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Albrecht, Jan (Supervisor) ; Obara-Michlewska, Marta (Auxiliary supervisior)
Place of publishing: Date issued/created: Degree name: Level of degree: Degree discipline : Degree grantor:Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN
Abstract:About 70 percent of the neurotransmitter glutamate (Glu) pool is from glutamine (Gln). Although increased glutamatergic transmission is a persistent element of epileptic seizures, neither the metabolic origin of the Glu surplus nor the mechanisms underlying its enhanced release in initial phase of the disease are known. We hypothesized that, inhibition of the active synthesis of glutamine (Gln), would decrease or even stop the initial ictal activity of the brain. To test this hypothesis, rats were administered with MSO, a specific glutamine synthetase inhibitor, or saline, and convulsive seizures were subsequently induced using pilocarpine (Pilo). The course of the seizures was analyzed for 1 h after the Pilo injection, using the Racine behavioral scale, EEG, EMG and intrahippocampal Glu biosensors; some of the animals also received 13C-labelled astrocytic or neuronal precursors of the TCA cycle, to assess metabolic changes under the action of MSO and/or Pilo. A separate series of experiments was also performed using acutely isolated brain slices isolated from MSO-pretreated animals, to examine changes in the uptake and efflux of a non-metabolizable Glu analogue, [3H]d-Asp. Expression of mRNA coding for the early response protein, c-Fos, was analyzed using qPCR. Pretreatment with MSO alleviated seizures and significantly delayed their onset, but did not attenuate the seizure-associated accumulation of extracellular Glu in the hippocampus. MSO did not markedly affect the de novo synthesis of Gln and Glu. As analyzed in brain slices, MSO significantly attenuated the release of [3H]d-Asp, but not its uptake. Expression level of c-Fos mRNA was negatively correlated with the latency onset to the first generalized seizure.The results demonstrate the effectiveness of MSO in attenuating the initial Pilo-induced seizures, especially in delaying their onset. However, metabolomic data indicate that the seizure-attenuating effects of MSO are not due to inhibition of glutamine synthase activity, but rather to its direct action on the Glu-releasing machinery. In perspective, the results suggest that MSO or its derivative(s) may become a useful tool in prevention or therapy of the very initial seizures.
Resource type: Detailed Resource Type: Format: Source:IMDiK PAN, sygn. ZS 419 ; click here to follow the link
Rights:Creative Commons Attribution BY 4.0 license
Terms of use:Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -
Digitizing institution:Mossakowski Medical Research Institute PAS
Original in:Library of the Mossakowski Medical Research Institute PAS
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