A Comparative GC/MS Analysis of Citrus Essential Oils: Unveiling the Potential Benefits of Herb-Drug Interactions in Preventing Paracetamol-Induced Hepatotoxicity.

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 µM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively.

Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.

Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 µg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 µM Trolox eq/mL juice, 718.95-3749.47 µM Trolox eq/mL juice, and 2304.74-4390.32 µM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.

In vivo antidiabetic potential of standardized Gymnocarpos decandrus Forssk. Extract.

BACKGROUND: Gymnocarpos decandrus (Caryophyllaceae) is a well-known wild plant used as a food for grazing animals. Recently it showed potent antidiabetic potential beside its established anti-inflammatory, analgesic and diuretic activities. G. decandrus antidiabetic potential was reported through in-vitro models and resulted in promising α-amylase, α-glucosidase and antiviral Coxsackie B4 inhibitory activities; however no in-vivo studies were conducted. PURPOSE: This study aims to examine Gymnocarpos decandrus ethanol extract (GDEE) safety and to evaluate its in vivo antidiabetic potential. METHOD: Adult albino rats were injected intraperitoneally with alloxan to induce diabetes mellitus and the glucose level was measured after two and four weeks against metformin as a standard drug. Additionally, GDEE characterization and standardization were carried out. RESULTS: GDEE LD50 was up to 5.8 mg/kg and exhibited significant antidiabetic activity 77.17% comparable to the standard drug metformin. Its total phenolics, and flavonoids amounted 127.2 ± 0.23 and 85.5 ± 0.21 mg/g respectively. Vitexin was used as a marker compound for GDEE (140.70 mg/100 gm). CONCLUSION: This study represents the sole in vivo scientific validation of G. decandrus recently documented in vitro antidiabetic potential.

Alginate, gelatin, and carboxymethyl cellulose coated nonwoven fabrics containing antimicrobial AgNPs for skin wound healing in rats.

Nonwoven fabrics containing silver nanoparticles (AgNPs) are widely utilized to assist management of infected wounds and those at risk of infection. However, such materials have varied responses due to their chemical nature. Herein we investigated the correlation between the concentration of AgNPs taken up by nonwoven viscose material and antibacterial activity in a simulated wound fluid model against two bacterial models (i.e., Escherichia coli and Staphylococcus aureus). Thereafter, the developed nonwoven viscose containing AgNPs were independently coated with two polyacid carbohydrate polymers (i.e., carboxymethyl chitosan (CMCs), alginate (ALG)), and gelatin (GEL) protein in order to study their influence on the physical and biological attributes in vitro and in vivo. Intensive characterizations were utilized to monitor the physicochemical features of the developed nonwoven viscose. The results demonstrated that higher concentrations of AgNPs were taken up by viscose fabric whilewhile increasing AgNPs in the colloidal solution during padding process. Overall, the treated nonwoven fabric with and without polymers' coatings showed remarkable antibacterial activity against two bacterial models in vitro. As well as they achieved high and speed wound recovery in rats which was almost similar to commercial dermazin treatment. Therefore, it validates excellent nonwoven dressing clinically relevant to the wound type and condition.

Anticholinesterase activity and metabolite profiling of Syagrus romanzoffiana (Cham.) Glassman leaves and fruits via UPLC-QTOF-PDA-MS.

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of Syagrus romanzoffiana (Cham.) Glassman via UPLC-QTOF-PDA-MS and to evaluate their anticholinesterase activities in a model of Alzheimer disease. The current study has identified 39 metabolites belonging to various chemical classes (i.e. flavonols, phenolic acids, fatty acids, stilbenoids and lignans). While the fatty acids predominated in both leaves and fruits, the stilbenoids were more predominant in leaves. Their neuroprotective effect was comparable to Aricept; the standard drug used in treatment of Alzheimer disease. Both extracts significantly decreased the acetylcholinesterase activity and improved the histopathological changes in the cerebral cortex and cerebellum of rat model of aluminium chloride-induced Alzheimer disease. In light of the current study, Syagrus romanzoffiana (Cham.) Glassman is recommended as promising candidate for palliative treatment in Alzheimer disease through inhibition of the acetylcholinesterase activity.

