By:Lebda, MA (Lebda, Mohamed A.)^[ 1 ] ; Sadek, KM (Sadek, Kadry M.)^[ 2 ] ; Abouzed, TK (Abouzed, Tarek K.)^[ 3 ] ; Tohamy, HG (Tohamy, Hossam G.)^[ 4 ] ; El-Sayed, YS (El-Sayed, Yasser S.)^[ 5 ]

Aims: The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. 

Main methods: Rats were allocated into four groups: placebo; thioacetamide (TAA) (200 mg/kg bwt, i.p twice weekly for two months); melatonin (5 mg/kg bwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-alpha, and interleukin-1 beta), fibrogenic-related genes (transforming growth factor-1 beta, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. 

Key findings: In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C = O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. 

Significance: Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions.

Author Keywords:Liver fibrosis; Melatonin; Oxidative stress; Cytokines; DNA damage; Growth factors; Gene expression

KeyWords Plus:INDUCED LIVER FIBROSIS; BILE-DUCT LIGATION; CARBON-TETRACHLORIDE; OXIDATIVE STRESS; STELLATE CELLS; RAT-LIVER; MECHANISMS; ENZYMES; HEPATOTOXICITY; HEPATOCYTES

Reprint Address: El-Sayed, YS (reprint author)

Damanhur Univ, Fac Vet Med, Dept Forens Med & Toxicol, Damanhour 22511, Egypt.

Addresses:

	[ 1 ] Alexandria Univ, Fac Vet Med, Dept Biochem, Alexandria, Egypt
	[ 2 ] Damanhur Univ, Fac Vet Med, Dept Biochem, Damanhour, Egypt
	[ 3 ] Kafr Elsheikh Univ, Fac Vet Med, Dept Biochem, Kafr Al Sheikh, Egypt
	[ 4 ] Alexandria Univ, Fac Vet Med, Dept Pathol, Alexandria, Egypt
	[ 5 ] Damanhur Univ, Fac Vet Med, Dept Forens Med & Toxicol, Damanhour 22511, Egypt

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Research Areas:Research & Experimental Medicine; Pharmacology & Pharmacy

Web of Science Categories:Medicine, Research & Experimental; Pharmacology & Pharmacy