Intraperitoneal Administration Of Cyclophosphamide Research Articles

Antidyslipidemic Effect of 5-Fluorouracil against Cyclophosphamide-Induced Dyslipidemia in Male Albino Rats

Background: Cyclophosphamide (CPA) is a drug with a wide spectrum of clinical uses. It is commonly used as anticancer and immuno suppressant agent. It induces hyperlipidemia and myocardium damage. 5-FU is widely used in the treatment of a range of cancers. 5-FU in combination with other chemotherapeutic agents improves response rates and survival in breast and head and neck cancers. Objectives: The present study aimed to evaluate the antidyslipidemic effect of 5-fluorouracil against dyslipidemia induced by cyclophosphamide in male albinorats. Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=5 for each group). Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken and prepared for biochemical measurements. Results: Intraperitoneal administration of CPA or 5-FU resulted in a significant increase in the levels of serum lipids. The cholesterol, Triglyceride, and LDL levels in serum of CPA or 5-FU treated rats were significantly increased when compared to controls. When CPA was administered followed by 5-FU prevented the increase in serum lipid levels highlighting its hypolipidemic role as antagonism. Also, a marked decrease in HDL cholesterol was noted in CPA treated rats. These changes produced by CPA to serum levels of HDL were normalized when 5-FU is given to the treated rats compared to CPA administered rats. Conclusion: It could be concluded that treatment of rats with CPA induced dyslipidemia. However, 5-FU and CPA combination could produce a significant amelioration in the dyslipidemic changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to prevent dyslipidemia. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism.

Antidyslipidemic Effect of 5-Fluorouracil against Cyclophosphamide induced Dyslipidemia y in Male Albino Rats

Background: Cyclophosphamide (CPA) is a drug with a wide spectrum of clinical uses. It is commonly used as anticancer and immuno suppressant agent. It induces hyperlipidemia and myocardium damage. 5-FU is widely used in the treatment of a range of cancers. 5-FU in combination with other chemotherapeutic agents improves response rates and survival in breast and head and neck cancers. Objectives: The present study aimed to evaluate the antidyslipidemic effect of 5-fluorouracil against dyslipidemia induced by cyclophosphamide in male albino rats. Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=5 for each group). Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken and prepared for biochemical measurements. Results: Intraperitoneal administration of CPA or 5-FU resulted in a significant increase in the levels of serum lipids. The cholesterol, Triglyceride, and LDL levels in serum of CPA or 5-FU treated rats were significantly increased when compared to controls. When CPA was administered followed by 5-FU prevented the increase in serum lipid levels highlighting its hypolipidemic role as antagonism. Also, a marked decrease in HDL cholesterol was noted in CPA treated rats. These changes produced by CPA to serum levels of HDL were normalized when 5-FU is given to the treated rats compared to CPA administered rats. Conclusion: It could be concluded that treatment of rats with CPA induced dyslipidemia. However, 5-FU and CPA combination could produce a significant amelioration in the dyslipidemic changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to prevent dyslipidemia. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism

Neuroprotective effect of Mulmina Mango against chemotherapy-induced cognitive decline in mouse model of mammary carcinoma

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain.

