The ameliorating effects of selenium and vitamin C against fenitrothion-induced blood toxicity in Wistar rats

Fenitrothion is widely used organophosphate pesticide in agriculture and health programs, but besides, it causes several toxic effects. The present study was designed to evaluate the possible protective effects of selenium (0.5 mg/kg b.w.) and vitamin C (100 mg/kg b.w) on altered haematological, biochemical and oxidative stress parameters in the blood of rats orally treated with fenitrothion (20 mg/kg b.w) for 30 days. Fenitrothion caused changes in body weight, food and water intake, and some haematological and biochemical parameters. Fenitrothion altered the glutathione redox status (GSH and GSSG) and decreased activity of antioxidant enzymes (GSH-Px, GST, SOD and CAT), leading to a lipid peroxidation. Selenium and vitamin C, by improving the activity of antioxidants, reduced oxidative stress and a lipid peroxidation, maintaining the values of examined parameters to optimal levels. Therefore, selenium and vitamin C could be useful in providing protection of exposed non-target organisms including people from fenitrothion.     

Variation in plasma cholinesterase activity in the clay-colored robin (<Emphasis Type="Italic">Turdus grayi</Emphasis>) in relation to time of day,season, and diazinon exposure

Cholinesterase (ChE) activity in birds is subject to interspecific and intraspecific species variations. Factors that influence enzyme activity have to be taken into account in order to obtain an accurate estimation of cholinesterase inhibition due to pesticide exposure in wild birds. This study evaluates variation of plasma cholinesterase activity in clay-colored robin (Turdus grayi) in relation to time of day, season, and exposure to diazinon. Other variables that can affect cholinesterase activity such as weight are also taken into account. The birds were marked, weighed and sexed using the cloacal technique. One dose of commercial diazinon mixed with papaya was fed to each bird at concentrations of 0.0, 0.5, 1.5 and 3.0 mg/kg ai. The results showed differences in ChE activity between seasons (t = −3.07, P < 0.05). Also, diurnal plasma cholinesterase variations were observed (20% in 2 h). The highest inhibition values were 73% for birds dosed with 1.5 mg/kg ai. Our study provides field and laboratory data on variation of ChE activity in a tropical bird species. Knowledge of the variation of ChE in the clay-colored robin will enable us to use this species as an indicator of exposure to ChE inhibiting pesticides in tropical agroecosystems.     

Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the α7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague–Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25 mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the α7* nicotinic receptor methyllycaconitine (MLA; 1–4 mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6 mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10 mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.     

Oxidative stress, protein carbonylation and heat shock proteins in the black tiger shrimp, Penaeus monodon, following exposure to endosulfan and deltamethrin

The impact of commonly used pesticides, endosulfan and deltamethrin, on the molecular stress level in black tiger shrimp Penaeus monodon, was assessed using classical oxidative stress biomarkers, protein carbonylation profiles, and levels of heat shock proteins. Results showed that 4 days exposure to 0.1 μg L⁻¹ deltamethrin significantly (p < 0.05) increased lipid peroxidation (LPO) level in gills (64.3 ± 3.2 compared to 34.2 ± 5.3 nmol MDA equiv. g⁻¹ tissue at day 0). However, no pesticide treatment had significant effect on the activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). Carbonylated protein profiles were determined on gills following 2,4-dinitrophenylhydrazine derivatization and 2D-PAGE along with Western blotting. Immunoblotting with dinitrophenol-specific antibody revealed 17 protein spots carbonylated in response to 4 days exposure to 0.1 μg L⁻¹ deltamethrin while 24 protein spots specifically oxidized at day 0 were no longer detected after deltamethrin treatment. On the other hand, endosulfan exposure at 0.1 and 1 μg L⁻¹ induced up to 2.1-fold increase of HSP90 level in muscle. This approach is providing new insights into the molecular impacts of deltamethrin and endosulfan on an economically important crustacean. While deltamethrin has shown a pro-oxidant effect in gills, endosulfan exposure rather induced proteotoxic effects in muscles. This argues that LPO level, protein carbonylation specificities, and HSP90 levels may be potential discriminating biomarkers to assess the chemical stress level in farm shrimp.     