The effect of low dose amphetamine in rotenone-induced toxicity in a mice model of Parkinson's disease.

OBJECTIVES: The effects of low dose amphetamine on oxidative stress and rotenone-induced neurotoxicity and liver injury were examined in vivo in a mice model of Parkinson's disease. MATERIALS AND METHODS: Male mice were treated with rotenone (1.5 mg/kg, every other day for two weeks, subcutaneously). Mice received either the vehicle or amphetamine intraperitoneally at doses of 0.5, 1.0, or 2.0 mg/kg. Oxidative stress was assessed by measurement of the lipid peroxidation product malondialdehyde (MDA), nitric oxide (NO), total anti-oxidant capacity (TAC), and paraoxonase-1 (PON-1) activity in the brain and liver. In addition, brain concentrations of nuclear factor kappa B (NF-κB) and tyrosine hydroxylase were determined and histopathology and Bax/Bcl-2 immunohistochemistry were performed. RESULTS: The levels of lipid peroxidation and NO were increased and TAC and PON-1 were decreased significantly compared with vehicle-injected control mice. There were also significantly increased NF-κB and decreased tyrosine hydroxylase in the brain following rotenone administration. These changes were significantly attenuated by amphetamine. Rotenone caused neurodegenerative changes in the substantia nigra, cerebral cortex, and hippocampus. The liver showed degenerative changes in hepatocytes and infiltration of Kupffer cells. Bax/Bcl2 ratio was significantly increased in brain and liver tissues. Amphetamine prevented these histopathological changes and the increase in apoptosis evoked by rotenone. CONCLUSION: These results suggest that low dose amphetamine exerts anti-oxidant and anti-apoptotic effects, protects against rotenone-induced neurodegeneration, and could prevent neuronal cell degeneration in Parkinson's disease.

Correction to: Capsaicin Exerts Anti-convulsant and Neuroprotective Effects in Pentylenetetrazole-Induced Seizures.

The original version of this article unfortunately contains an error in the Y axis units in Fig. 1b, c (the symbol µ is not clear: µmol/g.tissue). This has been corrected by publishing this erratum.

Capsaicin Exerts Anti-convulsant and Neuroprotective Effects in Pentylenetetrazole-Induced Seizures.

The transient receptor potential vanilloid-1 (TRPV1) receptor has been implicated in the development of epileptic seizures. We examined the effect of the TRPV1 agonist capsaicin on epileptic seizures, neuronal injury and oxidative stress in a model of status epilepticus induced in the rat by intraperitoneal (i.p.) injections of pentylenetetrazole (PTZ). Capsaicin was i.p. given at 1 or 2 mg/kg, 30 min before the first PTZ injection. Other groups were i.p. treated with the vehicle or the anti-epileptic drug phenytoin (30 mg/kg) alone or co-administered with capsaicin at 2 mg/kg. Brain levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1) activity, seizure scores, latency time and PTZ dose required to reach status epilepticus were determined. Histopathological assessment of neuronal damage was done. Results showed that brain MDA decreased by treatment with capsaicin, phenytoin or capsaicin/phenytoin. Nitric oxide decreased by capsaicin or capsaicin/phenytoin. GSH and PON-1 activity increased after capsaicin, phenytoin or capsaicin/phenytoin. Mean total seizure score decreased by 48.8% and 66.3% by capsaicin compared with 78.7% for phenytoin and 69.8% for capsaicin/phenytoin treatment. Only phenytoin increased the latency (115.7%) and threshold dose of PTZ (78.3%). Capsaicin did not decrease the anti-convulsive effect of phenytoin but prevented the phenytoin-induced increase in latency time and threshold dose. Neuronal damage decreased by phenytoin or capsaicin at 2 mg/kg but almost completely prevented by capsaicin/phenytoin. Thus in this model of status epilepticus, capsaicin decreased brain oxidative stress, the severity of seizures and neuronal injury and its co-administration with phenytoin afforded neuronal protection.