Abstract 2044: Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy

Abstract Background: Eflapegrastim is a long-acting G-CSF that is comprised of a G-CSF analog and a recombinant IgG4 Fc fragment conjugated at their N-termini via a short polyethylene glycol linker. Currently, G-CSF products are administered 24 hours after chemotherapy. We compared the duration of neutropenia (DN) after treatment with eflapegrastim and pegfilgrastim given on the same-day, at three different timepoints, and after 24 hours in chemotherapy-induced neutropenic rats. Method: Neutropenia was induced in rats via intraperitoneal administration of cyclophosphamide and docetaxel (TC) chemotherapy. Rats (5 animals per group) were assigned to dose groups of either vehicle or equivalent doses (based on human clinical doses) of pegfilgrastim (103.3 µg/kg) or eflapegrastim (61.8 µg/kg as G-CSF) on the same day as chemotherapy at 0, 2, and 5 hours or 24 hours after chemotherapy. The primary endpoint was the difference in DN after TC treatment and administration of eflapegrastim or pegfilgrastim at the specified timepoints. Results: In the vehicle group, the TC regimen induced neutropenia in all animals with an ANC nadir occurring on approximately Day 4 and a mean DN of nearly 7 days. The mean DN values for treatment with eflapegrastim on the same day, at 0, 2, and 5 hours, and after 24 hours were similar and the mean DN values for eflapegrastim were significantly lower than for pegfilgrastim at all dosing timepoints (Table). Time after Chemotherapy(hours)Mean Duration of Neutropenia (days)Difference (95% CI)Eflapegrastim Time vs 24 hoursDifference (95% CI)EflapegrastimPegfilgrastim00.62.2-1.6 (-3.067, -0.133)0.4 (-0.08, 1.28)20.21.8-1.6 (-2.84, -0.36)0 (-0.19, 0.59)50.01.2-1.2 (-1.20, -1.20)-0.2 (0, 0)240.21.8-1.6 (-2.84, -0.36)NA Conclusions: The DN for same-day treatment with eflapegrastim at 0, 2, and 5 hours was similar to that of the treatment after 24-hours. However, the mean DN values were significantly lower for eflapegrastim than pegfilgrastim at all time points. Further exploration of the potential advantage of same-day dosing with eflapegrastim in patients undergoing chemotherapy is warranted. Citation Format: Yu-Yon Kim, Eunjung Kim, Hyesun Han, Seungjae Baek, Shanta Chawla, Prasad Kolli, Gajanan Bhat, Francois Lebel. Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2044.

Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats.

Cyclophosphamide (CPA) is used in the management of autoimmune conditions and malignant illnesses. However, its therapeutic use is limited because of its severe side effects, especially hepatotoxicity attributed to oxidative stress. Nasturtium officinale R. Br (watercress or WC) has pharmacological properties, such as anti-inflammation, and antioxidant activities. Therefore, the present study was design to assess effects of WC or its active ingredient, quercetin (QE), against CPA-induced hepatotoxicity. For this study, 49 male Wistar rats (200-250g) were randomly selected and categorized into seven equal groups. The animals were pre- and post-treated with both hydroalcoholic extract of WC (500mg/kg) and quercetin (75mg/kg) for 10 consecutive days, and intraperitoneal administration of CPA (200mg/kg) was performed on only day 10, one hour before the last dose of WC or quercetin. On day 11, all the animals were sacrificed, and their blood and liver were gathered for evaluation of the liver enzyme, hepatic oxidative stress markers, antioxidant enzymes activity, and hematoxylin and eosin staining. CPA significantly increased malondialdehyde (MDA), protein carbonyl (PCO) and nitric oxide (NO) levels and liver biomarkers. Otherwise, hepatic catalase (CAT), reduced glutathione (GSH), total thiol content (tSH), and ferric reducing antioxidant power (FRAP) were considerably lower than the control group. Results showed that WC has the ability to reduce the changes (MDA, PCO, FRAP, CAT, ALT and AST) and QE (MDA, PCO, AST) induced by CPA (p < 0.05). Histopathological finding confirmed the indicated results. These findings propose that WC and QE have protective effect against the CPA-induced hepatotoxicity by decreasing oxidative stress.

Assessment of Efficacy and Safety of Clindamycin Against Methicillin- Resistant Staphylococcus aureus (MRSA) Infected Subcutaneous Abscess Model

