Luteolin Alleviates Methamphetamine-Induced Hepatotoxicity by Suppressing the p53 Pathway-Mediated Apoptosis, Autophagy, and Inflammation in Rats

Abstract

Misuse of the psychostimulant methamphetamine (METH) could induce serious hepatotoxicity. Our previous study revealed the effects of luteolin on alleviating METH-induced hepatotoxicity, however, the detailed mechanisms have not been elucidated. In this study, rats were orally pretreated with 100 mg/kg luteolin or sodium dodecyl sulfate water, and then METH (15 mg/kg, intraperitoneal [i.p.]) or saline was administered. Histopathological and biochemical analyses were used to determine the alleviative effects of luteolin. Based on the RNA-sequencing data, METH induced 1859 differentially expressed genes (DEGs) in comparison with the control group, which were enriched into 11 signaling pathways. Among these DEGs, 497 DEGs could be regulated through luteolin treatment and enriched into 16 pathways. The p53 signaling pathway was enriched in both METH administered and luteolin pretreated rats. Meanwhile, luteolin significantly suppressed METH-induced elevation of p53, caspase9, caspase3, cleaved caspase3, the ratio of Bax/Beclin-2, as well as autophagy-related Beclin-1, Atg5, and LC3-II. Luteolin also relieved METH-induced hepatotoxicity by decreasing inflammation factors, including TNF-α, IL-1β, and IL-18. Moreover, the levels of PI3K, p-Akt, and the normalized ratio of p-Akt/Akt declined after METH administration, whereas luteolin pretreatment failed to reverse these effects. Our results suggest that luteolin alleviates METH-induced hepatic apoptosis, autophagy, and inflammation through repressing the p53 pathway. It further illustrates the protective mechanisms of luteolin on METH-induced hepatotoxicity and provides a research basis for clinical treatment.

Antibiotics Attenuate Methamphetamine-Induced Hepatotoxicity by Regulating Oxidative Stress and TLR4/MyD88/Traf6 Axis

“…It has been confirmed that METH induces hepatotoxicity in humans, rats, and cells ( Dias Da Silva et al, 2013 ; Zhao et al, 2020 ; Zhang et al, 2021 ). Consistent with findings, this research demonstrated that the escalating dose/multiple binge METH model could also lead to hepatotoxicity in mice, indicated by histopathological examination and ALT and AST activities.…”

“…However, preconditioning of chlorogenic and caftaric acids could prevent liver toxicity and oxidative stress induced by METH injections ( Koriem and Soliman, 2014 ). Similarly, our team demonstrated that METH induced hepatotoxicity by inducing cell cycle arrest and activating apoptosis ( Wang et al, 2017 ) and luteolin exerted protective effects against METH hepatotoxicity by suppressing apoptosis, autophagy, and inflammation in rats ( Qu et al, 2020 ; Zhang et al, 2021 ).…”

Methamphetamine Disturbs Gut Homeostasis and Reshapes Serum Metabolome, Inducing Neurotoxicity and Abnormal Behaviors in Mice

“…A western blot assay was performed to investigate neurotoxicity and colonic toxicity associated with MA. The RIPA lysis method was used to isolate total proteins of striatum and colonic mucosa as previously described ( Zhang et al, 2021 ). The primary antibodies used were: anti-monoamine oxidase A (MAOA; 1:1,000, 4A Biotech, Cat# 4ab091383), anti-dopamine transporter (DAT; 1:1,000, Bioss, Cat# bs-1714R), anti-tyrosine hydroxylase (TH; 1:1,000, Proteintech, Cat# 25859-1-AP), anti-caspase 3 (1:1,000, ABclonal, Cat# A2156), anti-cleaved caspase 3 (1:1,000, CST, Cat# 9661), anti-p53 (1:1,000; 4A Biotech, Cat# 4ab087781), anti-Bax (1:1,000, CST, Cat# 2772), anti-Beclin 1 (1:1,000, CST, Cat# 3738), anti-LC3-II (1:1,000; Proteintech, Cat# 18725-1-AP), anti-autophagy-related 5 (Atg5; 1:1,000; HuaAn Biotechnology, Cat# ET1611-38), anti-Claudin-5 (1:1,000, Abclonal, Cat# A10207), anti-Occludin (1:1,000, Abclonal, Cat# A2601), anti-TLR4 (1:1,000, SANTA, Cat# sc-293072), anti-MyD88 (1:1,000, CST, Cat# 4283S), anti-NF-κB (1:1,000, Proteintech, Cat# 10745-1-AP), anti-NLRP3 (1:1,000, Abcam, Cat# ab263899), anti-IL-6 (1:1,000, 4A Biotech, Cat# 4ab044340), anti-IL-18 (1:1,000, Proteintech, Cat# 60070-1-lg), anti-TNF-α (1:1,000, 4A Biotech, Cat# 17590-1-AP), anti-caspase 1 (1:1,000, Proteintech, Cat# 22915-1-AP), and anti-β-actin (1:1,000; 4A Biotech, Cat# 4ab071291).…”

Silencing the Tlr4 Gene Alleviates Methamphetamine-Induced Hepatotoxicity by Inhibiting Lipopolysaccharide-Mediated Inflammation in Mice

“…Moreover, METH treatment impairs liver metabolism by disrupting the CYP1A2 metabolic pathway [ 7 ]. It also induces hepatotoxicity by arresting the cell cycle, inhibiting cell division, and activating apoptosis and autophagy [ 5 , 8 ]. The promotion of apoptosis restricts inflammation [ 9 ].…”