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

Enas S Gad; Sara A Aldossary; Mona R El-Ansary; Mona M Abd El-Galil; Asmaa Hassan Abd-El-Hamid; Amira R El-Ansary; Noha F Hassan

doi:10.1016/j.ejphar.2024.177194

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

Eur J Pharmacol. 2024 Dec 10:987:177194. doi: 10.1016/j.ejphar.2024.177194. Online ahead of print.

Authors

Enas S Gad¹, Sara A Aldossary², Mona R El-Ansary³, Mona M Abd El-Galil⁴, Asmaa Hassan Abd-El-Hamid⁴, Amira R El-Ansary⁵, Noha F Hassan⁶

Affiliations

¹ 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.
² Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, AL Ahsa, Saudi Arabia.
³ Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
⁴ Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt.
⁵ Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Cairo, Egypt.
⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt. Electronic address: Noha.Fawzy@pharm.mti.edu.eg.

PMID: 39667427
DOI: 10.1016/j.ejphar.2024.177194

Abstract

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.

Keywords: AMPK/SIRT-1; Cilostazol; Hepatic encephalopathy; Oxidative stress; PINK -1/parkin; Thioacetamide.