Cerium oxide nanoparticles impact on sepsis-induced cerebral injury: Deciphering miRNA / NF-κB/TLR signalling pathway.

Sepsis is regarded as an inflammatory syndrome that consists of complex biochemical and pathophysiological dysregulation, brought on by endogenous factors in response to systemic infection. Sepsis can cause short- and long-term cerebral injury. Cerium oxide nanoparticles (CeO2 NPs) have been reported to possess both anti-inflammatory and antioxidative properties. The current study investigated the potential role of cerium oxide nanoparticles in the management of sepsis-induced brain injury. To achieve this target, forty male albino rats were divided into 4 groups, ten rats each. Group (i) set as a shame group. Group (ii) set as shame group administrated CeO2 NPs. Group (iii) septic group treated with saline and Group (iv) septic group treated with CeO2 NPs. The sepsis model in rats was induced by cecal ligation and puncture (CLP). Results showed CeO2 NPs administration resulted in significant improvement in the survival rate of rats, suppression in serum sepsis biomarkers (CRP, ESM-1, PCT and D- dimer), amelioration of brain inflammatory mediators (TNF-α- IL-6, NF-kB and LTB4) as well as apoptotic markers (Cas-3 and BAX). Furthermore, immunomodulation of miRNAs expression (155,124 and 146a). These findings demonstrate a promising pivotal role of CeO2 NPs treatment in alleviating the deleterious effects induced by sepsis in the brain.

Plant-mediated green synthesis of gold nanoparticles using an aqueous extract of Passiflora ligularis, optimization, characterizations, and their neuroprotective effect on propionic acid-induced autism in Wistar rats.

The current study was conducted to examine an innovative method for synthesizing gold nanoparticles (AuNPs) from an aqueous sweet granadilla (Passiflora ligularis Juss) P. ligularis. Furthermore, the synthesized AuNPs were used to explore their potential neuroprotective impact against propionic acid (PPA)-induced autism. A sweet granadilla extract was used to achieve the synthesis of AuNPs. The structural and dimensional dispersion of AuNPs were confirmed by different techniques, including UV-Vis spectrophotometer (UV-Vis), X-ray Diffraction (XRD) Pattern, Energy Dispersive X-ray (EDX), Zeta potential, and High-Resolution Transmission Electron Microscopy (HRTEM) analysis. The AuNPs mediated by P. ligularis adopt a spherical shape morphology and the particle size was distributed in the range of 8.43-13 nm without aggregation. Moreover, in vivo, the anti-autistic effects of AuNPs administration were higher than those of P. ligularis extract per second. In addition, the reduced anxiety and neurobehavioral deficits of AuNPs were observed in autistic rats which halted the brain oxidative stress, reduced inflammatory cytokines, ameliorated neurotransmitters, and neurochemical release, and suppressed apoptotic genes (p < 0.05). The alleviated antiapoptotic gene expression and histopathological analysis confirmed that the treatment of AuNPs showed significant neural pathways that aid in reducing tissue damage and necrosis. The results emphasize that the biomedical activity was increased by using the green source synthesis P. ligularis -AuNPs. Additionally, the formulation of AuNPs demonstrates strong neuroprotective effects against PPA-induced autism that were arbitrated by a range of different mechanisms, such as anti-inflammatory, antioxidant, neuromodulator, and antiapoptotic effects.

Protective effect of cannabinoids on gastric mucosal lesions induced by water immersion restrain stress in rats.

