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1.
Neuroscience ; 281: 208-15, 2014 Dec 05.
Article in English | MEDLINE | ID: mdl-25286387

ABSTRACT

Caffeine, a methylated derivative of xanthine and widely consumed psychoactive substance, acts in several targets in the nervous system. We investigated its role in retinal explants of chick embryo analyzing the role of purinergic receptors in [(3)H]-GABA release induced by d-aspartate (d-asp). d-Asp increases GABA-release 4.5-fold when compared to basal levels from 13-day-old chick embryo retinal explants. Caffeine 500µM elevated d-asp-induced GABA release in 60%. The release was inhibited in the presence of NNC-711, a GABA transporter-1 (GAT-1) blocker or by MK-801, an N-methyl-d-aspartate receptor (NMDAR) antagonist. Caffeine did not modify [(3)H]-GABA uptake carried out for 5, 10, 30 and 60min and did not increase the release of d-asp or glutamate at basal or stimulated conditions. The caffeine effect was mimicked by the adenosine A1 receptor antagonist DPCPX and by the adenylyl cyclase (AC) activator forskolin. It was also blocked by the protein kinase A (PKA) inhibitor H-89, tyrosine kinase inhibitor genistein or by the src family kinase (SFK) inhibitor PP1. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels were reduced in the presence of the A1 receptor agonist CHA. Western blot analysis revealed that 500µM caffeine increased phosphoGluN2B expression levels in approximately 60% when compared to total GluN2B levels in embryonic E13 retina. The GluN2B subunit-containing NMDAR antagonist ifenprodil inhibited the caffeine effect. Our results suggest that caffeine potentiates d-asp-induced GABA release, which is mediated by GAT-1, via inhibition of adenosine A1 receptor and activation of the PKA pathway. Regulation of NMDAR by phosphorylation of GluN2B subunit by a SFK may also be involved in the effect promoted by caffeine.


Subject(s)
Caffeine/pharmacology , Central Nervous System Stimulants/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , D-Aspartic Acid/pharmacology , GABA Plasma Membrane Transport Proteins/metabolism , Receptor, Adenosine A1/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Retina/metabolism , Signal Transduction/drug effects , gamma-Aminobutyric Acid/metabolism , Animals , Chick Embryo , Cyclic AMP-Dependent Protein Kinases/drug effects , GABA Plasma Membrane Transport Proteins/drug effects , Receptor, Adenosine A1/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Retina/drug effects , gamma-Aminobutyric Acid/drug effects
2.
Parasitology ; 129(Pt 2): 137-46, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15376773

ABSTRACT

The neuromuscular systems of parasitic helminths are targets that are particularly amenable for anthelmintics. In this study, we describe a GABAergic neurotransmission in adult Schistosoma mansoni, the trematode responsible for high levels of morbidity in people living in developing countries. GABA immunoreactivity (GABA-IR) was detected in nerve cells and fibres of the cerebral ganglia and longitudinal nerve cords and the nerve plexuses ramifying throughout the parenchyma of male adult worms. In addition, strong GABA-IR was also found associated with the oral and ventral suckers as well as in testes indicating a role for GABA in fixation to the host vascular wall and spermatogenesis. The capacity to synthesize GABA from glutamate was confirmed by measurement of a glutamate decarboxylase (GAD) activity. Supporting these data, a single band with an apparent molecular weight of about 67 kDa was detected using an antibody raised against mammalian GAD. In vivo studies revealed that picrotoxin, a non-competitive antagonist of the GABAA receptor, produced a modification of the motility and locomotory behaviour of adult worms, suggesting that GABAergic signalling pathway may play a physiological role in the motonervous system of S. mansoni and could be considered as a potential target for the development of new drugs.


Subject(s)
Neurons/physiology , Schistosoma mansoni/physiology , Synaptic Transmission/physiology , gamma-Aminobutyric Acid/physiology , Animals , Central Nervous System Stimulants/pharmacology , Glutamate Decarboxylase/metabolism , Glutamic Acid/metabolism , Immunoblotting , Immunohistochemistry , Male , Molecular Weight , Movement/physiology , Neurons/metabolism , Picrotoxin/pharmacology , Signal Transduction/physiology , gamma-Aminobutyric Acid/biosynthesis , gamma-Aminobutyric Acid/metabolism
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