Gastroprotective activity and mechanism of novel dichlorido-zinc(II)-4-(2-(5-methoxybenzylideneamino)ethyl)piperazin-1-iumphenolate complex on ethanol-induced gastric ulceration

doi:10.1016/j.cbi.2011.11.008

Chemico-Biological Interactions

Volume 195, Issue 2, 25 January 2012, Pages 144-153

https://doi.org/10.1016/j.cbi.2011.11.008 Get rights and content

Abstract

Zinc complexes were reported to have anti-ulcer activity and used as drug for the treatment of gastrointestinal disorders. A novel compound dichlorido-zinc(II)-4-(2-(5-methoxybenzylidene amino)ethyl)piperazin-1-iumphenolate (ZnHMS) was synthesized, characterized and evaluated for its gastroprotective activity against ethanol-induced ulcer in rats. Gross and microscopic lesions, histochemical staining of glycogen storage, biochemical and immunological parameters were taken into consideration. Oral administration of ZnHMS (30 and 60 mg/kg; 14 days) dose-dependently inhibited gastric lesions. It significantly increased the mucus content and total acidity compared to the control group (P < 0.01). Serum levels of aspartate (AST), alanine (ALT) transaminases, pro-inflammatory interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and anti-inflammatory interleukin-10 (IL-10) in the rats exposed to ethanol induced ulceration have been altered. ZnHMS considerably enhances (P < 0.05) the protection of gastric epithelia by modulating the acute alterations of AST, ALT, IL-6, IL-10, TNF-α and stomach glycogen. Interestingly, ZnHMS did interfere with the natural release of nitric oxide. In addition, acute toxicity study revealed no abnormal sign to the rats treated with ZnHMS (2000 mg/kg). These findings suggest that the gastroprotective activity of ZnHMS might contribute in adjusting the inflammatory cytokine-mediated oxidative damage to the gastric mucosa.

Graphical abstract

New zinc complex was synthesized and characterized. The resulting compound was evaluated for acute toxicity and gastro-protective activities against ethanol induce ulcerations via FTIR, NMR and UV–visible spectroscopy.

Highlights

► Novel Zn(II) complex was synthesized and characterized. ► The complex was screened for acute toxicity and gastroprotection. ► The level of cytokines were evaluated. ► The compound did not interfere with nitric oxide synthase. ► The compound is toxic free.

Introduction

Gastric mucosal erosion was reported to be associated with the imbalance between the aggressive factors (physical, chemical or psychological) in the lumen and protective mechanisms [1] in the duodenal mucosa, causing chronic inflammation that leads to a defect in the regulation of gastrin production [2]. Gastrointestinal problems have now become a global problem, and many studies were conducted towards fixing it [3]. The ability of some ulcer models to suppress the production of prostaglandins and thromboxanes, and cause irreversible inactivation of the cyclooxygenases (which is essential for the production of prostaglandins) has provided a means for intense investigations [4], [5], [6]. It was suggested that, cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) play important roles in the acute phase inflammation as well as in maintenance and regulation of the severity of gastric ulcers [7]. The ulceration bestowed by ethanol causes an intense infiltration in the submucosa, decrease mucus, depletes sulfhydryl groups and decrease blood flow, which resulted in serious damage to the gastric mucosa [8]. This ulcer model has provided a means of determining the mechanistic way by which many compounds protects gastric against ulcerations.

Zinc is an essential element which plays an imperative role in cell-mediated immune functions. It is employed as a cofactor for metalloenzymes, superoxide dismutase, collagenase, alcohol dehydrogenase, alkaline phosphate, children’s growth and in spermatogenesis [9], [10]. Zinc is required for the proper functioning of mucosal cells and can arrest the advancement of gastrointestinal disease by free radical scavenging and interruption of the inflammatory process as an antioxidant and anti-inflammatory agent. Zinc deficiency can cause poor wound healing, loss of taste and smell and elevation in ROS [11], [12]. Zinc complex was reported to have anti-ulcer activity and used as drug for the treatment of gastrointestinal injuries in Japan [13]. This study considers the therapeutic potentials of piperazine derivatives, and the role played by zinc in wound healing to synthesize a novel compound with combine protective activity [14], [15]. The study, therefore, reported for the first time the synthesis, characterization, acute toxicity and gastroprotective activity of Zinc(II) complex (ZnHMS) derived from the Schiff base (E)-4-methoxy-2-((2-(piperazin-1-yl)ethylimino)methyl)phenol.