OBJECTIVES: This study aimed to determine the impact of cannabinoid agonists and antagonists on the mucosal lesion progress in the stomach induced by water-immersion restraint stress (WIRS). MATERIALS AND METHODS: Rats subjected to WIRS for 4 hr were treated with Dimethyl sulfoxide (DMSO), CBR1 agonist (NADA, 1 mg/kg), CBR1 antagonist (Rimonabant, 1 mg/kg), CBR2 agonist (GW405833 1 mg/kg) or CBR2 antagonist (AM630, 1 mg/kg SC) 30 min before WIRS. Microscopic lesions, oxidative stress, inflammatory cytokines biomarkers, and (Myeloperoxidase) MPO in gastric tissues were determined. RESULTS: Results indicated development of severe gastric lesions with a substantial increase in the contents of (nitric oxide) NO, (malondialdehyde) MDA, (interleukin-1 beta) IL-1ß, MPO, (tumor necrosis factor-alpha) TNF-α, and a significant fall in the content of GSH and the activity of PON-1 after WIRS. CONCLUSION: Treatment with NADA and AM630 protected gastric tissues against ulcers as demonstrated by a decrease in the contents of MDA, TNF-α, MPO, and IL-1ß along with an increase in the content of PON-1 activity and GSH in the stomach tissues. On the other hand, treatment with SR141716A or GW405833 showed no protective effects on ulcers development. It seems that cannabinoids exert their antioxidant potential and anti-inflammatory effects against WIRS-induced gastric ulcers by activation of CB1R.

The impact of nandrolone decanoate abuse on experimental animal model: Hormonal and biochemical assessment.

Nandrolone decanoate (ND) is one of the most commonly abused anabolic androgenic steroids compounds in the world owing to its ability to improve physical performance but its abuse is associated with several adverse effects. The current study was performed to evaluate the effect of recommended and overdose of nandrolone decanoate (ND) for short and long term on the alterations of biochemical markers related to kidney, liver, adrenal, thyroid gland functions and oxidant and antioxidant activities. Sixty male rats were randomly assigned into two major groups. The first was treated with ND for 6 weeks and the second was treated with same drug for 12 weeks. Each of these groups was further subdivided into three sub groups: 1-Control (untreated rats), 2- Rats intraperitoneally injected with ND 3 mg/kg weekly, 3- Rats intraperitoneally injected with ND 15 mg/kg weekly. Administration of high ND dose for either short or long term significantly elevated kidney function biomarkers, liver enzymes both in serum, cytosol and mitochondria, insignificantly increased thyroid function, significantly increased adrenal function while, decreased ACTH. Moreover, oxidative stress biomarkers were significantly upregulated associated with depression in antioxidants activities. Administration of high ND dose for either short or long term as well as the repeated use of recommended ND dose for long term proved to have harmful effects manifested in impairing the functions of kidneys, liver, thyroid and adrenal glands as well as oxidant antioxidant balance.

Neuroprotective effect of PPAR alpha and gamma agonists in a mouse model of amyloidogenesis through modulation of the Wnt/beta catenin pathway via targeting alpha- and beta-secretases.

The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidß (ßA) peptide. Mice were injected intracerebroventricularly with ßA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and ß-secretase, peroxisome proliferator-activated receptor (PPARα and ß), Wnt and ß-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and ß-secretase levels and a significant decrease in Wnt, ß-catenin, and PPARα and ß levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by ßA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.

Modulation of gastric acid secretion by cannabinoids in rats.

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 µg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.

Biochemical and Molecular Mechanisms of Platelet-Rich Plasma in Ameliorating Liver Fibrosis Induced by Dimethylnitrosurea.

BACKGROUND/AIMS: Hepatic fibrosis is a wound-healing process in the chronically injured liver. Clinical application of platelet-rich plasma (PRP) is of considerable interest for wound healing and regeneration. In view of the regeneration effect of PRP, we designed this study to explore the hypothesis that PRP could play a role in improving the biochemical and molecular changes that occur in liver fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Four groups were studied: control, PRP control, DMN (liver fibrosis), and DMN+PRP groups. Serum liver enzymes (alanine amino transferase ALT, aspartate amino transferase AST, gamma glutamyl transferase GGT, and lactate dehydrogenase LDH), and liver hydroxyproline content were measured colorimetrically.Interleukin-8 (IL-8) and B-cell lymphoma (Bcl2) were determined by enzyme-linked immunosorbent assay. And the expression levels of alpha-smooth muscle actin (α-SMA) ,transforming growth factor (TGF-ß), and nuclear factor kappa B1(NF-қB1) were evaluated by quantitative real-time polymerase chain reaction. RESULTS: Our results showed that PRP markedly improved the DMN-induced changes in liver enzymes accompanied by a significant decrease in liver hydroxyproline content and IL-8 level induced by DMN, and an increase in the anti-apoptotic marker Bcl-2. PRP also showed significant down-regulation of fibrosis-related genes α-SMA and TGF-ß and a significant decrease in the inflammatory marker NF-қB1. CONCLUSION: Based on these encouraging results, we consider that PRP could be a promising new agent for liver regeneration and alleviation of fibrosis.

