Cilostazol Counteracts Mitochondrial Dysfunction in Hepatic Encephalopathy Rat Model: Insights into the role of cAMP/AMPK/SIRT1/ PINK-1/Parkin hub and p-CREB /BDNF/ TrkB neuroprotective trajectory.

Autor: Gad ES; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, AL Ahsa, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia, Egypt., Aldossary SA; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, AL Ahsa, Saudi Arabia., El-Ansary MR; Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt., Abd El-Galil MM; Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt., Abd-El-Hamid AH; Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt., El-Ansary AR; Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Cairo, Egypt., Hassan NF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt. Electronic address: Noha.Fawzy@pharm.mti.edu.eg.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Dec 10, pp. 177194. Date of Electronic Publication: 2024 Dec 10.
DOI: 10.1016/j.ejphar.2024.177194
Abstrakt: A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Clio) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/ Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P<0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P<0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P<0.0001), restoration nuclear factor E2-related factor 2 ( Nrf2 ) (P<0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P<0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P<0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P=0.0002)/ tropomyosin-related kinase B (TrkB) (P<0.0001)/ cAMP response element-binding (CREB) (P<0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.
Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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