Sawsan Aboul-Fotouh

Lipopolysaccharide Repeated Challenge Followed by Chronic Mild Stress Protocol Introduces a Combined Model of Depression in Rats: Reversibility by Imipramine and Pentoxifylline

OBJECTIVES The present study examined the effect of combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together. This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of the tricyclic antidepressant imipramine and the anti-TNF-α pentoxyphylline were investigated. METHODS Wistar rats were exposed to either repeated LPS (50μg/kg i.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks of CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes. RESULTS Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression showed significant increase in the LPS/CMS model compared to those in saline, LPS or CMS groups. The immunohistochemical findings scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-α gene expression changes induced by the LPS/CMS protocol. CONCLUSION This study gave a clue to the neurobiological processes underlying, at least, the subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.

Effects of pentoxifylline, 7-nitroindazole, and imipramine on tumor necrosis factor-α and indoleamine 2,3-dioxygenase enzyme activity in the hippocampus and frontal cortex of chronic mild-stress-exposed rats

Objectives: This study aimed to investigate the role of tumor necrosis factor (TNF)-α and the neuronal nitric oxide synthase enzyme in dysregulation of indoleamine 2,3-dioxygenase (IDO) enzyme, and hence serotonin availability in chronic mild stress (CMS), an animal model of depression. Methods: Rats were divided into five groups: two control and CMS-exposed for 6 weeks, and another three groups exposed to CMS and administered pentoxifylline 50 mg/kg/day intraperitoneally, 7-nitroindazole 40 mg/kg/day subcutaneously, or imipramine 20 mg/kg/day intraperitoneally for the previous 3 CMS weeks. Rats were assessed for neurochemical and immunohistochemical abnormalities. Results: Pentoxifylline-, 7-nitroindazole-, and imipramine-treated rats showed amelioration of CMS-induced behavioral deficits that was accompanied by significant reduction in kynurenine/serotonin molar ratio and nitrates/nitrites in frontal cortex and hippocampus. In the pentoxifylline and 7-nitroindazole groups, serum TNF-α was reduced relative to the CMS group (18.54 ± 0.85 and 19.16 ± 1.54 vs 26.20 ± 1.83 pg/mL, respectively; P < 0.05). Exposure to CMS increased TNF-α and IDO immunohistochemical staining scores in both hippocampus and midbrain raphe nuclei. 7-Nitroindazole and pentoxifylline significantly (P < 0.05) reduced TNF-α immunostaining in hippocampus and raphe nuclei, with significant (P < 0.01) reduction of IDO immunostaining in raphe nuclei. Likewise, imipramine reduced TNF-α immunostaining (P < 0.05) in hippocampus. Conclusion: Neuronal nitric oxide synthase and TNF-α may play a concerted role in modulating IDO enzyme activity in CMS-exposed rats and provide additional evidence for possible alternative approaches to switch the neurobiological processes in depression.

The effects of antidepressants "fluoxetine and imipramine" on vascular abnormalities and Toll like receptor-4 expression in diabetic and non-diabetic rats exposed to chronic stress.

Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. Method: We investigated the effect of chronic administration of fluoxetine “FLU” and imipramine “IMIP” on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. Conclusion: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.

Atypical antipsychotics such as risperidone, but not paliperidone, worsen vascular endothelial function via upregulation of adhesion molecules VCAM-1, ICAM-1, and E-selectin in diabetic rats

