Ahmed M. Abdel-tawab

Potential neuroprotective effects of hesperidin on 3-nitropropionic acid-induced neurotoxicity in rats

Huntingtons disease (HD) is a progressive neurodegenerative disorder with a spectrum of cognitive, behavioral, and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes, primarily manifested as prepulse inhibition (PPI) deficit of acoustic startle stimuli, and selective striatal lesions in rats and primates mimicking those in HD. The implications of nitric oxide in a variety of neurodegenerative diseases attract attention to study the possible role of flavonoids in interaction with nitric oxide pathways involved in HD. The present study investigates the potential effect of hesperidin, a flavanone group member, on 3-NP-induced behavioral, neurochemical, histopathological and cellular changes. Systemic administration of 3-NP to rats for 5 days (20 mg/kg) caused reduction of locomotor activity by days 2 and 5, 55% deficit of PPI response, elevation of cortical, striatal and hippocampal malondialdehyde (MDA) levels by 63%, 41% and 56%, reduction of respective catalase activity by 50%. Immunohistochemical staining of cortices, striata and hippocampi showed patches of iNOS positive cells. Electron microscopic ultrastructural examination showed marked mitochondrial swelling, perivascular edema and shrunken nerve cells. Pretreatment with hesperidin (100 mg/kg) ahead of 3-NP prevented any changes of locomotor activity or PPI response, slightly increased cortical, striatal and hippocampal MDA levels by 10% and reduced respective catalase activity by 22%, 20% and 5%. Only few iNOS positive cells were detected in sections from rats pretreated with hesperidin which also reduced cellular abnormalities induced by 3-NP. This study suggests a potential neuroprotective role of hesperidin against 3-NP-induced Huntingtons disease-like manifestations. Such neuroprotection can be referred to its antioxidant and anti-inflammatory activities.

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.

Changes in glutamate decarboxylase enzyme activity and tau-protein phosphorylation in the hippocampus of old rats exposed to chronic mild stress: reversal with the neuronal nitric oxide synthase inhibitor 7-nitroindazole.

Effects of chronic stress are not completely understood. They may underlie depression and dementia. This study assessed the association between chronic stress, glutamate levels, tau-protein phosphorylation, and nitric-oxide in old rats exposed to chronic mild stress (CMS). Old (>15 months) male Wistar rats were exposed to CMS. Comparison groups included old and young control rats, young CMS-exposed, and old CMS-exposed rats treated with the neuronal nitric-oxide synthase (nNOS) enzyme inhibitor, 7-nitroindazole (20 mg/kg/day i.p.). Hippocampal glutamate levels and glutamate decarboxylase (GAD) activity were determined and tau protein phosphorylation was assessed. Age was a significant (p=0.025) source of variation in glutamate level [811.71+/-218.1, 665.9+/-124.9 micromol/g tissue protein (M+/-SD) in young and old control rats, respectively]. Old rats exposed to CMS were characterized by an increased risk to develop anhedonia. There was significant (p=0.035) decrease in GAD enzyme activity (-60.06%) and increased tau protein hyperphosphorylation in old rats exposed to CMS compared to control. Administration of 7-nitroindazole to CMS-exposed old rats significantly (p=0.002) increased GAD activity, decreased glutamate levels (7.19+/-3.19 vs. 763.9+/-91 micromol/g tissue protein; p=0.0005), and decreased phosphorylation of tau proteins compared to CMS exposed rats.

Albendazole and its metabolites in the breast milk of lactating women following a single oral dose of albendazole

AIMS Albendazole (ABZ) is used in several anthelminthic drug programs. ABZ side-effects are generally mild, but ABZ-induced pancytopenia may be serious. In filariasis programmes, it may be necessary to administer ABZ to breastfeeding women. Few data are available on safety of ABZ for breastfed infants. In addition, the pharmacokinetics of ABZ and its metabolites in human milk is insufficiently investigated. The aim was to study pharmacokinetics of ABZ and its metabolites [ABZ sulphoxide (ABSX) and ABZ sulphone] in the breast milk lactating women after one single oral dose of ABZ. METHODS Thirty-three lactating women (age 18-40 years) participated in the study. They received a single oral 400-mg dose of ABZ. Five milk samples were taken at 0, 6, 12, 24 and 36 h. One serum sample was taken after 6 h. Samples were analysed using high-performance liquid chromatography and pharmacokinetic analysis was performed. RESULTS ABZ was detectable in milk samples 6 h after the oral dose. The mean concentration of serum ABZ was 63.7 +/- 11.9 ng ml(-1). The pharmacokinetic parameters for ABSX were calculated as follows: 351.9 +/- 32.4 ng ml(-1), 6.9 +/- 0.5 h, 12.4 +/- 2.2 h and 5190.3 +/- 482.8 ng*h ml(-1) for C(max), T(max), t((1/2)) and AUC(0-36), respectively. The milk-to-serum ratios (range) for ABZ and ABSX were 0.9 (0.2-6.5) and 0.6 (0.1-1.5), respectively. CONCLUSIONS After an oral dose of 400 mg, ABZ and ABSX attain low concentrations in breast milk that are unlikely to be considered harmful for the breastfed infant.

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 neuroprotective effect of androst-5-ene-3β, 17β-diol (ADIOL) on the striatum, and substantia nigra in Parkinson's disease rat model

Parkinsons disease (PD) is a progressive neurodegenerative disorder with behavioral and motor abnormalities. Androst‐5‐ene‐3β, 17β‐diol (ADIOL), an estrogen receptor (ER) β agonist, was found to mediate a transrepressive mechanism that selectively modulates the extent of neuroinflammation and, in turn, neurodegeneration. In consensus, ERβ polymorphism was more frequently detected in early‐onset PD patients. Thus, in an approach to elucidate the role of ERβ agonists on PD, our study was designed to investigate the possible neuroprotective effect of ADIOL, in three dose levels (0.35, 3.5, 35 mg/kg/day), against rotenone (ROT)‐induced PD rat model. Amelioration in striatal dopamine (DA), nuclear factor‐kappa B (NF‐κB), and the expression of down‐stream inflammatory mediators, as well as apoptotic markers were observed in the striatum and substantia nigra (SN) upon pre‐treatment with the three doses of ADIOL. Similarly, light microscopy (LM) examination revealed declined degeneration of neurons upon pretreatment with ADIOL. Significant improvement in nigral tyrosine hydroxylase (TH) and reduction of nigral α‐synuclein densities were also detected after ADIOL pre‐treatment with better results frequently achieved with the middle dose (3.5 mg/kg/day). The middle dose of ADIOL showed behavioral improvement, with elevation in the ATP level, which was emphasized by the improvement in mitochondrial integrity observed upon electron microscopy (EM) examination. In conclusion, the present study confirmed for the first time the ability of ADIOL to protect against neuroinflammation and, in turn, neurodegeneration process and motor dysfunction in PD animal model, which was more obviously observed with the middle dose.

Management of multi drug-resistant gram-negative bacteria in the intensive care unit

Multidrug-resistant organisms as a cause of hospital-acquired infections represent a major problem. Here, we report a case of multidrug-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae infections in an ICU-admitted patient. The treatment options for these pathogens are discussed.