Background: Methicillin-resistant Staphylococcus aureus (MRSA) causes infection in the wound leading to life-threatening bacteriemia. It causes recalcitrant infections because of being resistant to various antibiotics. The recent studies reported clindamycin to be effective against MRSA rather than inducible clindamycin resistance and decrease the incidence of new infections after clindamycin treatment. The study focused on assessing the efficacy and safety of clindamycin against MRSA infected rats. Methods: The rats become neutropenic by intraperitoneal administration of cyclophosphamide at a dose of 150 mg/kg and 100 mg/kg for 4 days and 5th day respectively. The neutropenic rats were infected with MRSA by subcutaneous administration of 106 CFU/ml of MRSA. The 3 groups of rats such as Normal, MRSA infected, MRSA infected rats that were administered clindamycin orally at a dose of 90 mg/kg/ thrice daily for 14 days were used in the study. The abscess size, weight, and bacterial load were measured at the end of the study. The blood and liver samples were collected for biochemical analysis and histopathological evaluation. Results: The MRSA was confirmed by Polymerase Chain Reaction (PCR) method. The clindamycin minimum inhibitory concentration was 0.125 - 0.5 μg/ml. The MRSA showed negative D test for clindamycin indicating the absence of inducible clindamycin resistance. The decreased abscess size, weight, bacterial count, Intestinal Alkaline Phosphatase (IAP), weight loss, alteration in hematological parameters, mild changes in cholesterol, ALT and liver histology, no significant (P &gt; 0.05) change in triglycerides, AST, ALP, bilirubin, lactate, urea, and creatinine were seen in clindamycin treated MRSA infected rats. The MRSA infected clindamycin treated rats showed mild irritation and diarrhea. Conclusion: Our study concludes that the clindamycin showed better anti- MRSA activity and tolerable adverse effects such as anemia, weight loss, and mild irritation after oral treatment, but the intestinal dysbiosis is a severe adverse effect and causes diarrhea.

The Pathological Features of Cyclophosphamide Induced Multi-Organs Toxicity in Male Wister Rats

Cyclophosphamide has the ability to induce multi-organ toxicity. The current study was conducted to investigate the toxicity effects of one dose and two doses of intraperitoneal administration of cyclophosphamide at dose of 50 mg/kg of body weight in male Wister rats. Fifteen male rats were assigned into three group five rats each group namely, control, 1-dose, and 2-doses. 1-dose group rats received one dose of cyclophosphamide at dose of 50 mg/kg of body weight, and 2-doses group rats received two doses of cyclophosphamide at dose of 50 mg/kg of body weight. Liver, lungs, kidneys, spleen and testes weight were recorded and collected for histopathological examination. The results showed a decrement in testes and spleen weight of 2-doses treated rats. The histopathology results showed pathological changes in all examined organs of cyclophosphamide treated rat. The fibrosis lesion was observed in 2-doses group’s affected organs. Testicular injury in the 2-doses group involved 10% of the affected testis. In conclusion, cyclophosphamide treatment at dose of 50 mg/kg of body weight to male Wister rats induced multi-organs toxicity. The rats that received two doses of cyclophosphamide as dose of 50 mg/kg of body weight induced fibrosis in affected organs and elevated the testicular injury.

Effect and Safety of Cinnamaldehyde on Immunosuppressed Mice with Invasive Pulmonary Candidiasis.

To evaluate the effect and safety of cinnamaldehyde on immunosuppressed mice with invasive pulmonary candidiasis. An immunosuppressed BALB/c mouse model was established by intraperitoneal administration of cyclophosphamide (200 mg/kg) once daily for 2 days. The immunosuppressed mouse with invasive pulmonary candidiasis model was further established by nasal perfusion of Candida albicans suspension. In the cinnamaldehyde treatment group, immunosuppressed mice with invasive pulmonary candidiasis were orally given cinnamaldehyde 240 mg/(kg·d) for 14 consecutive days. Fluconazole and 0.9% saline were used as the positive and negative controls, respectively. The mice in the cinnamaldehyde safety evaluation group were orally administered cinnamaldehyde 480 mg/(kg·d) for 42 days to observe the safety of the drug. Microscopic identification, fungal culture, histopathological examination, and (1,3)-beta-D-glucans detection were conducted to analyze the effect of cinnamaldehyde on C. albicans. The fungal clearance rate in the cinnamaldehyde treatment group was higher than that in the fluconazole control group (80.00% vs. 56.67%, P<0.05). The level of (1,3)-β-D-glucan in the cinnamaldehyde treatment group was lower than that in the fluconazole positive control group (1160.62 ±89.65 pg/mL vs. 4285.87 ± 215.62 pg/mL, P<0.05). The survival rate of mice in the cinnamaldehyde safety evaluation group was 100%, and no significant pathological changes of kidney, lung and liver were observed. Cinnamaldehyde was effective and safe in treating immunosuppressed BALB/c mice with invasive pulmonary candidiasis. It would be a potentially novel drug for anti-candidiasis infection.