Deltamethrin-induced genotoxicity and testicular injury in rats: Comparison with biopesticide

Deltamethrin is a synthetic pyrethroid insecticide used extensively in pest control. Aim of the current study was to investigate the ability of deltamethrin-based commercial formulation to induce genotoxicity and testicular injury in rats in comparison to the use of the biopesticide; Bacillus thuringiensis. Rats were divided into three groups: Group I (DEL) received deltamethrin, 5 mg/kg b.w./day orally, in corn oil. Group II (Biopesticide, B. thuringiensis) received oral suspension of the biopesticide at daily dose of 8400 mg/kg b.w./day. Group III (Control) received appropriate volume of corn oil. After 4 weeks, deltamethrin-treated rats showed decreased serum testosterone, luteinizing and follicle-stimulating hormone levels. Testicular total oxidant capacity (TOC), poly (ADP-ribose) polymerase (PARP), lactate dehydrogenase (LDH) and DNA damage were significantly increased. Significant increase in bone marrow chromosomal aberrations, induced by deltamethrin, including chromatid breaks, deletions, fragments and gaps was also observed. RT-PCR demonstrated significant up-regulation in testicular mRNA for glutathione-s-transferase and heat-shock protein-70 (HSP-70) whereas steroidogenic acute regulatory (StAR) mRNA was down-regulated after deltamethrin exposure. Oral administration of the biopesticide, under the condition of our study, was found to be safe when compared to the deleterious effect of deltamethrin in rats.     

Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin

HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT + INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT + INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n = 6 in each group) were administered AZT alone (50 mg/kg b.w.), INH alone (25 mg/kg, b.w.), AZT + INH (50 mg/kg, b.w. and 25 mg/kg, b.w.), SBN alone (100 mg/kg, b.w.) and SBN + AZT + INH daily for sub-chronic period of 45 days orally. The control rats received saline/propylene glycol. INH alone and AZT + INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT + INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT + INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of phosphatidylcholines and studies are warranted on these lines to improve the therapeutic efficiency of SBN.     

Differential effects of pyrethroid insecticides on extracellular dopamine in the striatum of freely moving rats

In order to obtain a more complete understanding of pyrethroid neurotoxicity, effects of the pyrethroid insecticides, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II) on extracellular levels of dopamine (DA) and its metabolites in the striatum of conscious rats were studied by in vivo microdialysis. Rats were treated i.p. with pyrethroids or vehicle. Allethrin had a dual effect on DA release. The increase in the extracellular level of striatal DA by 10 mg/kg allethrin reached a maximum of 178% of baseline but 20 and 60 mg/kg inhibited DA release to 63% and 52% of baseline with a peak effect at 60-80 min after injection. Cyhalothrin 10, 20 and 60 mg/kg inhibited DA release to 65%, 56% and 45% of basal release, respectively, with a peak time of inhibition 40-80 min past injection. Deltamethrin (10 and 20 mg/kg) increased DA release to maximum of 187% and 252% of basal release whereas 60 mg/kg first reduced the efflux for 40 min to 50% of basal release and then increased the efflux to a maximum of 344% of basal release with a peak time of 120 min. Local infusion of 1 microM tetrodotoxin, a Na(+) blocker through the dialysis probe completely prevented the effect of allethrin (10 and 60 mg/kg), cyhalothrin (60 mg/kg) and deltamethrin (20 mg/kg) on DA release but only partially blocked the effects of 60 mg/kg deltamethrin. The effect of deltamethrin (60 mg/kg) on DA release was completely prevented by local infusion of 10 microM nimodipine, an L-type Ca(++) channel blocker. All three pyrethroids did not alter the extracellular levels of DOPAC, 3-MT and HVA except that 20 and 60 mg/kg of allethrin and cyhalothrin increased 3-MT levels. Effect of the pyrethroids on synaptosomal DA uptake was also examined. The DA uptake was decreased in rats exposed to 60 mg/kg of allethrin and cyhalothrin but was increased in rats exposed to 60 mg/kg of deltamethrin. Our results demonstrate that striatal DA release and DA uptake are differentially affected by type I and the two type II pyrethroids indicating that dopaminergic circuitry, striatal DA in particular, may be a pyrethroid target and that pyrethroids may be acting on striatal DA by multiple mechanisms.     

Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice

Hepatoprotective potential of the aqueous extract of the roots of Decalepis hamiltonii (DHA) against cyclophosphamide (CP)-induced oxidative stress has been investigated in mice. Administration of CP (25 mg/kg b.w., i.p) for 10 days induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases (AST, ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Parallel to these changes CP induced oxidative stress in the liver as evident from the increased lipid peroxidation (LPO), reactive oxygen species (ROS), depletion of glutathione (GSH), and reduced activities of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Treatment with DHA (50 and 100 mg/kg b.w., po) mitigated the CP-induced oxidative stress. Moreover, expression of genes for the antioxidant enzymes, were down-regulated by CP treatment which was reversed by DHA. Our study shows the DHA protected the liver from toxicity induced by CP and therefore, it could be serve as a safe medicinal supplement during cyclophosphamide chemotherapy.     

