Peroxisome Proliferator Activator Receptor (PPAR)-γLigand, but Not PPAR-α, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver

Abstract

Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.

Chemoprotective effect of vitamin E in cyclophosphamide-induced hepatotoxicity in rats

“…Five regions of each section were evaluated; histopathological damage was graded from 0 to 3, where 0 was none, 1 was mild, 2 was moderate, and 3 was severe [17]. The sections were also assessed in terms of hydropic degeneration, necrosis, pleomorphism, mitosis, fatty changes, and periportal inflammation.…”

<smlcap>L</smlcap>-Carnitine Ameliorates Cancer Cachexia in Mice Partly via the Carnitine Palmitoyltransferase-Associated PPAR-&#947; Signaling Pathway

“…PGC-1α is a nuclear transcription factor and is well known to interact with PPAR-γ, permitting the interaction of PPAR-γ with multiple transcription factors. Thereby, PPAR-γ plays essential roles in fatty acid metabolism and in the anti-inflammatory response [17]. However, the relationship between L -carnitine and PPAR-γ in cancer cachexia, and especially the role of the PPAR-γ signaling pathway, in the ameliorative effects of L -carnitine on cancer cachexia is incompletely known to date.…”

Impacto da suplementação de vitamina C sobre níveis de peroxidação lipídica e glutationa reduzida em tecido hepático de camundongos com imunossupressão induzida por ciclofosfamida

“…El-Sheikh& Rifaai 10 , em estudo realizado em ratos albinos machos sobre a hepatotoxicidade induzida pela ciclofosfamida (150mg/ kgintraperitoneal) e seus mecanismos fisiológicos, verificaram aumento das Thiobarbituric Acid Reactive Substances (TBARS, Substâncias Reativas ao Ácido Tiobarbitúrico) com diminuição da glutationa reduzida e aumento do nível de citocinas pró-inflamatórias após quatro semanas, indicando, de maneira geral, um estado pró-oxidante após o tratamento com ciclofosfamida. Como o tecido hepático é responsável por metabolizar a ciclofosfamida e também é alvo da sua toxicidade, a busca por substâncias que minimizem esse efeito colateral torna-se importante 2 .…”

“…Esse modelo de imunossupressão também induziu o dano oxidativo verificado pelo aumento dos níveis de TBARS em, aproximadamente, 40%da amostra. El-Sheikh & Rifaai 10 , em estudo realizado com ratos albinos, machos e adultos, utilizaram a ciclofosfamida em dose única de 150 mg/kg de peso, cinco dias antes do término do experimento. O grupo que recebeu somente a ciclofosfamida apresentou níveis significativamente superiores de lipoperoxidação em tecido hepático (aproximadamente 230%).…”