New prospects of mesenchymal stem cells for ameliorating temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is present in 30% of epileptic patients and does not respond to conventional treatments. Bone marrow derived mesenchymal stem cells (BMSCs) induce endogenous neural stem cells, inhibit neurodegeneration, and promote brain self-repair mechanisms. The present study addresses the feasibility of BMSCs transplantation against pilocarpine-induced TLE experimentally. BMSCs were injected either intravenously (IV) or in hippocampus bilaterally (IC). Increased cell count of BMSCs was achieved via IC route. BMSCs treatment ameliorated the pilocarpine-induced neurochemical and histological changes, retained amino acid neurotransmitters to the normal level, downregulated the immunoreactivity to insulin growth factor-1 receptor, synaptophysin, and caspase-3 and reduced oxidative insult and inflammatory markers detected in epileptic model. It is worth noting that BMSCs IC-administered showed more pronounced effects than those administered via IV route. BMSCs transplantation presents a promise for TLE treatment that has to be elucidated clinically.

Silver oxide nanoparticles alleviate indomethacin-induced gastric injury: a novel antiulcer agent.

Silver and silver oxides are gaining interest in medical applications for their prominent antibacterial and antimicrobial potentials. Recent studies suggest that nanosilver oxide has remarkable anti-inflammatory effects and enhances wound healing. Nevertheless, its effect on gastric ulcer has not yet been illustrated. Thus the current study aimed to explore the prospect protective effect of nanosilver oxide against indomethacin-induced gastric ulcer. A new approach has been followed to synthesize nanosilver oxide. X-ray diffraction, UV-Vis spectroscopy and transition electron microscope techniques have been successfully used to characterize the synthesized nanoparticles. Treatment of ulcerated rats with different doses of nanosilver oxide especially (175 and 350 ppm/p.o.) alleviated adverse effects of indomethacin-induced gastric injury as demonstrated by decreasing ulcer index and elevating % of ulcer inhibition. These positive effects excelled those exerted by the reference antiulcer drug omeprazole. Nanosilver oxide suppressed gastric inflammation by reducing myeloperoxidase, tumor necrosis alpha, interleukin 1beta and interferon gamma. Moreover, nanosilver oxide halted gastric oxidative stress via inhibiting lipid  peroxidation and enhancing glutathione and paraoxonase-1. Regarding gastric apoptosis, nanosilver oxide down regulated the expression of caspase 9, tumor protein 53, and nuclear factor kappa B and allograft inflammatory factor-1 genes. These findings emphasize the antiulcerogenic potential of nanosilver oxide against indomethacin-induced gastric ulcers which are multi-factorial including anti-inflammatory, antioxidant and antiapoptotic effects.

Nanofiber-expanded stem cells mitigate liver fibrosis: Experimental study.

OBJECTIVES: This study examines a pretreatment strategy to strengthen the hepatic lineage divergence of mesenchymal stem cells (MSCs). DESIGN AND METHODS: BMSCs were expanded in the presence or absence of nanofiber (NF) and treated with growth factors (GF) prior to transplantation. Thioacetamide (TA) was used for liver fibrosis induction and transplantation of NF-expanded BMSCs was compared biochemically and histologically to the cells expanded without NF scaffold. RESULTS: The ultraweb NF caused better proliferation and characterization of MSCs. MSCs transplantation significantly improved liver functions, increased hepatic HGF and Bcl-2 levels, whereas decreased serum fibronectin, hepatic TNF-α and TGF-ß1 levels. Hepatic HNF4α, FOXa2, CYP7a1 genes expression were enhanced while ß-5-Tub and AFP genes expression were depressed. Histological study documented these results. Differentiated NF-MSCs showed pronounced enhancement of the aforementioned parameters as compared to differentiated MSCs in the absence of NF. CONCLUSION: pretreatment with growth factors in the presence of NF augment homing, repopulation and hepatic differentiation abilities of MSCs and proves to be a promising approach for the treatment of liver fibrosis.

