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PLoS ONEVolume 12, Issue 7, July 2017, Article number e0180739

Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro(Article)(Open Access)

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  • aFederal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
  • bInstitute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russian Federation
  • cFederal State Autonomous Educational Institution of Higher Professional Education, Ural Federal University Named after the First President of Russia B. N. Yeltsin, Ekaterinburg, Russian Federation
  • dInstitute of Organic Synthesis, Ural Division of Russian Academy of Sciences, Ekaterinburg, Russian Federation
  • eTomsk State University, Department of Vertebrate Zoology, Tomsk, Russian Federation

Abstract

The aim of the present study was to examine how administration of a compound of 1,3,4-thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/ kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism. © 2017 Shevelev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Indexed keywords

EMTREE drug terms:1,3,4 thiadiazine class 2 morpholino 5 phenyl 6h 1,3,4 thiadiazine hydrobromide1,3,4 thiadiazine derivativeneurotransmitterunclassified drugthiadiazine derivative
EMTREE medical terms:adultanimal cellanimal experimentanimal modelanimal tissueArticleblood flow velocitybody temperature measurementbrain metabolismcontrolled studyenergy metabolismexcitatory junction potentialexcitatory postsynaptic potentialhypothermiain vitro studyin vivo studyinhibitory postsynaptic potentialmalemitochondrionnerve cell cultureneuroimagingneurotoxicitynonhumannuclear magnetic resonance spectroscopyrattoxicity testinganimalbody temperaturebrainchemistrydrug effectsinduced hypothermiamagnetic resonance angiographymetabolismSprague Dawley rat
MeSH:AnimalsBody TemperatureBrainHypothermia, InducedIn Vitro TechniquesMagnetic Resonance AngiographyMagnetic Resonance SpectroscopyMaleRatsRats, Sprague-DawleyThiadiazines

Chemicals and CAS Registry Numbers:

Thiadiazines

Funding details

Funding sponsor Funding number Acronym
Russian Science Foundation14-14-00221RSF
  • 1

    The study was supported by the Russian Science Foundation (grant No 14-14-00221) http://www.rscf.ru/. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • ISSN: 19326203
  • CODEN: POLNC
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1371/journal.pone.0180739
  • PubMed ID: 28678857
  • Document Type: Article
  • Publisher: Public Library of Science

  Shevelev, O.B.; Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation;
© Copyright 2017 Elsevier B.V., All rights reserved.

Cited by 4 documents

Alshubramy, M.A. , Asem, M. , Abdel-Motaal, M.
Efficient Synthesis of New Fused Thiadiazines and Their Spectroscopic, In Silico Drug Likeness, and ADME Properties
(2022) Russian Journal of Organic Chemistry
Sarapultsev, A. , Vassiliev, P. , Grinchii, D.
Combined in silico, ex vivo, and in vivo assessment of L-17, a thiadiazine derivative with putative neuro-and cardioprotective and antidepressant effects
(2021) International Journal of Molecular Sciences
Komendantova, A.S. , Ivanova, K.A. , Lyssenko, K.V.
Facile Synthesis of Carboxamide-Substituted 1,3,4-Thiadiazines and 5,6-Dihydro-4H-1,3,4-Thiadiazin-5-Ols
(2019) Chemistry of Heterocyclic Compounds
View details of all 4 citations
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