Colonization and immunoregulation of Lactobacillus plantarum BF_15, a novel probiotic strain from the feces of breast-fed infants.

Immunosuppression is a manifestation imbalance in the immune system, often during unhealthy states. In recent years, lactic acid bacteria (LAB) have been found to be important components of the body's innate immune system, and indispensable to maintaining normal immune function. Lactobacillus plantarum BF_15, a novel strain isolated from the feces of breast-fed infants, which has shown potential as an immunomodulator in vitro. In the present study, with the Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR-DGGE) based on RNA-polymerase beta subunit encoding gene (rpoB) to analyze the colonization of L. plantarum BF_15 in the intestine of mice. In addition, Lactobacillus rhamnosus GG (LGG) as a positive control strain, by measuring immune-related indexes and the diversity of intestinal microbiota, the effects of BF_15 on immunoregulation and intestinal microbiota dysbiosis were investigated to elucidate whether the attenuation of immunosuppression is related to the modulation of intestinal microbiota. Results did indeed support this notion that BF_15 did colonize murine intestines well, in which it could still be detected in mice feces 14 days after stopping the probiotic administration. Moreover, BF_15 found to protect mice against reduction in the levels of several immune-related indicators, including the thymus and spleen indexes, splenic lymphocyte proliferation, toe swelling degree, serum hemolysin-antibody level, and macrophage phagocytosis index, triggered by high-dose (200 mg kg-1) intraperitoneal administration of cyclophosphamide (CTX). In addition, the strain was also found to effectively balance intestinal microbiota dysbiosis in the mice. Collectively, these results indicated that L. plantarum BF_15 can not only successfully colonize murine intestines, but also can effectively alleviate CTX-induced immunosuppression, once established, by rebalancing the intestinal microbiota. This, therefore, provides strong evidence for the view that BF_15 has the potential to become a highly effective immunomodulating probiotic in human microbiota as well.

A study of the effect of complexes of 3d-metal ions with gluconic acid on synthesis of cytokines in experimental immunodeficiency

Aim. Evaluation of the influence of synthesized gluconates of 3d-metals on production of cytokines in blood serum of mice with experimental immunodeficiency.&#x0D; Materials and Methods. The effect of complex compounds of bivalent 3d-metals (Mn, Fe, Co, Cu, Zn) with glucuronic acid on production of cytokines: interleukin (IL)-1β, IL-6, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) in blood serum of mice with experimental immunodeficiency induced by a single intraperitoneal administration of cyclophosphamide at the dose of 50 mg/kg was studied. 3d-Metal gluconates (10-2mol/l) were orally introduced for comparison with immunostimulatory drug «Licopid®» and calcium gluconate (doses were calculated according to the instructions) daily for two weeks, starting from the second day after the injection of cyclophosphamide. Levels of cytokines were determined by immunoenzyme analysis.&#x0D; Results. On the 16th day after the induction of immunodeficiency, levels of cytokines in blood serum of mice decreased: IL-1β – by 75.0%, IL-6 – by 65.2%, IFN-γ – by 61.6%, TNF-α –by 55.6% (p&lt;0.05). Stimulatory effect of gluconates of 3d-metals on synthesis of cytokines depended on the used metal: the effect of MnGl, FeGl, CoGl, CuGl was lower than of licopid. ZnGl produced a weaker effect than licopid only on synthesis of IL-6, and equal effect on secretion of IL-1β and IFN-γ, and the highest effect on TNF-α (p&lt;0.05 for all comparisons). Calcium gluconate did not produce any significant effect on the content of cytokines.&#x0D; Conclusion. The obtained results show a significant role of 3d-metals in maintenance of immune homeostasis, which, taking into account the literature data, may be explained by their action through activation of the nuclear transcription factor NF-κB which controls expression of cytokines.

Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, intravenous, and intraperitoneal administration of cyclophosphamide

OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4-hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, IV, and IP administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive cyclophosphamide (200 mg/m2) via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration-versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients.