Efficient wound healing composite hydrogel using Egyptian Avena sativa L. polysaccharide containing ß-glucan.

The purpose of this study was to develop an efficient wound healing PVA-biopolymer composite hydrogel using the polysaccharide derived from Egyptian Avena sativa L. The prepared polysaccharide showed high ß-glucan content which accelerates wound healing. The ß-glucan content was 13.28% and GC analysis revealed that glucose was the major sugar component (71.19%). Different PVA-polysaccharide hydrogels combined with different polymers and loaded with 0.3% bacitracin zinc were developed using the freezing-thawing method. The used polymers were; polyvinylpyrrolidone (PVP), Carbopol 940 (CP), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), and sodium carboxymethylcellulose (Na CMC). The prepared hydrogels were characterized by determination of gel fraction, swelling ratio, mechanical and bioadhesive properties. The results revealed that hydrogels prepared using anionic (NaCMC and CP) and more hydrophilic (HEC) polymers showed better swelling ratio, bioadhesive and mechanical characters compared with hydrogels prepared using cationic (PVP) or less hydrophilic (HPMC) polymers. For two selected formulations containing HEC (F7) and NaCMC (F9), disk diffusion method and In vitro microbial penetration were performed for microbiological assessment. In addition, In vivo evaluation of the anti-inflammatory and wound healing activity compared with conventional products were performed on rats. The results showed higher anti-inflammatory activity of F7 (21.4% edema reduction) compared with F9 (19.8% edema reduction). Similarly, F7 showed better healing (99% relative wound size reduction) than F9 (75%). The current study revealed the potential of using the prepared Egyptian Avena sativa L. polysaccharide and HEC for development of an efficient wound healing dressing with antimicrobial and anti-inflammatory activities.

Nutritional and biological evaluation of Phoenix canariensis pollen grains

ABSTRACT The nutritional value of pollens of Phoenix canariensis Chabaud, Arecaceae, was evaluated. HPLC analysis of vitamins revealed the predominant presence of vitamin C (109.13 ppm), followed by vitamin A (53.71 ppm) and vitamin E (40.60 ppm) and the total carbohydrates (28.12%), proteins (17.10%). In addition, 16 amino acids of which nine are essential (75.07%), and seven are non-essential (24.93%) were determined. On the other hand, two steroidal saponins (dioscin and methyl protodioscin) were isolated from the pollens, their structures were elucidated by spectroscopic techniques, including 1H NMR and 13C NMR. Their content in the 70% ethanolic extract was quantified using reversed phase HPLC and found to be 0.013% and 19.35%, respectively. The modulatory effect of the isolated compounds on the prevention of benign prostatic hyperplasia induced in rats and their moderate curative effect on stressed testicular tissue were studied. Being a good source of carbohydrates, proteins, vitamins, and amino acids pollens of P. canariensis can be used as a promising source of dietary supplement. Meanwhile pollens can act as prophylactic agent against benign prostatic hyperplasia.

Design, Synthesis and In-vivo Anti-inflammatory Activity of New Celecoxib Analogues as NSAID.

