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  1. Article ; Online: Modeling in systems biology: Causal understanding before prediction?

    Barsi, Szilvia / Szalai, Bence

    Patterns (New York, N.Y.)

    2021  Volume 2, Issue 6, Page(s) 100280

    Abstract: Babur et al. (2021) developed ... ...

    Abstract Babur et al. (2021) developed the
    Language English
    Publishing date 2021-06-11
    Publishing country United States
    Document type News
    ISSN 2666-3899
    ISSN (online) 2666-3899
    DOI 10.1016/j.patter.2021.100280
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva.

    Vajda, Szilvia / Gunda, Bence / Knézy, Krisztina / Barsi, Péter / Varga, Csaba / Maurovich-Horvat, Pál / Bereczki, Dániel / Nagy, Zsolt Zoltán

    Ideggyogyaszati szemle

    2024  Volume 77, Issue 3-4, Page(s) 89–96

    Abstract: Background and purpose: ... The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised ... ...

    Title translation Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options.
    Abstract Background and purpose:

    The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.

    .
    Methods:

    We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo­gical and cardiovascular findings compared to those in the thrombolysis project. 

    .
    Results:

    Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 
    2 pa­tients had improved visual acuity, 2 pa­tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.

    .
    Conclusion:

    CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.

    .
    MeSH term(s) Humans ; Thrombolytic Therapy/methods ; Carotid Stenosis/complications ; Carotid Stenosis/therapy ; Retinal Artery Occlusion/drug therapy ; Retinal Artery Occlusion/diagnosis ; Stroke/drug therapy ; Conservative Treatment ; Ischemic Stroke
    Language Hungarian
    Publishing date 2024-04-09
    Publishing country Hungary
    Document type Review ; English Abstract ; Journal Article
    ZDB-ID 2240317-6
    ISSN 0019-1442
    ISSN 0019-1442
    DOI 10.18071/isz.77.0089
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An Unexpected Enzyme in Vascular Smooth Muscle Cells: Angiotensin II Upregulates Cholesterol-25-Hydroxylase Gene Expression.

    Kovács, Kinga Bernadett / Szalai, Laura / Szabó, Pál / Gém, Janka Borbála / Barsi, Szilvia / Szalai, Bence / Perey-Simon, Bernadett / Turu, Gábor / Tóth, András Dávid / Várnai, Péter / Hunyady, László / Balla, András

    International journal of molecular sciences

    2023  Volume 24, Issue 4

    Abstract: Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H) ...

    Abstract Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H), also have detrimental effects on vascular health by affecting vascular smooth muscle cells (VSMCs). We investigated AngII-induced gene expression changes in VSMCs to explore whether AngII stimulus and 25-HC production have a connection in the vasculature. RNA-sequencing revealed that
    MeSH term(s) Animals ; Rats ; Angiotensin II/metabolism ; Cells, Cultured ; Chromatography, Liquid ; Gene Expression ; Muscle, Smooth, Vascular/enzymology ; Myocytes, Smooth Muscle/metabolism ; Tandem Mass Spectrometry ; Steroid Hydroxylases/genetics
    Chemical Substances Angiotensin II (11128-99-7) ; cholesterol 25-hydroxylase (EC 1.14.99.38) ; Steroid Hydroxylases (EC 1.14.-)
    Language English
    Publishing date 2023-02-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24043968
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  4. Article ; Online: Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity.

    Barsi, Szilvia / Papp, Henrietta / Valdeolivas, Alberto / Tóth, Dániel J / Kuczmog, Anett / Madai, Mónika / Hunyady, László / Várnai, Péter / Saez-Rodriguez, Julio / Jakab, Ferenc / Szalai, Bence

    PLoS computational biology

    2022  Volume 18, Issue 4, Page(s) e1010021

    Abstract: Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug ... ...

    Abstract Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity-and not inverse similarity-between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.
    MeSH term(s) Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cell Membrane ; Cholesterol ; Drug Repositioning/methods ; Humans ; SARS-CoV-2 ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2022-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1010021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-

    Zádor, Ferenc / Mohammadzadeh, Amir / Balogh, Mihály / Zádori, Zoltán S / Király, Kornél / Barsi, Szilvia / Galambos, Anna Rita / László, Szilvia B / Hutka, Barbara / Váradi, András / Hosztafi, Sándor / Riba, Pál / Benyhe, Sándor / Fürst, Susanna / Al-Khrasani, Mahmoud

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 6

    Abstract: The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- ...