Updates in the pathophysiological mechanisms of Parkinson's disease: Emerging role of bone marrow mesenchymal stem cells.

AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson's disease (PD) pathophysiology. METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done. RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-ß1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs. CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.

Ozone Therapy in Ethidium Bromide-Induced Demyelination in Rats: Possible Protective Effect.

Multiple sclerosis, an autoimmune inflammatory disease of the central nervous system, is characterized by excessive demyelination. The study aimed to investigate the possible protective effect of ozone (O3) therapy in ethidium bromide (EB)-induced demyelination in rats either alone or in combination with corticosteroids in order to decrease the dose of steroid therapy. Rats were divided into Group (1) normal control rats received saline, Group (2) Sham-operated rats received saline, Group (3) Sham-operated rats received vehicle (oxygen), Group (4) EB-treated rats received EB, Group (5) EB-treated rats received O3, Group (6) EB-treated rats received methylprednisolone (MP), and Group (7) EB-treated rats received half the dose of MP concomitant with O3. EB-treated rats showed a significant increase in the number of footfalls in the grid walk test, decreased brain GSH, and paraoxonase-1 enzyme activity, whereas brain MDA, TNF-α, IL-1ß, INF-γ, Cox-2 immunoreactivity, and p53 protein levels were increased. A significant decline in brain serotonin, dopamine, norepinephrine, and MBP immunoreactivity was also reported. Significant improvement of the above-mentioned parameters was demonstrated with the administration of either MP or O3, whereas best amelioration was achieved by combining half the dose of MP with ozone.

The prognostic significance of p53, p63 and her2 expression in non-muscle-invasive bladder cancer in relation to treatment with bacille Calmette-Guerin.

OBJECTIVE: To investigate whether the immunohistochemical expression of p53, p63 and her2/neu is correlated with the prognosis of tumour recurrence and progression in patients with non-muscle invasive (NMI) bladder cancer. PATIENTS AND METHODS: In all, 88 patients diagnosed with NMI transitional cell carcinoma of the bladder in a Urology Department from May 2009 to April 2014 were included in the study. Paraffin-embedded specimens were obtained by transurethral resection of the bladder tumours. Sections on haematoxylin and eosin-stained slides were examined histologically and tumour grade was classified according to the World Health Organisation system (2004) Mostofi classification. The sections were evaluated using p63, p53 and her2/neu immunohistochemical staining before and after immunotherapy with bacille Calmette-Guerin (BCG), and patients were followed up for 36 months in the Urology Department. RESULTS: For tumour grade there was a significant relationship with the overexpression of p53 (P = 0.010), her2 (P = 0.025) and negativity of p63 (P = 0.025). There was no significant relationship between p53 or her2/neu overexpression and tumour stage. However, there was a significant correlation (P = 0.005) between p63 negativity and tumour stage. There was a significant relationship between p53 (P = 0.01), her2/neu (P = 0.025) overexpression and p63 negativity (P = 0.005) and tumour recurrence and progression. CONCLUSION: Patients with transitional cell carcinoma who are selected for BCG treatment should preferably be positively immunoreactive for p63, but negative for both p53 and her2/neu. These patients were less susceptible to recurrence and/or progression after BCG adjuvant therapy. Further studies are needed to investigate the relationship between these three markers and treatment with anti-her2/neu therapies.

Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-ß levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD.

Cannabis-induced impairment of learning and memory: effect of different nootropic drugs.

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain.

Selenium and lycopene attenuate cisplatin-induced testicular toxicity associated with oxidative stress in Wistar rats.