Section snippets

Reagents

The primary amine 2-(piperazin-1-yl)ethanamine, 5-methoxysalicylaldehyde, Zn(II)chloride dihydrate and potassium hydroxide was purchased from Merck, Kuala Lumpur, Malaysia. ELISA kits for IL-6, IL-10 and TNF-α were purchased from Ray Biotech, USA. All other chemicals and reagents were of analytical grade.

Synthesis of dichlorido-zinc(II)-4-(2-(5-methoxybenzylideneamino)ethyl)piperazin-1-iumphenolate

A weighed amount of 2-(piperazin-1-yl)ethanamine (1.29 g, 10 mmol) dissolved in an absolute ethanol 25 mL was added drop wise to an ethanolic solution 25 mL of 5-methoxysalicylaldehyde (1.52 g, 10

Spectroscopy

C₁₄H₂₁N₃O₂: IR (KBr disc cm⁻¹, 4000–400 cm⁻¹): 3270 υ (O–Hs), 2941 υ (C–Hs), 1638 υ (C double bond N), 1488 υ (C–O), 618 υ (arC–H). ¹H NMR (400 MHz, DMSO): δ 2.1s (piperazinic N–H), δ 6.30–7.47 m (arH) δ 8.54s (iminic, HCN), δ 11.26s (phenolic O–H), methylene δ 2.37s (CH₂), UV–VIS (λ_max ε, mol⁻¹ L⁻¹cm⁻¹): 312 nm (2235), 268 nm (3046).

C₁₄H₂₁Cl₂N₃ZnO₂: yield, (0.2 g, 76%); anal calc. C, 42.07; H, 5.30; N, 10.51. Found: C, 39.48; H, 4.91; N, 9.54. IR: 3466 cm⁻¹ υ (N–H), 2969 cm⁻¹ υ (C–H), 1629 cm⁻¹ υ (C double bond N), 1535 cm⁻¹ υ

Discussion

The IR spectral analysis showed absorption at 1638 cm⁻¹ which can be ascribed to azomethine, confirming the formation of Schiff base and the absence of aldehydic group [22], [23], [24], [25]. This band shifted to 1629 cm⁻¹ in the spectra of the complex which indicates chelate formation [26], [27], [28]. This coordination was confirmed by the appearance of new bands at 592 and 416 cm⁻¹ affordable to metal-phenolate (M-O) and metal-nitrogen (M-N) bands, respectively [29], [30], [31], [32], [33], [34]

Conflict of interest statement

None declared.

Acknowledgements

The authors acknowledge the Grants PS358/2009C and ER009-2011A provided by University of Malaya for the conduct of this study.

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Gastroprotective activity and mechanism of novel dichlorido-zinc(II)-4-(2-(5-methoxybenzylideneamino)ethyl)piperazin-1-iumphenolate complex on ethanol-induced gastric ulceration

Abstract

Graphical abstract

Highlights

Introduction

Section snippets

Reagents

Synthesis of dichlorido-zinc(II)-4-(2-(5-methoxybenzylideneamino)ethyl)piperazin-1-iumphenolate

Spectroscopy

Discussion

Conflict of interest statement

Acknowledgements

J. Ethnopharmacol.

Chem. Biol. Interact.

Chem. Biol. Interact.

Life Sci.

Coord. Chem. Rev.

Int. J. Pharm.

J. Ethnopharmacol.

Int. J. Pharm.

Chem. Biol. Interact.

Inorg. Chem. Commun.

Spectrochim. Acta A.

J. Non-Cryst. Solids

Inorg. Chim. Acta.

J. Mol. Struct.

Polyhedron

Polyhedron

J. Ethnopharmacol.

J. Ethnopharmacol.

Fitoterapia

Life. Sci.

Phytochemistry

The gastrins: their production and biological activities

Annu. Rev. Physiol.

Pharmacologic management of common gastrointestinal health problems in women

J. Nurse-Midwifery

Diseases of the stomach

Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs

Am. J. Vet. Res.

Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH in patients with gastroesophageal reflux disease (GERD)

Am. J. Gastroenterol.