    Abstract The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-
    MeSH term(s) Analgesics, Opioid/chemical synthesis ; Analgesics, Opioid/chemistry ; Analgesics, Opioid/pharmacology ; Analgesics, Opioid/therapeutic use ; Animals ; Binding, Competitive ; Codeine/chemical synthesis ; Codeine/chemistry ; Codeine/pharmacology ; Codeine/therapeutic use ; Freund's Adjuvant ; Gastrointestinal Transit/drug effects ; Inflammation/drug therapy ; Injections, Intraventricular ; Male ; Mice ; Naloxone/pharmacology ; Naloxone/therapeutic use ; Nociception/drug effects ; Pain/drug therapy ; Rats, Wistar ; Receptors, Opioid, mu/metabolism
    Chemical Substances Analgesics, Opioid ; Receptors, Opioid, mu ; Naloxone (36B82AMQ7N) ; Freund's Adjuvant (9007-81-2) ; Codeine (UX6OWY2V7J)
    Language English
    Publishing date 2020-03-17
    Publishing country Switzerland
    Document type Comparative Study ; Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25061370
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  6. Article ; Online: Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity.

    Szilvia Barsi / Henrietta Papp / Alberto Valdeolivas / Dániel J Tóth / Anett Kuczmog / Mónika Madai / László Hunyady / Péter Várnai / Julio Saez-Rodriguez / Ferenc Jakab / Bence Szalai

    PLoS Computational Biology, Vol 18, Iss 4, p e

    2022  Volume 1010021

    Abstract: Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug ... ...

    Abstract Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity-and not inverse similarity-between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570 ; 572
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Glycine transporter inhibitors: A new avenue for managing neuropathic pain.

    Al-Khrasani, Mahmoud / Mohammadzadeh, Amir / Balogh, Mihály / Király, Kornél / Barsi, Szilvia / Hajnal, Benjamin / Köles, László / Zádori, Zoltán S / Harsing, Laszlo G

    Brain research bulletin

    2019  Volume 152, Page(s) 143–158

    Abstract: Interneurons operating with glycine neurotransmitter are involved in the regulation of pain transmission in the dorsal horn of the spinal cord. In addition to interneurons, glycine release also occurs from glial cells neighboring glutamatergic synapses ... ...

    Abstract Interneurons operating with glycine neurotransmitter are involved in the regulation of pain transmission in the dorsal horn of the spinal cord. In addition to interneurons, glycine release also occurs from glial cells neighboring glutamatergic synapses in the spinal cord. Neuronal and glial release of glycine is controlled by glycine transporters (GlyTs). Inhibitors of the two isoforms of GlyTs, the astrocytic type-1 (GlyT-1) and the neuronal type-2 (GlyT-2), decrease pain sensation evoked by injuries of peripheral sensory neurons or inflammation. The function of dorsal horn glycinergic interneurons has been suggested to be reduced in neuropathic pain, which can be reversed by GlyT-2 inhibitors (Org-25543, ALX1393). Several lines of evidence also support that peripheral nerve damage or inflammation may shift glutamatergic neurochemical transmission from N-methyl-D aspartate (NMDA) NR1/NR2A receptor- to NR1/NR2B receptor-mediated events (subunit switch). This pathological overactivation of NR1/NR2B receptors can be reduced by GlyT-1 inhibitors (NFPS, Org-25935), which decrease excessive glycine release from astroglial cells or by selective antagonists of NR2B subunits (ifenprodil, Ro 25-6981). Although several experiments suggest that GlyT inhibitors may represent a novel strategy in the control of neuropathic pain, proving this concept in human beings is hampered by lack of clinically applicable GlyT inhibitors. We also suggest that drugs inhibiting both GlyT-1 and GlyT-2 non-selectively and reversibly, may favorably target neuropathic pain. In this paper we overview inhibitors of the two isoforms of GlyTs as well as the effects of these drugs in experimental models of neuropathic pain. In addition, the possible mechanisms of action of the GlyT inhibitors, i.e. how they affect the neurochemical and pain transmission in the spinal cord, are also discussed. The growing evidence for the possible therapeutic intervention of neuropathic pain by GlyT inhibitors further urges development of drugable compounds, which may beneficially restore impaired pain transmission in various neuropathic conditions.
    MeSH term(s) Animals ; Glycine/pharmacology ; Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors ; Glycine Plasma Membrane Transport Proteins/metabolism ; Humans ; Hyperalgesia/drug therapy ; Neuralgia/drug therapy ; Neuralgia/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Phenols/pharmacology ; Piperidines/pharmacology ; Receptors, N-Methyl-D-Aspartate/metabolism ; Serine/analogs & derivatives ; Serine/pharmacology ; Spinal Cord Dorsal Horn/metabolism ; Synapses/metabolism ; Synaptic Transmission/drug effects
    Chemical Substances ALX 1393 ; Glycine Plasma Membrane Transport Proteins ; NR2A NMDA receptor ; Phenols ; Piperidines ; Receptors, N-Methyl-D-Aspartate ; Ro 25-6981 ; Serine (452VLY9402) ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2019-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 197620-5
    ISSN 1873-2747 ; 0361-9230
    ISSN (online) 1873-2747
    ISSN 0361-9230
    DOI 10.1016/j.brainresbull.2019.07.008
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  8. Article ; Online: Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6- O -sulfate and Codeine-6- O -sulfate