OBJECTIVE: To investigate the potential protective effects of selenium and lycopene, either alone or in combination, for cisplatin-induced oxidative stress and testicular dysfunction in male rats. METHODS: A total of 50 adult male Wistar rats were divided into 5 groups of 10 animals each, as follows: control group (treated with placebo); cisplatin-alone group; cisplatin + lycopene group; cisplatin + selenium group; and cisplatin + selenium + lycopene group. The weights and dimensions of testes, epididymes, and accessory glands as well as sperm concentration, motility, and proportion of normal morphology were assessed. Testicular tissue malondialdehyde (MDA) and glutathione (GSH) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, and plasma testosterone were determined. RESULTS: Cisplatin treatment caused significant reductions in weights and dimensions of testes, epididymes, and accessory glands, sperm concentration, motility, and proportion of normal morphology, enzymatic and nonenzymatic antioxidants, and plasma testosterone levels. There was significantly increased MDA. The co-administration of selenium and lycopene, either separately or in combination, significantly attenuated the harmful effects of cisplatin-induced lipid peroxidation, oxidative stress, loss of genital organ weight and dimensions, as well as function of reproductive organs collectively in the Wistar rat model. The combination of selenium and lycopene was more effective than supplementation of either agent alone in preventing cisplatin-induced testicular damage. CONCLUSION: Selenium and lycopene supplementation reduced cisplatin-induced testicular toxicity, improved testicular function and prevented cisplatin-related injury to the rat testes by suppression of oxidative stress.

Effect of aspartame on oxidative stress and monoamine neurotransmitter levels in lipopolysaccharide-treated mice.

This study aimed at investigating the effect of the sweetener aspartame on oxidative stress and brain monoamines in normal circumstances and after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS; 100 µg/kg) in mice. Aspartame (0.625-45 mg/kg) was given via subcutaneous route at the time of endotoxin administration. Mice were euthanized 4 h later. Reduced glutathione (GSH), lipid peroxidation (thiobarbituric acid-reactive substances; TBARS), and nitrite concentrations were measured in brain and liver. Tumor necrosis factor-alpha (TNF-α) and glucose were determined in brain. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in liver. The administration of only aspartame (22.5 and 45 mg/kg) increased brain TBARS by 17.7-32.8%, decreased GSH by 25.6-31.6%, and increased TNF-α by 16.7-44%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline, and dopamine. Aspartame did not alter liver TBARS, nitrite, GSH, AST, ALT, or ALP. The administration of LPS increased nitrite in brain and liver by 26.8 and 37.1%, respectively; decreased GSH in brain and liver by 21.6 and 31.1%, respectively; increased brain TNF-α by 340.4%, and glucose by 39.9%, and caused marked increase in brain monoamines. LPS increased AST, ALT, and ALP in liver tissue by 84.4, 173.7, and 258.9%, respectively. Aspartame given to LPS-treated mice at 11.25 and 22.5 mg/kg increased brain TBARS by 15.5-16.9%, nitrite by 12.6-20.1%, and mitigated the increase in monoamines. Aspartame did not alter liver TBARS, nitrite, GSH, ALT, AST, or ALP. Thus, the administration of aspartame alone or in the presence of mild systemic inflammatory response increases oxidative stress and inflammation in the brain, but not in the liver.

Effects of Cannabis sativa extract on haloperidol-induced catalepsy and oxidative stress in the mice.

Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms due to blockade of dopamine D2 receptors in the striatum. Interest in medicinal uses of cannabis is growing. Cannabis sativa has been suggested as a possible adjunctive in treatment of Parkinson's disease. The present study aimed to investigate the effect of repeated administration of an extract of Cannabis sativa on catalepsy and brain oxidative stress induced by haloperidol administration in mice. Cannabis extract was given by subcutaneous route at 5, 10 or 20 mg/kg (expressed as Δ(9)-tetrahydrocannabinol) once daily for 18 days and the effect on haloperidol (1 mg/kg, i.p.)-induced catalepsy was examined at selected time intervals using the bar test. Mice were euthanized 18 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (the concentrations of nitrite/nitrate) were determined in brain and liver. In saline-treated mice, no catalepsy was observed at doses of cannabis up to 20 mg/kg. Mice treated with haloperidol at the dose of 1 mg/kg, exhibited significant cataleptic response. Mice treated with cannabis and haloperidol showed significant decrease in catalepsy duration, compared with the haloperidol only treated group. This decrease in catalepsy duration was evident on days 1-12 after starting cannabis injection. Later the effect of cannabis was not apparent. The administration of only cannabis (10 or 20 mg/kg) decreased brain MDA by 17.5 and 21.8 %, respectively. The level of nitric oxide decreased by 18 % after cannabis at 20 mg/kg. Glucose in brain decreased by 20.1 % after 20 mg/kg of cannabis extract. The administration of only haloperidol increased MDA (22.2 %), decreased GSH (25.7 %) and increased brain nitric oxide by 44.1 %. The administration of cannabis (10 or 20 mg/kg) to haloperidol-treated mice resulted in a significant decrease in brain MDA and nitric oxide as well as a significant increase in GSH and glucose compared with the haloperidol-control group. Cannabis had no significant effects on liver MDA, GSH, nitric oxide in saline or haloperidol-treated mice. It is concluded that cannabis improves catalepsy induced by haloperidol though the effect is not maintained on repeated cannabis administration. Cannabis alters the oxidative status of the brain in favor of reducing lipid peroxidation, but reduces brain glucose, which would impair brain energetics.

