galindo 2005). Likewise neurotransmitter release induced by veratridine in synaptosomes depends on the presence of external Na + , is sensitive to tetrodotoxin and is independent of external Ca 2+ (Sitges 1989;Sitges and Chiu 1995;Galindo and Sitges 2004;Sitges and Galindo 2005). Therefore the sensitivity of a veratridine induced response to a drug (particularly in the absence of external Ca 2+ ) is highly indicative of a reduction in Na + channels permeability. In previous studies, we found that various antiepileptic drugs inhibited the rise in Na + and the release of the excitatory amino acid neurotransmitter Glu induced by veratridine in hippocampus synaptosomes under external Ca 2 + free conditions (Sitges et al. 2006(Sitges et al. , 2007. For the purpose of unmasking, a possible effect of sertraline on cerebral pre-synaptic Na + channels permeability, in the present study the effect of sertraline on the rise in Na + and on the release of several neurotransmitters, including the excitatory amino acid neurotransmitter Glu in hippocampus isolated nerve endings under resting and veratridine depolarized conditions was investigated. Materials and methods Source of materials Isolation of hippocampus nerve endingsThe hippocampi from four male Wistar rats (250-300 g) were dissected, immediately placed in cold isotonic sucrose (1/10, wt/vol) and homogenized (6 strokes at 2000 rpm, 0.15 mm pestle-vessel clearance). The resulting suspensions were centrifuged at 1500 g for 10 min, and the supernatants obtained from this centrifugation centrifuged at 9000 g for another 20 min. The resulting pellets containing the P2 fraction of the hippocampus isolated nerve endings were suspended in standard Krebs Ringer HEPES (KRH). For the [ 3 H]Glu release experiments, the P2 fraction of hippocampus synaptosomes was pur...

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Study on the possible involvement of protein kinases in the modulation of brain presynaptic sodium channels; comparison with calcium channels

Cited by 21 publications

References 45 publications

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine

Sertraline inhibits pre‐synaptic Na⁺ channel‐mediated responses in hippocampus‐isolated nerve endings

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Study on the possible involvement of protein kinases in the modulation of brain presynaptic sodium channels; comparison with calcium channels

Cited by 21 publications

References 45 publications

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine

Sertraline inhibits pre‐synaptic Na+ channel‐mediated responses in hippocampus‐isolated nerve endings

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Sertraline inhibits pre‐synaptic Na⁺ channel‐mediated responses in hippocampus‐isolated nerve endings