Intrathecal administration of TRPA1 antagonists attenuate cyclophosphamide-induced cystitis in rats with hyper-reflexia micturition.

BackgroundThe activation of TRPA1 channel is implicated in hyper-reflexic micturition similar to overactive bladder. In this study, we aimed to investigate the effects of blocking TRPA1 via intrathecal administration of antagonists on the afferent pathways of micturition in rats with cystitis.MethodsThe cystitis was induced by intraperitoneal cyclophosphamide administration. Cystometry was performed in control and cystitis rats, following the intrathecal injection of the TRPA1 antagonists HC-030031 and A-967079. Real-time PCR, agarose gel electrophoresis, western blotting and immunohistochemistry were used to investigate the levels of TRPA1 mRNA or protein in the bladder mucosa and L6-S1 dorsal root ganglia (DRG).ResultsEdema, submucosal hemorrhaging, stiffness and adhesion were noted during removal of the inflamed bladder. The expression of TRPA1 mRNA and protein was higher in the cystitis group in both the mucosa and DRG, but the difference was significant in the DRG (P < 0.05). Intrathecal administration of HC-030031 and A-967079 decreased the micturition reflex in the cystitis group. A 50 μg dose of HC-030031 increased the intercontraction interval (ICI) to 183 % of the no-treatment value (P < 0.05) and decreased the non-voiding contraction (N-VC) to 60 % of control (P < 0.01). Similarly, the treatment with 3 μg A-967079 increased the ICI to 142 % of the control value (P < 0.05) and decreased the N-VC to 77 % of control (P < 0.05). The effects of both antagonists weakened approximately 2 h after injection.ConclusionsThe TRPA1 had a pronounced upregulation in DRG but more slight in mucosa in rat cystitis. The blockade of neuronal activation of TRPA1 by intrathecal administration of antagonists could decrease afferent nerve activities and attenuated detrusor overactivity induced by inflammation.

ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis

Given the previous evidence for involvement of prostanoid EP1 receptors in facilitation of the bladder afferent nerve activity and micturition reflex, the present study investigated the effect of ONO-8130, a selective EP1 receptor antagonist, on cystitis-related bladder pain in mice. Cystitis in mice was produced by intraperitoneal administration of cyclophosphamide at 300 mg/kg. Bladder pain-like nociceptive behavior and referred hyperalgesia were assessed in conscious mice. Phosphorylation of extracellular signal-regulated kinase (ERK) in the L6 spinal cord was determined by immunohistochemistry in anesthetized mice. Cyclophosphamide treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms, including increased bladder weight and vascular permeability and upregulation of cyclooxygenase-2 in the bladder tissue. Oral preadministration of ONO-8130 at 0.3–30 mg/kg strongly prevented both the bladder pain-like behavior and referred hyperalgesia in a dose-dependent manner, but had slight effect on the increased bladder weight and vascular permeability. Oral ONO-8130 at 30 mg/kg also reversed the established cystitis-related bladder pain. Intravesical administration of prostaglandin E 2 caused prompt phosphorylation of ERK in the L6 spinal cord, an effect blocked by ONO-8130. Our findings strongly suggest that the prostaglandin E 2/EP1 system participates in processing of cystitis-related bladder pain, and that EP1 antagonists including ONO-8130 are useful for treatment of bladder pain, particularly in interstitial cystitis. Prostaglandin E 2 contributes to cystitis-related bladder pain via EP1 receptors in mice, indicating possible therapeutic usefulness of selective EP1 antagonists.