BACKGROUND: A new series of Celecoxib analogues were easily synthesized via reactions of 4-(2-(1-chloro-2-oxopropylidene)hydrazinyl)benzene sulfonamide (1) with active methylene compounds and dialkyl malonate. In addition, compound 1 was reacted also with thiourea derivatives and thiosemicarbazone derivatives to afford thiazole derivatives 9 and 11, respectively. Furthermore, triazolo pyrimidine derivatives 13 were prepared via reaction of compound 1 with pyrimidine thione derivatives. The structures of the new synthesized compounds were assigned by elemental analysis and spectroscopic data. The new analogues were screened for their in vivo anti-inflammatory activity using carrageenan-induced paw edema method. CONCLUSION: They showed moderate to good in vivo anti-inflammatory effects. Compounds 1, 6 and 11b were the most active compounds that reduced the paw edema induced by carrageenan by 12.25 %, 12.96 % and 12.97% respectively, as compared to the Indomethacin that inhibited the oedema volume by 7.47 %.

Protection by Neostigmine and Atropine Against Brain and Liver Injury Induced by Acute Malathion Exposure.

We examined the effect of treatment with neostigmine alone or with atropine on brain oxidative stress and on brain and liver tissue damage following acute malathion toxicity. Rats were intraperitoneally treated with malathion 150 mg/kg along with neostigmine (200 or 400 µg/kg) or neostigmine (200 µg/kg) + atropine (1 mg/kg) and euthanized 4 h later. Results indicated that compared with the saline group, malathion resulted in (i) higher brain malondialdehyde (MDA) and nitric oxide (46.4% and 86.2%); (ii) decreased brain reduced glutathione (GSH) (67.6%); (iii) decreased brain paraoxonase-1 (PON1), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities (31.2%, 21.6% and 60%); (iv) decreased brain glucose (-38.1%); (v) neuronal degeneration in cortex and hippocampus and markedly increased glial fibrillary acidic protein (GFAP) immunostaining in the hippocampus; (v) hydropic and fatty degeneration in liver. Rats treated with malathion along with neostigmine or neostigmine + atropine showed no change in brain MDA but decreased nitric oxide (-34.2%-48%). GSH increased after neostigmine 200 µg/kg or neostigmine + atropine (35.8% and 41%). PON1 activity increased (42%-35.2%) and glucose concentrations increased (91.5%-81.5%) by 400 µg/kg neostigmine or neostigmine + atropine. Brain AChE activity remained unchanged but BChE activity showed 18.3% increment after 400 µg/kg neostigmine. Rats treated with 400 µg/kg neostigmine or neostigmine + atropine had normal neuronal appearance in cortex and hippocampus and weak GFAP expression in hippocampus. Liver damage was prevented by neostigmine + atropine. These results suggest that treatment with neostigmine + atropine afforded protection against the deleterious effects of acute malathion on the brain and liver.

Nitric oxide synthase inhibitors protect against brain and liver damage caused by acute malathion intoxication.

