Protective effect of leukotriene receptor antagonist, montelukast, against cyclophosphamide-induced placental toxicity via modulation of NLRP3/IL-1ß signaling pathway in rats.

BACKGROUNDS & AIM: Placental insufficiency is a serious complication that affects pregnancy and fetal growth. Cyclophosphamide (CYC) is considered one of the chemotherapeutic agents. Unfortunately, CYC not only affects tumor cells but also affects healthy cells causing multiple injuries including the placenta. The present study aimed to evaluate the effect of cysteinyl leukotriene receptor antagonist; montelukast (MK), on CYC-induced placental injury in rats. MATERIALS AND METHODS: Forty-eight female Wister rats were randomly divided into 8 experimental groups. Group 1: control pregnant group; Group 2: MK 5 mg-treated pregnant rats; Group 3: MK 10 mg-treated pregnant rats; Group 4: MK 20 mg-treated pregnant rats; Group 5: pregnant rats received CYC (20 mg/kg, i.p); Group 6: pregnant rats received MK 5 mg and CYC; Group 7: pregnant rats received MK 10 mg and CYC; Group 8: pregnant rats received MK 20 mg and CYC. Placental malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), placental growth factor (PlGF), and Nod-like receptor p3 (NLRP3) inflammasome were measured. Histological changes, interleukin-1ß (IL-1ß), and cleaved caspase-3 immuno-expressions were also evaluated. RESULTS: CYC showed a significant decrease in placental GSH, TAC, and PlGF with a significant increase in placental MDA, NLRP3, and immuno-expression of IL-1ß and caspase-3. MK showed significant improvement in all oxidative stress (MDA, GSH and TAC), inflammatory (NLRP3 and IL-1ß), and apoptotic (caspase-3) parameters. CONCLUSION: According to the findings, MK was proved to have a possible protective role in CYC-induced placental injury via modulation of NLRP3/IL-1ß signaling pathway with anti-oxidant, anti-inflammatory, and anti-apoptotic effects.

Protective effect of rivastigmine against lung injury in acute pancreatitis model in rats via Hsp 70/IL6/ NF-κB signaling cascade.

Acute lung injury (ALI) that develops as a result of AP can progress to acute respiratory distress syndrome. Some hypotheses are proposed to explain the pathophysiology of AP and its related pulmonary hazards. This experiment aimed to evaluate the mitigating action of rivastigmine (Riva) in lung injury that occurs on the top of acute pancreatitis (AP) induced in rats. Thirty-two male Wister rats were randomized to one of four groups: control, Riva-treated, acute pancreatitis (AP), and acute pancreatitis treated by Riva. Serum amylase and lipase levels were assessed. Pulmonary oxidative stress and inflammatory indicators were estimated. A pancreatic and pulmonary histopathological examination, as well as an immunohistochemical study of HSP70, was carried out. Riva significantly attenuated the L-arginine-related lung injury that was characterized by increased pulmonary inflammatory biomarkers (interleukin-6 [IL-6]), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), increased pulmonary oxidative markers (total nitrite/nitrate [NOx]), MDA, decreased total antioxidant capacity (TAC), and reduced glutathione level (GSH)) with increased caspase-3 expression. Therefore, Riva retains potent ameliorative effects against lung injury that occur on the top of AP by relieving oxidative stress, inflammation, and apoptosis via HSP70/IL6/NF-κB signaling.

Atorvastatin protects against cyclophosphamide-induced thyroid injury in rats via modulation of JNK/ ERK/ p38 MAPK signaling pathway.

