Nada Sallam

RATIONALE AND OBJECTIVE: Estradiol decline has been associated with depression and anxiety in post-menopausal women. Agomelatine (Ago) is an agonist of the melatonergic MT1/MT2 receptors and an antagonist of the serotonergic 5-HT2c receptors. The present study aimed to evaluate the effects of combining Ago with 17β-estradiol (E2) on ovariectomy (OVX)-induced depressive- and anxiety-like behaviors in young adult female rats.

METHODS: OVX rats were treated with Ago (40 mg/kg/day, p.o.) for 10 days starting 1 week after surgery alone or combined with two doses of E2 (40 μg/kg/day, s.c.) given before behavioral testing.

RESULTS: Co-administration of E2 enhanced the anti-depressant and anxiolytics effects of Ago as evidenced by decreased immobility time in the forced swimming test, as well as increased time spent in the open arms and number of entries to open arms in the elevated plus-maze. In parallel, Ago increased hippocampal norepinephrine, dopamine, melatonin, and brain-derived neurotrophic factor (BDNF). Meanwhile, Ago-treated rats exhibited reduced hippocampal nuclear factor kappa beta (NF-kB) P65 expression and pro-inflammatory cytokine level. Ago upregulated estrogen receptor (ER α and β) mRNA expression in the hippocampus of OVX rats and elevated serum estradiol levels. Co-administration of E2 with Ago synergistically decreased NF-kB P65 expression and pro-inflammatory cytokines, and increased BDNF levels.

CONCLUSION: E2 augmented the neuroprotective effect of Ago in OVX rats via its anti-inflammatory and neurotrophic effects. The combined treatment of E2 and Ago should be further investigated as a treatment of choice for depression, anxiety, and sleep disturbances associated with menopause.

Deregulated activity of protein kinase B/mammalian target of rapamycin complex-1 (Akt/mTORC1) incites crucial pathological characteristics of diabetic nephropathy. The acyclic monoterpene geraniol has been recently reported to possess antidiabetic effects; however, its potential renoprotective effect in diabetes has not yet been elucidated. This study aimed to assess the possible modulatory effect of geraniol on the Akt/mTORC1 pathway in diabetes-induced nephropathy in rats compared to the standard antidiabetic drug gliclazide. Geraniol and gliclazide was administered daily to diabetic rats for 6 weeks starting on the 3rd-day post diabetes induction by streptozotocin (STZ). Geraniol amended the deteriorated renal function (serum creatinine; blood urea nitrogen). It exerted a remarkable antihyperglycemic effect that is comparable to that of gliclazide and suppressed the fibrotic marker, transforming growth factor-β. Geraniol restored redox balance and inhibited lipid peroxidation by reducing nicotine amide adenine dinucleotide phosphate oxidase and enhancing the antioxidant enzyme, superoxide dismutase. These beneficial effects were associated with a robust downregulation of miRNA-21 and consequently, reversion of tumor suppressor protein phosphatase and tension homolog (PTEN)/Akt/mTORC1 cue and its downstream proteins required for mesangial cell proliferation and matrix protein synthesis. The current study indicates that geraniol interfered with miRNA-21/ PTEN/AKT/mTORC1 pathway signaling that contributes largely to the progression of mesangial expansion and extracellular matrix deposition in diabetic nephropathy.

The variable nature of vascular dysfunction in diabetes is not well understood. We explored the functional adaptation of different arteries in mice in relation to increased severity and duration of diabetes. We compared endothelium-dependent and -independent vasodilation in the aortae, as well as the carotid and femoral arteries, of mice at three ages in parallel with increased body weight, oxidative stress, and deterioration of glycemic control. Vascular responses to in vitro generation of reactive oxygen species (ROS) and expression of superoxide dismutase (SOD) isoforms were assessed. There was a progressive impairment of endothelium-dependent and -independent vasorelaxation in the aortae of mice. The carotid artery was resistant to the effects of and in vitro induced oxidative stress, and it maintained unaltered vasodilatory responses, likely because the carotid artery relaxed in response to ROS. The femoral artery was more reliant on dilation mediated by endothelium-dependent hyperpolarizing factor(s), which was reduced in mice at the earliest age examined and did not deteriorate with age. Substantial heterogeneity exists between the three arteries in signaling pathways and protein expression of SODs under physiological and diabetic conditions. A better understanding of vascular heterogeneity will help develop novel therapeutic approaches for targeted vascular treatments, including blood vessel replacement.

Hepatotoxicity and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in 2 different doses (35 and 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison with N-acetylcysteine (250 mg/kg, i.p.). Inflammatory, oxidative stress, and apoptotic biomarkers were investigated to show the influence of ambroxol on hepatotoxicity and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (aspartate aminotransferase and alanine aminotransferase) and kidney function tests (blood urea nitrogen and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-α, interleukin-1β, and nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2. Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c-Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinase (p-ERK) were attenuated by ambroxol associated with a decrease in the expression of caspase-3; these results were consistent with histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage, and this was confirmed by MTT assay.

Despite the availability of effective antiulcer medications, their suboptimal safety profile ignites the search for alternative/complementary treatments. Drug repositioning is an attractive, efficient, and low-risk strategy. Cilostazol, a clinically used phosphodiesterase 3 inhibitor, has pronounced anti-inflammatory and vasodilatory effects suggesting antiulcer activity. Using ethanol-induced and pyloric ligation-induced gastric ulcer models, we investigated the gastroprotective effect of cilostazol (5 or 10 mg/kg, p.o.) in comparison with the standard antiulcer ranitidine (50 mg/kg, p.o.) in rats. Gastric mucosa was examined macroscopically, histologically, and biochemically for ulcer severity, markers of oxidative stress, proinflammatory cytokines, apoptotic, and cytoprotective mediators. Gastric acidic output, peptic activity, and mucin content were measured in gastric fluids. Pretreatment with cilostazol reduced ulcer number and severity, ameliorated redox status (reduced glutathione and malonaldehyde content), and decreased levels of IL-1β, IL-6, and TNF-훼 in gastric mucosa, in parallel with increases in mucosal defensive factors nitric oxide (NO), prostaglandin E (PGE), and heat-shock protein 70 (HSP70) promoting mucus secretion, tissue perfusion, and regeneration. Histological examination confirmed the beneficial effects of cilostazol in terms of reducing focal necrosis and infiltration of inflammatory cells, as well as increasing mucopolysaccharide content. These beneficial effects are likely secondary to an increase in cAMP and decrease in apoptosis regulator Bcl-2-associated X protein (BAX). Cilostazol, in a dose-dependent effect, exhibited vasodilatory, anti-inflammatory, and antiapoptotic actions in the gastric mucosa resulting in significant antiulcer activity comparable with the standard drug, ranitidine, but devoid of antisecretory activity. Therefore, its use should be dose and ulcer-inducer dependent.

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