Schizophrenia doubles the odds of diabetes, and atypical antipsychotics (AAPs) also increase risk of diabetes. Indeed, little is known about the effects of AAPs on vascular dysfunctions associated with diabetes. This study aimed to determine the effects of risperidone (RISP) and paliperidone (PALI) on the vascular function of diabetic rats. Diabetes was induced by feeding with a high-fat diet followed by the administration of streptozotocin (35 mg·(kg body mass)(-1), by intraperitoneal injection). Rats received RISP or PALI (1.25 mg·kg(-1)·d(-1), per os) for 3 weeks. Endothelium-dependent relaxation, systolic blood pressure, lipid profile, insulin resistance, and adhesion molecules, vascular cell-adhesion-molecule-1 (VCAM-1), intracellular-adhesion-molecule-1 (ICAM-1), and E-selectin were investigated. RISP significantly worsened the impaired endothelium-dependent relaxation of diabetic aortic rings with upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin, and proinflammatory cytokines MPC-1 and TNF-α. RISP augmented the metabolic dysfunctions and reduced insulin sensitivity in the insulin tolerance test as well as HOMA-IR. PALI produced insignificant effects on vascular and metabolic aberrations. Our results suggest that RISP, but not PALI, aggravates the metabolic abnormalities and vascular dysfunction associated with diabetes, which may be mediated by upregulation of VCAM-1, ICAM-1, and E-selectin. Nevertheless, future investigation for the possible mechanisms underlying the difference noticed between the 2 AAPs is warranted.

Behavioural, metabolic, and endothelial effects of the TNF-α suppressor thalidomide on rats subjected to chronic mild stress and fed an atherogenic diet

There is accumulating evidence suggesting that depression is a risk factor for cardiovascular diseases. This study aimed to examine the hypothesis that the proinflammatory cytokine TNF-α would partially explain the link between depression and atherosclerotic endothelial changes. Rats were distributed among 6 groups: (i) control group; (ii) group subjected to chronic mild stress (CMS); (iii) group fed a cholesterol-cholic acid-thiouracil (CCT diet); and (iv) CMS group fed the CCT diet and treated with the vehicle for 8 weeks. The last 2 groups were subjected to CMS-CCT and received thalidomide (THAL) or imipramine (IMIP). Rats were assessed behaviorally (sucrose preference, open field, and forced-swimming tests). TNF-α protein was assessed from the serum, aorta, and liver. Aortic TNF-α gene expression (assessed using RT-PCR), serum lipid profile, and insulin levels were measured. Endothelial function was assessed in isolated aortic rings. The THAL and IMIP groups showed ameliorated CMS-CCT-related behavioral changes. CMS-CCT-induced metabolic and endothelial dysfunctions were improved in the THAL group but were worsened in the IMIP group. RT-PCR showed a significant reduction of aortic TNF-α mRNA expression in the THAL and IMIP treatment groups. These data paralleled the findings for aortic immunohistochemistry. The THAL group, but not the IMIP group, showed improved CMS-CCT-induced changes in the vascular reactivity of the aortic rings. Thus, TNF-α provides a target link between depression, metabolic syndrome, and endothelial dysfunction. This could open a new therapeutic approach to address the comorbidities of depression.

Potential involvement of JNK1 repression in the hepatic effect of sitagliptin and metformin in rats subjected to high fat diet and chronic mild distress

BACKGROUND Depression and non-alcoholic steatohepatitis (NASH) are highly co-morbid, and hepatic JNK pathway may be involved in their relation. AIM To evaluate the impact of depression on NASH through the involvement of JNK1 and to assess the effect of sitagliptin and metformin on hepatic JNK1 expression in both NASH and NASH associated with depression. METHODS Eight groups of male Wistar rats were used: naïve rats, non-stressed NASH, non-stressed NASH sitagliptin treated, non-stressed NASH metformin treated, stressed, stressed NASH untreated, stressed NASH sitagliptin treated and stressed NASH metformin treated. Behavioral, biochemical, molecular and histopathological studies were performed. RESULTS Non-stressed NASH group showed depressive like symptoms, disturbed glucose homeostasis, impairment of liver functions, decrease adiponectin and increase malondialdehyde, which were aggreviated by stress. Sitagliptin produced significant improvement compared to metformin regarding biochemical and histopathological parameters. Furthermore, sitagliptin significantly decreased expression of hepatic JNK1 in both stressed and non-stressed rats. All these changes were accompanied by significant improvement of behavioral changes. CONCLUSIONS The link between NASH and depression raised the role of JNK activation through increase expression of JNK1. Since sitagliptin was associated with preferable effects than metformin, therefore, it is potentially preferred in the management of either NASH or NASH associated with depression.

