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
European Journal of Pharmacology, ISSN: 0014-2999, Vol: 987, Page: 177194
2025
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Article Description
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 (Cilo) 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.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0014299924008847; http://dx.doi.org/10.1016/j.ejphar.2024.177194; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85211970245&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/39667427; https://linkinghub.elsevier.com/retrieve/pii/S0014299924008847; https://dx.doi.org/10.1016/j.ejphar.2024.177194
Elsevier BV
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