OBJECTIVE: To investigate the effect of NG-nitro-l-arginine methyl ester (l-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, and 7-nitroindazole (7-NI), a selective neuronal NOS inhibitor, on oxidative stress and tissue damage in brain and liver and on DNA damage of peripheral blood lymphocytes in malathion intoxicated rats. METHODS: Malathion (150 mg/kg) was given intraperitoneally (i.p.) along with l-NAME or 7-NI (10 or 20 mg/kg, i.p.) and rats were euthanized 4 h later. The lipid peroxidation product malondialdehyde (MDA), nitric oxide (nitrite), reduced glutathione (GSH) concentrations and paraoxonase-1 (PON-1) activity were measured in both brain and liver. Moreover, the activities of glutathione peroxidase (GPx) acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), total antioxidant capacity (TAC), glucose concentrations were determined in brain. Liver enzyme determination, Comet assay, histopathological examination of brain and liver sections and inducible nitric oxide synthase (iNOS) immunohistochemistry were also performed. RESULTS: (i) Rats treated with only malathion exhibited increased nitric oxide and lipid peroxidation (malondialdehyde) accompanied with a decrease in GSH content, and PON-1 activity in brain and liver. Glutathione peroxidase activity, TAC, glucose concentrations, AChE and BChE activities were decreased in brain. There were also raised liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and increased DNA damage of peripheral blood lymphocytes (Comet assay). Malathion caused marked histopathological changes and increased the expression of iNOS in brain and liver tissues. (ii) In brain of malathion-intoxicated rats, l-NAME or 7-NI resulted in decreased nitrite and MDA contents while increasing TAC and PON1 activity. Reduced GSH and GPx activity showed an increase by l-NAME. AChE activity increased by 20 mg/kg l-NAME and 10 mg/kg 7-NI. AChE activity decreased by the higher dose of 7-NI while either dose of 7-NI resulted in decreased BChE activity. (iii) In liver of malathion-intoxicated rats, decreased MDA content was observed after l-NAME or 7-NI. Nitrite level was unchanged by l-NAME but increased after 7-NI which also resulted in decreased GSH concentration and PON1 activity. Either inhibitor resulted in decreased liver ALT activity. (iv) DNA damage of peripheral blood lymphocytes was markedly inhibited by l-NAME or 7-NI treatment. (v) iNOS expression in brain and liver decreased by l-NAME or 7-NI. (vi) More marked improvement of the histopathological alterations induced by malathion in brain and liver was observed after 7-NI compared with l-NAME. CONCLUSIONS: In malathion intoxicated rats, the neuronal NOS inhibitor 7-NI and to much less extent l-NAME were able to protect the brain and liver tissue integrity along with improvement in oxidative stress parameters. The decrease in DNA damage of peripheral blood lymphocytes by NOS inhibitors also suggests the involvement of nitric oxide in this process.

Comparative chemical and biological studies of leaves and pollens of Phoenix canariensis hort. ex Chabaud.

AIM: Phoenix canariensis hort. ex Chabaud is one of the most important palm plants. In spite of that, it has not been extensively investigated from a phytochemical or a biological perspective. MATERIALS & METHODS: Air-dried powdered leaves and pollen grains of the plant were extracted using 70% ethanol. The residues were fractionated with different solvents of increasing polarity. Antioxidant, anti-inflammatory, hepatoprotective, anti-hyperglycemic activities were determined using adult male albino rats of wistar strain. RESULTS: Phytochemical investigation of Phoenix canariensis (Arecaceae) leaves and pollens led to the isolation of five compounds; isorhamnetin-3-O-ß-glucoside and isorhamnetin 7-O-rutinoside from the leaves in addition to isorhamnetin-3-O-rutinoside and rutin together with ß sitosterol-3-O-ß-D-glucoside from pollens. The 70% ethanolic extracts of both organs were found to possess the highest antioxidant activity followed by their ethyl acetate fractions. Seventy percent ethanolic leaf extract and its ethyl acetate fraction showed the most potent hepatoprotective, anti-inflammatory and anti-hyperglycemic activities as compared with reference drugs. Isorhamnetin-7-O-rutinoside and ß-sitosterol-3-O-ß-D-glucoside were isolated from the genus and from Phoenix canariensis for the first time. CONCLUSION: This study reveals that Phoenix canariensis is an efficient natural source of safe antioxidants, anti-hyperglycemic, anti-inflammatory and hepatoprotective agents.

Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication.

OBJECTIVE: To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. METHODS: Rats were received intraperitoneal (i.p.) injection of malathion 150 mg/kg along with citric acid (200 or 400 mg/kg, orally), atropine (1 mg/kg, i.p.) or citric acid 200 mg/kg + atropine 1 mg/kg and euthanized 4 h later. RESULTS: Malathion resulted in increased lipid peroxidation (malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase (GPx) activity, total antioxidant capacity (TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase (AChE) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase (iNOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain AChE increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and iNOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, AChE and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and iNOS expression in brain and liver. CONCLUSIONS: The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure.

Acetylcholinesterase, butyrylcholinesterase and paraoxonase 1 activities in rats treated with cannabis, tramadol or both.