Mitigation of Delayed Sodium Hypochlorite-Induced Lung Injury by Phosphodiesterase Enzyme Inhibitors (PDEIs), Pentoxifylline and Theophylline, in Guinea Pigs

Sodium hypochlorite (NaOCI) is widely used as an industrial material as well as an ingredient in household cleaning products. Exposure to high concentrations of NaOCl, a powerful oxidant, results in acute lung injury that may proceed to delayed airway hyper responsiveness and remodeling. The present study aims at investigating the effects of two nonselective PDEIs, pentoxifylline ‘PTX’ and theophylline ‘THEO‘, versus dexamethasone ‘DEX’ on delayed airway functional and histopathological injury induced by NaOClinhalation in guinea pigs. Forty-eight guinea pigs were classified into 8 groups; 2 groups (control, 4% NaOClinhalation for 20 min) and another 6 groups were exposed to NaOCl and administrated intraperitoneally vehicle, PTX (50 mg/kg/day), THEO (50 mg/kg/day), DEX (20 mg/kg/day), PTX+DEX or THEO+DEX for 3 weeks. Guinea pigs were assessed for airway functional, biochemical and histopathological dysfunctions. Treatment with PENT or THEO, as monotherapy or in combination with DEX, reduced airway resistance and bronchial reactivity to methacholine. Similar findings were noticed with inflammatory markers such as total cell count, neutrophil percentage and TNF-α in bronchoalveolar lavage and lung myeloperoxidase activity and neutrophil infiltration. These data were parallel to lung histopathology and Aschorft fibrosis score that were improved in treatment groups. PENT, but not THEO or DEX could ameliorate oxidative stress biomarkers, malondialdehyde and superoxide dismutase, in lungs. Co-administration of PENT or THEO with DEX improved the effect of DEX on NaOCl-induced airway injury. In conclusion, ‘PENT and THEO’ are effective in mitigation of delayed NaOCl-induced lung injury in guinea pigs and if these findings were to translate into actual clinical benefit, they might provide a suitable alternative to corticosteroids or at least, reduce its dose needed in management of NaOCl and chlorine-induced lung toxicity.

Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression

Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.

A case report of asystole after a test dose of ceftriaxone in an adult man

Ceftriaxone is a commonly used antibiotic for various infections such as respiratory tract infection, urinary tract infection, and enteric fever, as well as in surgical prophylaxis. Hypersensitivity reactions after ceftriaxone therapy are uncommon but are potentially life-threatening, and they may lead to cardiac arrest. Here we report a 44-year-old man who presented with bradycardia, bronchospasm, hypotension, and cardiac arrest (asystole) after a single injected dose of ceftriaxone introduced for surgical prophylaxis. Epinephrine was given intravenously, and cardiopulmonary resuscitation was performed successfully. The patient regained his conscious level 2 h later and became hemodynamically stable within 4 h; next, he was extubated and closely observed for 24 h and then discharged. Physicians should be aware of the risk of anaphylaxis and asystole that may occur after the first dose of ceftriaxone and be ready for managing it properly.

Antibiotics prophylaxis in surgery. Part 1 ( gastroenterological surgeries)

Surgical site infections account for ∼15% of nosocomial infections and are associated with prolonged hospital stay and increased costs. Prophylactic use of antibiotics aims at reducing the incidence of postsurgical wound infection. Inappropriate prophylaxis, whether unnecessary use of broad-spectrum agents or continuation of therapy beyond the recommended time period, is frequently seen. Indeed, this increases the risk of adverse effects and promotes the emergence of resistant organisms. Controversy remains as to the necessity of prophylaxis in specific surgical procedures, as well as with regard to the duration of prophylaxis. The aim of this review is to discuss the criteria upon which decisions pertaining to the use of prophylactic antibiotics are based using the best clinical evidence available. Special emphasis is directed towards the selection and proper time and duration of administration. This review focuses on gastroenterological surgeries. Analyses of other surgeries will follow.