Comparative study of natural antioxidants - curcumin, resveratrol and melatonin - in cadmium-induced oxidative damage in mice

The present study was designed to examine the antioxidative effect of curcumin, resveratrol and melatonin pre-treatment on cadmium-induced oxidative damage and cadmium distribution in an experimental model in mice. Male CD mice were treated once daily for 3 days with curcumin (50mg/kg b.w., p.o.), resveratrol (20mg/kg b.w., p.o.) or melatonin (12mg/kg, p.o.), dispersed in 0.5% methylcellulose. One hour after the last dose of antioxidants cadmium chloride was administered (7mg/kg b.w., s.c.) to pre-treated animals and control animals receiving methylcellulose. At 24th h after Cd administration the lipid peroxidation (LP - expressed as malondialdehyde production), reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx) were estimated in liver homogenates. Cadmium concentration was measured in the liver, kidneys, testes and brain by AAS. Cadmium chloride administration to mice induced hepatic lipid peroxidation (to 133%, p<0.001), decreased GSH content (to 65%, p<0.001) and inhibited catalase (to 68%, p<0.001) and GPx activity (to 60%, p<0.001) in the liver. Curcumin, resveratrol and melatonin oral pre-treatment completely prevented the Cd-induced lipid peroxidation and Cd-induced inhibition of GPx hepatic activity. Resveratrol was effective against Cd-induced inhibition of catalase activity (p<0.001). The decrease in hepatic GSH level was not prevented by curcumin, resveratrol or melatonin pre-treatment. In mice treated with antioxidants alone the level of LP, GSH, GPx or CAT was not different from control levels. The pre-treatment with antioxidants did not affect cadmium distribution in the tissues of Cd-intoxicated mice. The results demonstrate that curcumin, resveratrol and melatonin pre-treatment effectively protect against cadmium-induced lipid peroxidation and ameliorate the adverse effect of cadmium on antioxidant status without any reduction in tissue Cd burden.     

In Vivo Micronucleus Assay and GST Activity in Assessing Genotoxicity of Plumbagin in Swiss Albino Mice

Information available on the mutagenicity of a large number of indigenous drugs commonly employed in the Siddha and Ayurveda systems of medicine is scanty. In this context, the current investigation on plumbagin, 5-hydroxy-2methyl-1,4-napthoquinone, an active principle in the roots of Plumbago zeylanica used in Siddha and Ayurveda for various ailments, was carried out; 16 mg/kg b.w. (LD₅₀) was fixed as the maximum dose. Subsequent dose levels were fixed as 50% and 25% of LD₅₀ amounting to 8 mg and 4 mg/kg b.w., respectively, and given orally for 5 consecutive days in 1% Carboxyl Methyl Cellulose (CMC) to Swiss albino mice weighing 25–30 g. The micronucleus assay was done in mouse bone marrow. Plumbagin was found to induce micronuclei at all the doses studied (4 mg/kg, 8 mg/kg, 16 mg/kg b.w.), and it proves to be toxic to bone marrow cells of Swiss albino mice. Animal treated with cyclophosphamide (40 mg/kg b.w.) served as positive control. In addition, glutathione S-transferase (GST) activity was observed in control, plumbagin (4 mg, 8 mg, 16 mg/kg b.w., respectively), and genotoxin-treated experimental group of animals. No significant change in GST activity was observed with plumbagin dose of 4 mg/kg b.w., whereas GST activity was significantly inhibited by higher doses of plumbagin (8 mg and 16 mg/kg b.w.) and cyclophosphamide.     

