TY - JOUR

T1 - Inhibition of Glutamate Release, but Not of Glutamine Recycling to Glutamate, Is Involved in Delaying the Onset of Initial Lithium-Pilocarpine-Induced Seizures in Young Rats by a Non-Convulsive MSO Dose

AU - Pawlik, Marek J.

AU - Aldana, Blanca I.

AU - Belfiori-Carrasco, Lautaro F.

AU - Obara-Michlewska, Marta

AU - Popek, Mariusz P.

AU - Czarnecka, Anna Maria

AU - Albrecht, Jan

N1 - This article belongs to the Special Issue Non-genetic Modifiers of Synaptic Plasticity and Neurotransmission in the Central Nervous System (CNS) in Health and Disease.

PY - 2021

Y1 - 2021

N2 - Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition of conversion of Glu/Gln precursors to neurotransmitter Glu, and/or from b) altered synaptic Glu release. Pilo was administered 60 min prior to sacrifice, MSO at 75 mg/kg, i.p., 2.5 h earlier. [1,2-13C]acetate and [U-13C]glucose were i.p.-injected either together with Pilo (short period) or 15 min before sacrifice (long period). Their conversion to Glu and Gln in the hippocampus and entorhinal cortex was followed using [13C] gas chromatography-mass spectrometry. Release of in vitro loaded Glu surrogate, [3H]D-Asp from ex vivo brain slices was monitored in continuously collected superfusates. [3H]D-Asp uptake was tested in freshly isolated brain slices. At no time point nor brain region did MSO modify incorporation of [13C] to Glu or Gln in Pilotreated rats. MSO pretreatment decreased by ~37% high potassium-induced [3H]D-Asp release, but did not affect [3H]D-Asp uptake. The results indicate that MSO at a non-convulsive dose delays the initial Pilo-induced seizures by interfering with synaptic Glu-release but not with neurotransmitter Glu recycling.

AB - Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition of conversion of Glu/Gln precursors to neurotransmitter Glu, and/or from b) altered synaptic Glu release. Pilo was administered 60 min prior to sacrifice, MSO at 75 mg/kg, i.p., 2.5 h earlier. [1,2-13C]acetate and [U-13C]glucose were i.p.-injected either together with Pilo (short period) or 15 min before sacrifice (long period). Their conversion to Glu and Gln in the hippocampus and entorhinal cortex was followed using [13C] gas chromatography-mass spectrometry. Release of in vitro loaded Glu surrogate, [3H]D-Asp from ex vivo brain slices was monitored in continuously collected superfusates. [3H]D-Asp uptake was tested in freshly isolated brain slices. At no time point nor brain region did MSO modify incorporation of [13C] to Glu or Gln in Pilotreated rats. MSO pretreatment decreased by ~37% high potassium-induced [3H]D-Asp release, but did not affect [3H]D-Asp uptake. The results indicate that MSO at a non-convulsive dose delays the initial Pilo-induced seizures by interfering with synaptic Glu-release but not with neurotransmitter Glu recycling.

KW - Epilepsy

KW - Glutamatergic transmission

KW - Glutamine synthesis

KW - Metabolomics

KW - Methionine sulfoximine

U2 - 10.3390/ijms222011127

DO - 10.3390/ijms222011127

M3 - Journal article

C2 - 34681786

AN - SCOPUS:85117062039

VL - 22

JO - International Journal of Molecular Sciences (CD-ROM)

JF - International Journal of Molecular Sciences (CD-ROM)

SN - 1424-6783

IS - 20

M1 - 11127

ER -