OBJECTIVE: To investigate the effect of Cannabis sativa resin and/or tramadol, two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents. METHODS: Rats were treated with cannabis resin (5, 10 or 20 mg/kg) (equivalent to the active constituent Δ9-tetrahydrocannabinol), tramadol (5, 10 and 20 mg/kg) or tramadol (10 mg/kg) combined with cannabis resin (5, 10 and 20 mg/kg) subcutaneously daily for 6 weeks. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in brain and serum. We also measured the activity of paraoxonase-1 (PON1) in serum of rats treated with these agents. RESULTS: (i) AChE activity in brain increased after 10-20 mg/kg cannabis resin (by 16.3-36.5%). AChE activity in brain did not change after treatment with 5-20 mg/kg tramadol. The administration of both cannabis resin (5, 10 or 20 mg/kg) and tramadol (10 mg/kg) resulted in decreased brain AChE activity by 14.1%, 12.9% and 13.6%, respectively; (ii) BChE activity in serum was markedly and dose-dependently inhibited by cannabis resin (by 60.9-76.9%). BChE activity also decreased by 17.6-36.5% by 10-20 mg/kg tramadol and by 57.2-63.9% by the cannabis resin/tramadol combined treatment; (iii) Cannabis resin at doses of 20 mg/kg increased serum PON1 activity by 25.7%. In contrast, tramadol given at 5, 10 and 20 mg/kg resulted in a dose-dependent decrease in serum PON1 activity by 19%, 36.7%, and 46.1%, respectively. Meanwhile, treatment with cannabis resin plus tramadol resulted in 40.2%, 35.8%, 30.7% inhibition of PON1 activity compared to the saline group. CONCLUSIONS: These data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users.

Citric acid effects on brain and liver oxidative stress in lipopolysaccharide-treated mice.

Citric acid is a weak organic acid found in the greatest amounts in citrus fruits. This study examined the effect of citric acid on endotoxin-induced oxidative stress of the brain and liver. Mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 200 µg/kg). Citric acid was given orally at 1, 2, or 4 g/kg at time of endotoxin injection and mice were euthanized 4 h later. LPS induced oxidative stress in the brain and liver tissue, resulting in marked increase in lipid peroxidation (malondialdehyde [MDA]) and nitrite, while significantly decreasing reduced glutathione, glutathione peroxidase (GPx), and paraoxonase 1 (PON1) activity. Tumor necrosis factor-alpha (TNF-α) showed a pronounced increase in brain tissue after endotoxin injection. The administration of citric acid (1-2 g/kg) attenuated LPS-induced elevations in brain MDA, nitrite, TNF-α, GPx, and PON1 activity. In the liver, nitrite was decreased by 1 g/kg citric acid. GPx activity was increased, while PON1 activity was decreased by citric acid. The LPS-induced liver injury, DNA fragmentation, serum transaminase elevations, caspase-3, and inducible nitric oxide synthase expression were attenuated by 1-2 g/kg citric acid. DNA fragmentation, however, increased after 4 g/kg citric acid. Thus in this model of systemic inflammation, citric acid (1-2 g/kg) decreased brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation.

Effects of afferent and efferent denervation of vagal nerve on endotoxin-induced oxidative stress in rats.

