Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways

doi:10.1016/j.bioorg.2020.104444

Bioorganic Chemistry

Volume 105, December 2020, 104444

https://doi.org/10.1016/j.bioorg.2020.104444 Get rights and content

Highlights

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Flavonoids from Barnebydendron riedelii leaf extract showed beneficial effects against hepatic encephalopathy.
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Flavonoid containg butanol fraction improved motor impairment, cognitive deficits and serum hepatotoxic biomarkers.
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Modulatory effects of flavonoidal content on NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.
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Flavonoidal content ameliorated liver and brain histopathological changes as well as apoptotic marker; Caspase-3.

Abstract

Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP⁺) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.

Graphical abstract

Introduction

Hepatic encephalopathy (HE) is one of the most striking challenges resulting from liver diseases. It is defined as a neuropsychiatric syndrome that results as a consequence of liver ineffectuality and includes a broad spectrum of neurological disorders extending from subclinical changes to coma [1]. A combination of distinct pathophysiological mechanisms is contributed to HE incidence such as neurotoxins, inflammation, brain energy metabolism impairment, oxidative stress (OS), impaired blood brain barrier (BBB) permeability and accumulation of bile acids [2], [3], [4].

Ammonia is the most characterized neurotoxin related to HE pathogenesis and contributes to astrocyte swelling. Under normal conditions, nitrogen source compounds are metabolized to ammonia by the action of gut microbiota then detoxified in the liver via entering urea cycle with a subsequent renal excretion [5]. In the setting of liver diseases, due to the disability of liver to detoxify ammonia, it accumulates in the blood leading to hyperammonemia. Ammonia can cross the BBB and target astrocytes where it is metabolized to glutamine resulting in astrocyte swelling with a subsequent brain edema [5]. Moreover, this swelling can participate in overproduction of reactive oxygen species (ROS) resulting in neuronal OS, which initiates an array of antioxidant gene expression [6]. The neuromuscular and cognitive deficits noticed during HE are eventually due to the neurotransmission alterations [7]. In addition to the ammonia hypothesis, inflammation and cytokine release due to liver injury are considered to be the major hallmarks in HE development. Acute liver injury results in the upregulation of inflammatory cytokines [8]. In the setting of liver injuries, ROS and free radical generation can induce the expression of pro-inflammatory genes that irritate an intracellular signaling cascade leading to more ROS production which results in cellular dysfunction [9].

The importance of medicinal plants came from a significant achievement therapy of hepatic and neurodegenerative diseases. Traditional plant drugs have been established to be effective as hepato-neuroprotective agents by preventing progression of liver and brain injuries due to the presence of many active compounds especially flavonoids [10] which are convenient to display an essential fundamental biological role as hepatoprotective and neuroprotective agents due to their strong antioxidant and anti-inflammatory characteristics [11].

The genus of Barnebydendron (Family Fabaceae), first defined as Phyllocarpus Riedel ex Tul. (1843), was regarded to be a monospecific genus limited to the Atlantic forest in the vicinity of Rio de Janeiro, Brazil [12]. Barnebydendron riedelii, a flowering member recognized as Monkey-flower tree, is the only species in genus Barnebydendron. It originated in the tropical dry forests of Central America, but it has been widely grown in other tropical areas worldwide as an ornamental tree [12]. To the best of the authors’ knowledge, no phytochemical studies have been carried out on this species, so it was important to study the chemical constituents of this plant with special intend in the flavonoidal compounds.

In the course of searching for novel hepato-neuroprotective agents from medicinal plants, the possible protective effect of flavonoids-rich butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of B. riedelii against behavioral, biochemical, molecular and pathological alterations in thioacetamide-induced HE in rats was investigated. Furthermore, lactulose (LAC); a standard hypoammonemic drug, has been used as a reference drug.

Section snippets

General experimental procedure

UV spectra were obtained using a JASCO V-630 spectrophotometer. NMR was recorded on a Varian Gemini (400 MHz for ¹H and 100 MHz for ¹³C). Chemical shifts were given on δ-scale with tetramethylsilane as an internal standard. HPLC analysis was performed using an Agilent 1260 series. The separation was carried out using C18 column (4.6 mm × 250 mm i.d., 5 μm). Mobile phase A was acetonitrile and mobile phase B was water with 1% acetic acid. The gradient elution used was timed as follows: 0–25 min

Phytochemical investigation

Kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucocpyranoside, nicotiflorin (1) (Fig. 2): Amorphous yellow powder, UV λ_max nm (MeOH): 266.5, 349; + NaOMe: 275, 399.5; + AlCl₃: 268.5, 306 sh, 351; + AlCl₃/HCl: 274.5, 303.5 sh, 346, 394 sh; + NaOAc: 274, 303 sh, 368; + NaOAc/H₃BO₃: 273.5, 302 sh, 370. The ¹H NMR (400 MHz, CD₃OD) δ: 8.09 (2H, d, J = 8.8 Hz, H-2′, H-6′), 6.88 (2H, d, J = 9.2 Hz, H-3′, H-5′), 6.39 (1H, d, J = 2.0 Hz, H-8), 6.20 (1H, d, J = 2.0 Hz, H-6), 5.11 (1H, d, J = 7.6 Hz,

Discussion

The dried 70% aqueous methanolic leaf extract of B. riedelii was dissolved in distilled water and the aqueous solution was successively extracted with methylene chloride, ethyl acetate then water-saturated n-butanol. The material from the n-butanol extract was chromatographed using polyamide column, repeated preparative TLC and Sephadex LH- 20 column chromatography to afford the flavonoid glycosides 1–3. The isolates were identified using chemical and spectral means as well as by comparison

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This research was supported by National Research Centre, Giza, Egypt. The authors appreciate the assistance of Dr. Adel Girgis (Prof. of Organic Chemistry, National Research Centre) and Dr. Azza Hassan (Prof. of Pathology, Faculty of Veterinary Medicine, Cairo University).

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Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

General experimental procedure

Phytochemical investigation

Discussion

Declaration of Competing Interest

Acknowledgements

J. Hepatol.

Clin. Liver Dis.

J. Hepatol.

Neurochem. Int.

J. Clin. Exp. Hepatol.

Oxid. Med. Cell. Longevity

Asian J. Pharm. Sci.

Anal. Biochem.

Behav. Brain Res.

Clin. Chim. Acta; Int. J. Clin. Chem.

Anal. Biochem.

Anal. Biochem.

Methods

Biochim. Biophys. Acta (BBA) – Mol. Cell Res.

Biochim. Biophys. Acta (BBA) - General Subjects

J. Photochem. Photobiol., B

Chem. Biol. Interact.

Brain Res.

Neurochem. Int.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Hepatic encephalopathy in chronic liver disease, Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver

Hepatology

Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy

Metab. Brain Dis.

Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy

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Hepato-, neuroprotective effects and QSAR studies on flavoalkaloids and flavonoids from Astragalus monspessulanus

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Comparison of probiotics and lactulose in the treatment of minimal hepatic encephalopathy in rats

WJG

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Hepatology