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Tytuł:
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Prasugrel anti-ischemic effect in rats: Modulation of hippocampal SUMO2/3-IкBα/Ubc9 and SIRT-1/miR-22 trajectories.
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Autorzy:
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Gomaa AA; Department of Pharmacology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
El-Abhar HS; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Abdallah DM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: .
Awad AS; Department of Pharmacology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
Soubh AA; Department of Pharmacology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
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Źródło:
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Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2021 Sep 01; Vol. 426, pp. 115635. Date of Electronic Publication: 2021 Jun 24.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: New York, NY : Academic Press
Original Publication: New York.
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MeSH Terms:
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Brain Ischemia/*drug therapy
Hippocampus/*drug effects
Neuroprotective Agents/*therapeutic use
Platelet Aggregation Inhibitors/*therapeutic use
Prasugrel Hydrochloride/*therapeutic use
Purinergic P2Y Receptor Antagonists/*therapeutic use
Animals ; Behavior, Animal/drug effects ; Brain Ischemia/blood ; Brain Ischemia/metabolism ; Brain Ischemia/pathology ; Hippocampus/metabolism ; Hippocampus/pathology ; Lipid Peroxidation/drug effects ; Male ; MicroRNAs/blood ; NF-KappaB Inhibitor alpha/metabolism ; Neuroprotective Agents/pharmacology ; Platelet Aggregation Inhibitors/pharmacology ; Prasugrel Hydrochloride/pharmacology ; Purinergic P2Y Receptor Antagonists/pharmacology ; Rats, Wistar ; Sirtuin 1/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Spatial Memory/drug effects ; Ubiquitin-Conjugating Enzymes/metabolism ; Rats
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Contributed Indexing:
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Keywords: Cerebral I/R; GFAP; NF-κB; Rats; SUMOylation; Y-maze
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Substance Nomenclature:
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0 (MIRN22 microRNA, rat)
0 (MicroRNAs)
0 (Neuroprotective Agents)
0 (Platelet Aggregation Inhibitors)
0 (Purinergic P2Y Receptor Antagonists)
0 (SUMO2 protein, rat)
0 (SUMO3 protein, rat)
0 (Small Ubiquitin-Related Modifier Proteins)
139874-52-5 (NF-KappaB Inhibitor alpha)
EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
EC 3.5.1.- (Sirt1 protein, rat)
EC 3.5.1.- (Sirtuin 1)
EC 6.3.2.- (ubiquitin-conjugating enzyme UBC9)
G89JQ59I13 (Prasugrel Hydrochloride)
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Entry Date(s):
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Date Created: 20210626 Date Completed: 20210806 Latest Revision: 20240226
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Update Code:
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20240226
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DOI:
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10.1016/j.taap.2021.115635
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PMID:
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34174262
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The beneficial role of prasugrel, a P2Y12 receptor blocker, in several neurointerventional procedures has been reviewed clinically. Beyond its antiplatelet capacity, the potential neuroprotective mechanisms of prasugrel are poorly addressed experimentally. Relevant to the imbalance between neuro-inflammation and neuroprotective pathways in cerebral ischemia/reperfusion (I/R), our study evaluated the anti-ischemic potential of prasugrel treatment through tackling novel targets. Male Wistar rats were allocated into 2 sets; set 1 (I/R 60 min/3 days) to assess the neurological deficits/biochemical impact of prasugrel and set 2 (I/R 60 min/5 days) for evaluating short memory/morphological/immunoreactive changes. Each set comprised 4 groups designated as sham, sham + prasugrel, I/R, and I/R + prasugrel. Post-administration of prasugrel for 3 and 5 days reduced neurological deficit scores and improved the spontaneous activity/short term spatial memory using the Y-maze paradigm. On the molecular level, prasugrel turned off SUMO2/3-inhibitory kappa (Iκ)Bα, Ubc9 and nuclear factor kappa (NF-κ)B. Besides, it inhibited malondialdehyde (MDA) and inactivated astrocytes by downregulating the glial fibrillary acidic protein (GFAP) hippocampal immune-expression. Conversely, it activated its target molecule cAMP, protein kinase (PK)A, and cAMP response element-binding protein (CREB) to enhance the brain-derived nuclear factor (BDNF) hippocampal content. Additionally, cAMP/PKA axis increased the hippocampal content of deacetylator silent information regulator 1 (SIRT1) and the micro RNA (miR)-22 gene expression. The crosstalk between these paths partakes in preserving hippocampal cellularity. Accordingly, prasugrel, regardless inhibiting platelets activity, modulated other cellular components; viz., SUMO2/3-IκBα/Ubc9/NF-κB, cAMP/PKA related trajectories, CREB/BDNF and SIRT1/miR-22 signaling, besides inhibiting GFAP and MDA to signify its anti-ischemic potential.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Erratum in: Toxicol Appl Pharmacol. 2023 May 1;466:116476. (PMID: 36934858)