    Ferenc Zádor / Amir Mohammadzadeh / Mihály Balogh / Zoltán S. Zádori / Kornél Király / Szilvia Barsi / Anna Rita Galambos / Szilvia B. László / Barbara Hutka / András Váradi / Sándor Hosztafi / Pál Riba / Sándor Benyhe / Susanna Fürst / Mahmoud Al-Khrasani

    Molecules, Vol 25, Iss 6, p

    2020  Volume 1370

    Abstract: The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- O -sulfate (14-OMeC6SU), compared to the reference compounds codeine-6- O - ... ...

    Abstract The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- O -sulfate (14-OMeC6SU), compared to the reference compounds codeine-6- O -sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [ 35 S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.
    Keywords peripheral antinociception ; 14-methoxycodeine-6- o -sulfate ; codeine-6- o -sulfate ; Organic chemistry ; QD241-441
    Subject code 570
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model.

    Mohammadzadeh, Amir / Lakatos, Péter P / Balogh, Mihály / Zádor, Ferenc / Karádi, Dávid Árpád / Zádori, Zoltán S / Király, Kornél / Galambos, Anna Rita / Barsi, Szilvia / Riba, Pál / Benyhe, Sándor / Köles, László / Tábi, Tamás / Szökő, Éva / Harsing, Laszlo G / Al-Khrasani, Mahmoud

    International journal of molecular sciences

    2021  Volume 22, Issue 5

    Abstract: The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding ... ...

    Abstract The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30-60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.
    MeSH term(s) Animals ; Glycine/cerebrospinal fluid ; Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors ; Hyperalgesia/metabolism ; Hyperalgesia/pathology ; Hyperalgesia/prevention & control ; Male ; Motor Activity ; Neuralgia/drug therapy ; Neuralgia/metabolism ; Neuralgia/pathology ; Rats ; Rats, Wistar ; Sarcosine/analogs & derivatives ; Sarcosine/pharmacology ; Spinal Cord/drug effects ; Spinal Cord/metabolism ; Spinal Cord/pathology
    Chemical Substances Glycine Plasma Membrane Transport Proteins ; N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine ; Slc6a5 protein, rat ; Slc6a9 protein, rat ; Glycine (TE7660XO1C) ; Sarcosine (Z711V88R5F)
    Language English
    Publishing date 2021-03-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22052479
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  10. Article ; Online: Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

    Amir Mohammadzadeh / Péter P. Lakatos / Mihály Balogh / Ferenc Zádor / Dávid Árpád Karádi / Zoltán S. Zádori / Kornél Király / Anna Rita Galambos / Szilvia Barsi / Pál Riba / Sándor Benyhe / László Köles / Tamás Tábi / Éva Szökő / Laszlo G. Harsing / Mahmoud Al-Khrasani

    International Journal of Molecular Sciences, Vol 22, Iss 5, p

    2021  Volume 2479

    Abstract: The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding ... ...

    Abstract The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.
    Keywords neuropathic pain ; NFPS ; Org-25543 ; CSF glycine content ; glycine transporter inhibitor combination ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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