Amelioration of the haloperidol-induced memory impairment and brain oxidative stress by cinnarizine.

Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms and impaired memory, owing to blockade of striatal dopamine D2 receptors. Cinnarizine is a calcium channel blocker with D2 receptor blocking properties which is widely used in treatment of vertiginous disorders. The present study aimed to see whether cinnarizine would worsen the effect of haloperidol on memory function and on oxidative stress in mice brain. Cinnarizine (5, 10 or 20 mg/kg), haloperidol, or haloperidol combined with cinnarizine was administered daily via the subcutaneous route and mice were examined on weekly basis for their ability to locate a submerged plate in the water maze test. Mice were euthanized 30 days after starting drug injection. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) were determined in brain. Haloperidol substantially impaired water maze performance. The mean time taken to find the escape platform (latency) was significantly delayed by haloperidol (2 mg/kg, i.p.) on weeks 1-8 of the test, compared with saline control group. In contrast, those treated with haloperidol and cinnarizine showed significantly shorter latencies, which indicated that learning had occurred immediately. Haloperidol resulted in increased MDA in cortex, striatum, cerebellum and midbrain. GSH decreased in cortex, striatum and cerebellum and nitric oxide increased in cortex. Meanwhile, treatment with cinnarizine (20 mg/kg) and haloperidol resulted in significant decrease in MDA cortex, striatum, cerebellum and midbrain and an increase in GSH in cortex and striatum, compared with haloperidol group. These data suggest that cinnarizine improves the haloperidol induced brain oxidative stress and impairment of learning and memory in the water maze test in mice.

Evaluation of the potential toxicity of dibromoacetonitrile-induced apoptosis and tumor-initiating activity in rat liver.

Dibromoacetonitrile (DBAN) is water disinfectant by-product. Its broad-spectrum toxicity in different test systems in vivo and in vitro has been reported. However, there is a scanty of information regarding dibromoacetonitrile hepatotoxicity. Therefore, this study aimed to investigate the possible mechanisms for dibromoacetonitrile-induced tumor initiation in rat liver cells. Dibromoacetonitrile was orally administered to rats as an acute (60 mg/kg) and fractionated (7.5mg/kg) doses, weekly twice for 4 weeks and once weekly for 8 weeks. Significant increase in malondialdehyde level (approximately 7-, 6- and 4-folds) and extensive depletion in total antioxidant capacity were detected following acute and fractionated doses respectively. Alanine aminotransferase (about 2- and 1-folds) and aspartate aminotransferase (3- and 2-folds) were significantly increased after acute dose and fractionated doses for 4 weeks. Also, these doses of dibromoacetonitrile produced high levels of DNA fragmentation, micronucleated polychromatic erythrocytes and changes in the expression of hepatocyte growth factor gene and proto-oncogenes (c-met and c-myc) in liver tissues. Ability of dibromoacetonitrile to induce DNA damage and alterations in the expression of tumor-initiating genes was suggested to be due to hepatotoxicity, oxidative stress and disturbance in the oxidant/antioxidant status of rat liver.