Acute treatment with diphenyl diselenide inhibits glutamate uptake into rat hippocampal slices and modifies glutamate transporters, SNAP-25, and GFAP immunocontent.
Diphenyl diselenide (PhSe)(2) is a selenium organic compound that has been described to inhibit glutamate binding at synaptic membranes and uptake into cortical slices, but there are no studies about its effects on glutamate transporters and related synaptic proteins. Hippocampal slices from rats treated acutely with (PhSe)(2) (1, 10, and 100 mg/kg, oral route) were evaluated on glutamate uptake, redox state, the immunocontent of glial (glutamate/aspartate transporter [GLAST] and glutamate transporter type I [GLT1]), neuronal (excitatory amino acid carrier 1 [EAAC1]), and vesicular (vesicular glutamate transporter 1 [VGLUT1]) glutamate transporters. Besides, cell viability was evaluated by glial fibrillar acid protein (GFAP) and synaptosomal-associated protein 25 (SNAP-25) immunocontent and 4', 6-diamidino-2-phenylindole (DAPI) and Fluoro Jade C staining. Hippocampal slices from rats treated with (PhSe)(2) exhibited a nondose-dependent inhibition of glutamate uptake (53, 38, and 45%, respectively). All doses increased EAAC1, decreased SNAP-25, did not modify GLT1 immunocontent, and there was no evidence of oxidative stress. (PhSe)(2) (100 mg/kg) increased 32% GLAST, decreased 34% VGLUT1, and 21% GFAP immunocontent. Besides, (PhSe)(2) (100 mg/kg) decreased by 25% GFAP-stained astrocytes and 27% DAPI-stained cells in the CA1 subfield. Our results suggest that the increase of EAAC1 and GLAST immunocontent by (PhSe)(2) might be a compensatory mechanism by surviving cells in order to reduce extracellular glutamate levels, avoiding possible neurotoxic effects. The impairment of glutamate uptake by the highest dose of (PhSe)(2) seems to be related to a decrease on VGLUT1, SNAP-25, and damage to astrocytes. Since there were no signs of oxidative stress, our findings revealed that depending on the dose, acute administration of (PhSe)(2) causes modifications in important synaptic-related proteins and damage to the astrocytes, and these events must be taken into account in its pharmacological properties.
Ardais
Ana P
AP
Laboratory of Studies on the Purinergic System, Post-Graduation Program in Biological Sciences-Biochemistry, Department of Biochemistry, Health and Basic Sciences Institute, Federal University of Rio Grande do Sul, Porto Alegre/RS, Brazil.
Viola
Giordano G
GG
Costa
Marcelo S
MS
Nunes
Fernanda
F
Behr
Guilherme A
GA
Klamt
Fábio
F
Moreira
José C F
JC
Souza
Diogo O
DO
Rocha
João B T
JB
Porciúncula
Lisiane O
LO
D027322:Amino Acid Transport System X-AG / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D016566:Organoselenium Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D050825:Synaptosomal-Associated Protein 25 / Q000276:immunology / Q000378:metabolism*; D023382:Toxicity Tests, Acute; D050496:Vesicular Glutamate Transport Proteins / Q000276:immunology / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D001555:Benzene Derivatives; D005904:Glial Fibrillary Acidic Protein; D016566:Organoselenium Compounds; D050825:Synaptosomal-Associated Protein 25; D050496:Vesicular Glutamate Transport Proteins; C061132:diphenyldiselenide; D018698:Glutamic Acid