This study investigated the role of vagal innervation in oxidative stress after systemic administration of lipopolysaccharide (LPS) endotoxin. Control rats and rats subjected to bilateral subdiaphragmatic vagotomy, perivagal capsaicin application (5 mg/ml) or cholinergic receptor blockade with subcutaneous atropine (1 mg/kg), were intraperitoneally injected with 300 µg/kg of LPS and euthanized 4 h later. Results indicated that; (1) surgical vagotomy and sensory denervation by perivagal capsaicin increased brain oxidative stress and decreased reduced glutathione in basal condition (saline-treated rats) and following endotoxin challenge; (2) oxidative stress decreased after cholinergic blockade with atropine in endotoxemic rats; (3) nitric oxide decreased by abdominal vagotomy, sensory deafferentation and cholinergic blockade after endotoxin injection; (4) liver lipid peroxidation decreased after surgical vagotomy and cholinergic blockade but increased after sensory deafferentation; (5) liver reduced glutathione decreased following vagotomy and sensory denervation in basal state and by cholinergic blockade in basal state and during endotoxemia; (6) nitric oxide increased by vagotomy in basal state and by sensory denervation and cholinergic blockade in basal state and during endotoxemia; (7) liver histological damage increased by subdiaphragmatic vagotomy, sensory denervation or cholinergic blockade. These findings suggest that: (1) sensory fibers (signals from the periphery) running in the vagus nerves are important in maintaining the redox status of the brain; (2) capsaicin vagal sensory nerves are likely to maintain nitric oxide tone in basal conditions; (3) the vagus nerve modulates liver redox status and nitric oxide release, (4) the vagus nerve mediates protective role in the liver with both cholinergic and capsaicin-sensitive mechanisms being involved.

Flavonoid glycosides and pharmacological activity of Amphilophium paniculatum.

BACKGROUND: Nothing is reported on Amphilophium paniculatum (L.) Kunth. This study aimed at investigation of chemical constituents of the leaves of Amphilophium paniculatum, grown in Egypt, in addition to pharmacological evaluation. MATERIALS AND METHODS: Isolation of a new compound, along with 5 known flavonoids. Pharmacological activities were carried out on different extracts of A. paniculatum leaves. RESULTS: Identification of a new flavone glycoside, acacetin 8-C-ß-D- glucopyranosy l-(1→2)-α-L-rhamnopyranoside (1) in addition to 5 known flavonoids. The 70% ethanol crud extract and its successive chloroform, ethyl acetate, and 100% ethanol extracts showed significant anti-inflammatoryactivity,analgesic effect, antipyretic activity, antioxidant activity, and anti-hyperglycemic activity. Determination of the median lethal dose (LD50) revealed that the different extracts were safe.

Brain and liver oxidative stress after sertraline and haloperidol treatment in mice.

BACKGROUND: Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal side effects. Sertraline is an antidepressant drug which has been reported to cause extrapyramidal symptoms. We aimed to see whether treatment with sertraline would worsen the effect of haloperidol on oxidative stress in the brains of mice. METHODS: Sertraline (10 or 20 mg/kg), haloperidol (2 mg/kg), haloperidol combined with sertraline or saline was administered daily via the subcutaneous route and mice were euthanized 10 days later when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (nitrite) levels, total antioxidant capacity (TAC), acetylcholinesterase (AChE), catalase and paraoxonase 1 (PON1) activities were determined in the brain and liver. RESULTS: Sertraline monotherapy did not alter GSH, MDA, TAC or nitrite in the brain. Haloperidol decreased GSH and TAC and increased MDA and nitrite. The combined treatment with sertraline and haloperidol resulted in increased MDA, but to a lesser extent than haloperidol monotherapy. A significant increase in GSH and TAC and decreased nitrite was observed after the combination treatment was compared with haloperidol monotherapy. Catalase activity decreased with sertraline or haloperidol treatment. PON1 activity decreased with sertraline and haloperidol monotherapy and showed a further decrease with the combination therapy compared with haloperidol monotherapy. AChE activity decreased after haloperidol and increased with the combination treatment compared with haloperidol monotherapy. In the liver, GSH was unaltered after sertraline, haloperidol or their combination. MDA increased with sertraline, haloperidol and their combination. TAC decreased after combination therapy. Nitric oxide increased after sertraline, haloperidol or their combination. PON1 activity decreased with sertraline, haloperidol and with sertraline-haloperidol co-treatment. CONCLUSIONS: Sertraline did not worsen brain oxidative stress-induced with haloperidol, however, liver peroxidation increased. Sertraline decreased catalase and PON1 activity which might expose the brain to further oxidative insults.