Attenuation of cyclophosphamide-induced neurotoxicity in rat by yellow dye extract from root of Brimstone tree (Morinda lucida)

Cyclophosphamide is an anticancer and immunosuppressant drug that induces reactive oxygen species (ROS) production, so causing malondialdehyde (MDA) production, which is toxic to cells. This study therefore sought to assess the antioxidant and the protective effect of dietary inclusion (0.5 and 1.0%) of yellow dye from root of Brimstone tree (used to enhance the sensory quality of foods and in folk medicine) on cyclophosphamide-induced oxidative stress in brain. Wistar strain albino rats were placed on diet containing 0.5 and 1.0% yellow dye preparation from root of Brimstone tree for 14 days. Intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) 24 h before the termination of the experiment caused a significant (P<0.05) increase in the brain malondialdehyde (MDA) content (147.2%) and serum activities of aspartate aminotransferase (AST) (21.7 UI/l), alanine amino-transferase (ALT) (29.6 UI/l), alkaline phosphatase (43.8 UI/l) and total bilirubin (1.7 mg/dl). However, there was a significant decrease (P<0.05) in the MDA of content of the brain and serum enzyme activities, in those rats fed diet containing the yellow dye in a dose dependent manner. The inhibition of oxidative stress in brain and serum enzymes and metabolites by the dye could be attributed to its high total phenol content and antioxidant activity as typified by its reducing power, free-radical scavenging ability, Fe(II) chelating ability and inhibition of lipid peroxidation. Therefore, dietary inclusion of the yellow dye from root of Brimstone tree could prevent cyclophosphamide-induced oxidative stress in brain and the associated toxicity to the liver.

Inhibition of Cyclophosphamide-Induced Oxidative Stress in Brain by Dietary Inclusion of Red Dye Extracts from Sorghum (Sorghum bicolor) Stem

The stem of sorghum is used as color additives in cooking meals and taken as beverages when steeped or boiled in water as folklore for the management of anemia and some other diseases. This study sought to assess the antioxidant and neuroprotective potentials of red dye extract from sorghum stem on cyclophosphamide-induced oxidative stress in rat brain. Wistar strain albino rats were fed diet supplemented with the red dye (0.5% and 1.0% inclusion) for 14 days. There was no significant difference (P > .05) in average feed intake and weight gain of rats fed the basal diet and the red dye-supplemented diet. However, intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) 24 hours prior the termination of the experiment caused a significant (P < .05) increase in the brain malondialdehyde (MDA) content and serum activities of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in those rats fed diet without the dye supplement, whereas there was a significant decrease (P < .05) in brain MDA content and serum enzyme activities in rats fed diet with the dye in a concentration-dependent manner. The protective effect of the red dye against cyclophosphamide-induced oxidative stress could be attributed to the high phenolic content (56.2%) and antioxidant activities of the red dye as typified by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging ability, reducing properties, and Fe(2+) chelating ability. Therefore, dietary inclusion of the red dye from sorghum stem could be harnessed in the management of neurodegenerative diseases associated with oxidative stress.

Inhibition of cyclophosphamide-induced oxidative stress in rat brain by polar and non-polar extracts of Annatto ( Bixa orellana) seeds

Annatto ( Bixa orellana) seeds are widely distributed throughout the Tropics and have been used to provide both colour and flavour to food. This study sought to assess the ability of dietary inclusion of polar (water) and non-polar (chloroform) extracts of Annatto ( B. orellana) seeds on cyclophosphamide-induced oxidative stress in rat brain. The total phenol content and antioxidant activities of polar (water) and non-polar (chloroform) extracts of Annatto seeds were determined in vitro and in vivo. The results of the study showed that intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) caused a significant increase ( P<0.05) in the malondialdehyde (MDA) content of the brain; however, dietary inclusion of Annatto seed extracts (0.1% and 0.2%) caused dose-dependent significant decrease ( P<0.05) in the MDA content of the brain. Likewise, the extracts also caused dose-dependent inhibition of the elevated serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin. However, the non-polar extract had significantly higher inhibitory effects on the elevated MDA production in brain and serum liver function markers. This higher protective effect of the non-polar extract could be attributed to its higher antioxidant properties as typified by its significantly higher ( P<0.05) reducing power, free-radical scavenging and Fe (II) chelating ability. Therefore, dietary inclusion of Annato seed extracts as food colourant could prevent oxidative stress occasioned by cyclophosphamide administration, but the non-polar extract is a better protectant.