BACKGROUND: Cancer chemotherapy is associated with various tissue toxicities that limit its use. Cyclophosphamide (CYC) is one of the most commonly used antineoplastic and immunosuppressive agent. Thyroid dysfunction is a critical side effect of anticancer drugs. Atorvastatin (ATV) is antihyperlipedemic drug with different tissue protective activities. The aim of this study was to determine the potential protective effect of ATV against CYC-induced thyroid injury in rats. METHODS: ATV was administered in the presence and absence of CYC. Thirty-two adult Wistar rats were randomly divided into four groups: control group, ATV group (20 mg/kg/day, p.o. for 14 day), CYC group (200 mg/kg, i.p. on day 9) and ATV/CYC group. Triiodothyronine (T3), thyroxine (T4), reduced glutathione (GSH), malondialdehyde (MDA), total nitrite/nitrate (NOx), p38 mitogen-activated protein kinase (P38MAPK), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) were measured. In addition, thyroid histopathology and caspase 3 immunohistochemistry were performed. RESULTS: CYC significantly increased thyroid MDA, NOx, P38MAPK, ERK and JNK with decrease in GSH, T3 and T4 levels. Histopathological features of thyroid lesions and increased caspase 3 immune expression were appeared. ATV significantly normalized distributed oxidative, inflammatory and apoptotic indicators, resulting in an improvement of histopathological features and reduction of caspase 3 immunoexpression. CONCLUSION: These findings suggest that ATV protects against CYC-induced thyroid injury by regulating the JNK/ERK/p38-MAPK signaling pathway.

Rupatadine ameliorated ulcerative colitis in rats via modulation of platelet-activatiweng factor/interleukin-6/vascular endothelial growth factor signalling pathway.

OBJECTIVES: This study aimed to analyse the potential effect of rupatadine (RUP) on ulcerative colitis (UC) induced by acetic acid (AA). METHODS: Forty male adult Wistar rats were divided into five groups: Control group: received vehicles for 14 days; AA model group: received AA at the 13th day; Sulfasalazine (SLZ) + AA group: received SLZ (250 mg/kg) for 14 days and AA at the 13th day; RUP-3 + AA group: received RUP (3 mg/kg/day) for 14 days and AA at the 13th day; and RUP-6 + AA group: received RUP (6 mg/kg/day) for 14 days and AA at the 13th day. Evidence of UC was assessed both macroscopically and microscopically. Oxidative stress markers (total antioxidant capacity and malondialdehyde), antioxidant enzyme (superoxide dismutase), histamine and platelet-activating factor (PAF) were determined. Immunohistochemical estimations of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were done. KEY FINDINGS: The AA group showed evidence of UC that was associated with a significant increase in oxidative stress, histamine and PAF levels with significant elevation in colonic VEGF and IL-6 immuno-expressions. RUP, in a dose-dependent manner, significantly ameliorated UC. CONCLUSION: RUP protects against UC by reducing oxidative stress and by regulating the PAF/IL-6/VEGF pathway.

Protective effect of mirtazapine against acetic acid-induced ulcerative colitis in rats: Role of NLRP3 inflammasome pathway.

AIMS: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation on the innermost lining of the colon and rectum. Mirtazapine (MRT) is a well-known antidepressant that was proven to have anti-inflammatory activity; however, to date, its role has not been investigated in UC. The current study aimed to investigate the role and mechanism of MRT in UC. MAIN METHOD: Acetic acid (AA) was used for UC induction, and sulfasalazine (SLZ) was used as a positive control. Rats were divided into five equal groups; as follows; normal control, AA, SLZ (received SLZ in a dose of 250 mg/kg for 14 days), MRT10 (received MRT in a dose of 10 mg/kg/day for 14 days), and MRT30 (received MRT in a dose of 30 mg/kg/day for 14 days) groups. Macroscopic and microscopic examinations together with oxidative stress parameters evaluation were done. NOD-like receptors-3 (NLRP3), caspase-1, TNF-α, and nuclear factor kappa B (NF-κB) expression together with interleukin (IL)-1ß and IL-18 levels were examined. KEY FINDING: MRT, in a dose-dependent manner, prevented the macroscopic and microscopic colonic damage and corrected the oxidative stress induced by AA. Moreover, MRT decreased the colonic tissue NLRP3 inflammasome, caspase-1, NF-κB, TNF-α expressions, IL-1ß, and IL-18 levels that were elevated in colonic tissue by the AA. SIGNIFICANCE: MRT has a dose-dependent protective effect against UC that was mediated mainly by its anti-inflammatory activity with modulation of NLRP3/caspase-1 inflammatory pathway.