Cyclophosphamide-induced oxidative stress in brain: Protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum)

This study sought to characterize the distribution of phenols and antioxidant activities in hot short pepper (Capsicum frutescens var. abbreviatum) and their inhibition of cyclophosphamide-induced oxidative stress in rat's brain. The total phenol content and antioxidant activities of pepper flesh (pericarp) and seeds were determined in vitro and in vivo. The results of the study revealed that intraperitoneal administration of cyclophosphamide (75mg/kg of body weight) caused a significant increase (P<0.05) in the malondialdehyde (MDA) content of the brain; however, there was a significant decrease (P<0.05) in the brain MDA content, in those of rats fed diet containing pepper; the flesh showed a higher inhibitory effect. In addition, dietary inclusion of the pepper (seed and flesh) also caused a dose-dependent inhibition of serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin; likewise, dietary inclusion of the flesh inhibited MDA production than the seeds. The higher inhibition of oxidative stress in brain and serum enzymes and metabolites by the flesh could be attributed to its significantly higher (P<0.05) total phenol content, reducing power and free-radical scavenging ability. Therefore, dietary hot short pepper (Capsicum frutescens L. var. abbreviatum) could prevent cyclophosphamide-induced oxidative stress in brain; although the flesh is a better protectant, the possible contributory role of the seeds cannot be neglected. However, this protective effect of the pepper could be attributed to their antioxidant properties.

EFFICACY OF LL-37 AND GRANULOCYTE COLONY-STIMULATING FACTOR IN A NEUTROPENIC MURINE SEPSIS DUE TO PSEUDOMONAS AERUGINOSA

A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.

Tachyplesin III and granulocyte-colony stimulating factor enhance the efficacy of tazobactam/piperacillin in a neutropenic mouse model of polymicrobial peritonitis

We investigated the efficacy of tazobactam/piperacillin (TZP), tachyplesin III and granulocyte-colony stimulating factor (G-CSF) in an experimental murine neutropenic intraabdominal infection. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days −4 and −2 pre-infection. Septic shock was induced by cecal ligation and puncture . Animals received intravenously isotonic sodium chloride solution (control group C 1), 1 mg/kg of tachyplesin III, 120 mg/kg of TZP, 0.1 mg/kg of G-CSF, tachyplesin III plus TZP, G-CSF plus TZP and finally tachyplesin III plus G-CSF plus TZP, respectively. Lethality, bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes, endotoxin, IL-6 and TNF-alpha concentrations in plasma were evaluated. All compounds reduced the lethality when compared to controls. Endotoxin and cytokine plasma levels were significantly higher in TZP-treated animals compared to tachyplesin III-treated animals. Finally, all drug combinations showed to be the most effective treatment in reducing all variables measured. Interestingly, the strongest results concerning the bacterial growth inhibition, lethality and endotoxemia were obtained when the three compounds were contemporaneously administered. The presence of their positive interaction makes tachyplesin III and G-CSF potentially valuable as an adjuvant for antimicrobial chemotherapy of sepsis.

Up-regulation of galanin and corticotropin-releasing hormone mRNAs in the key hypothalamic and amygdaloid nuclei in a mouse model of visceral pain

Cyclophosphamide (CP)-induced cystitis is often used as an animal model of visceral pain. Various neuropeptides in the hypothalamic and amygdaloid nuclei are implicated in pain-induced responses. However, little information is available regarding the regulation of the neuropeptides in response to visceral pain. In the present study, we examined the effects of CP-induced cystitis on the levels of mRNAs encoding galanin, corticotropin-releasing hormone (CRH), substance P, and enkephalins in the hypothalamic and limbic nuclei using in situ hybridization histochemistry in mouse. Galanin mRNA levels in CP-treated group increased significantly in the arcuate nucleus and the paraventricular nucleus (PVN) but not in the medial preoptic area after the intraperitoneal administration of CP (200 mg/kg body weight) in comparison to those in saline-treated group. CRH mRNA levels in CP-treated group also increased significantly in the central amygdala as well as the PVN after the CP administration. In contrast, CP-induced cystitis failed to upregulate the preprotachykinin-A and preproenkephalin genes which encode substance P and enkephalins, respectively in the hypothalamic and limbic nuclei at any of the time points examined. These results suggest that visceral nociception may upregulate both galanin and CRH gene expression in the hypothalamic and limbic nuclei.