Melatonin reduces oxidative damage induced by aluminium in rat kidney

We evaluated the effect of melatonin (Mel), in male Wistar rats which received aluminium (Al) lactate for 12 weeks (0.57 mg Al/100 g body weight (b.w.), i.p. three times per week). Moreover rats received Mel (10 mg/kg b.w. i.p. 5 days/weeks) for 12 weeks. At the end of the treatment water and sodium balances were studied, and nephrogenic cyclic adenosine monophosphate (cAMP) was also measured. Urinary osmolality was measured after the administration of desmopressin (vasopressin agonist) to assess concentrating capacity. Oxidative stress in renal tissue and Na⁺–K⁺ATPase and gamma-glutamyl transferase (GGT) activities in whole plasma membrane were determined. Sodium and water balances were impaired by Al. We found decreased urinary concentrating ability and nephrogenic cAMP excretion. Al increased the Na⁺–K⁺ATPase activity, and serum aldosterone concentration. Mel normalized serum aldosterone level, the Na⁺–K⁺ATPase activity and potassium urinary without improving water and sodium excretion. Mel treatment did not improve the impaired urinary concentrating ability. Al reduced the GGT activity, an effect that persists in Al⁺ Mel. Al exposure promoted oxidative stress with an increase in lipid peroxidation (LPO), and a decrease in glutathione (GSH) and glutathione peroxidase (GSH-Px) and catalase (CAT) activities. Mel markedly attenuated oxidative stress produced by Al. This may result from the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes. However, it only reduced some alterations in the renal functions particularly related to the water and sodium excretion, which would be independent of the increased production of reactive oxygen substances.     

A role for casein kinase 1 epsilon in the locomotor stimulant response to methamphetamine

Rationale  We previously colocalized a quantitative trait locus (QTL) for sensitivity to the locomotor stimulant effects of methamphetamine (MA) with a QTL for expression of casein kinase 1 epsilon (Csnk1-ɛ) in the nucleus accumbens (NAc). Subsequently, we identified a single nucleotide polymorphism in CSNK1E (rs135745) that was associated with increased sensitivity to the subjective effects of d-amphetamine in healthy human subjects. Based on these results, we hypothesized that differential expression of Csnk1-ɛ causes differential sensitivity to MA-induced locomotor activity in mice. Objective  In the present study, we used PF-670462 (PF), which is a selective inhibitor of Csnk1-ɛ, to directly evaluate the role of Csnk1-ɛ in the locomotor stimulant response to MA in male C57BL/6J mice. Methods  We administered vehicle, PF, MA, or MA + PF, either via intraperitoneal injections or bilateral intra-NAc microinjections. We also examined Darpp-32 phosphorylation in mice receiving intraperitoneal injections. Results  Intraperitoneal PF (20–40 mg/kg) attenuated the locomotor stimulant response to MA (2 mg/kg) without affecting baseline activity. The high dose of PF also significantly inhibited MA-induced phosphorylation of Darpp-32, providing a potential mechanism by which Csnk1-ɛ contributes to MA-induced locomotor activity. Furthermore, microinjection of PF (5 μg/side) into the NAc completely blocked the locomotor stimulant response to MA (2.5 μg/side) without affecting baseline activity. Conclusions  These results provide direct evidence that Csnk1-ɛ is crucial for the locomotor stimulant response to a moderate dose of MA and suggest that genetic polymorphisms affecting Csnk1-ɛ expression or function could influence sensitivity to amphetamines in both mice and humans. Funding: DA021336-02 (A.A.P.), DA09397 (P.V.), 2T32DA007255 (C.D.B.), 5T32GM07281 (M.G.D.).     

Monte Carlo simulation analysis of ceftobiprole,dalbavancin, daptomycin,tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit‐isolated methicillin‐resistant Staphylococcus aureus

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Dissociation between circling behaviour and striatal dopamine activity following unilateral deltamethrin administration to rats

Summary The neurotoxic pyrethroid, deltamethrin, induces a severe motor syndrome characterised by tremor and choreoathetosis when injected systemically to rats. The interaction between deltamethrin and the two major dopaminergic pathways — the nigrostriatal and mesolimbic pathways — was investigated in rats. Striatal catecholamines, indoleamines and metabolites were measured by HPLC with electrochemical detection. Unilateral injection of deltamethrin (1.0 g) into the ventral tegmental nucleus or substantia nigra induced rapid ipsilateral or contralateral circling respectively but was ineffective at other basal ganglia sites. Both the sham and vehicle injections at either site, resulted in a marked increase above normal in DA turnover in the ipsilateral striatum without inducing circling behaviour. DA turnover was increased to the same extent in the ipsilateral striatum of deltamethrin-treated rats where rapid circling was present. Therefore the neurochemical findings were not consistent with the rotation theories based on striatal DA asymmetry but rather followed alternative mechanisms previously proposed, where circling behaviour can occur by mechanisms not causally related to striatal DA. These findings also indicate that a degree of selectivity exists in the action of deltamethrin, a sodium channel toxin that might be expected to act on all neuronal systems within the SN or VTN or equally at other sites within the basal ganglia associated with circling behaviour.Abbreviations DA Dopamine - DHBA dihydroxybenzylamine - DC 3,4-dihydroxyphenylacetic acid - 5-HIAA 5-hydroxyindole-3-acetic acid - 5-HT serotonin - HVA homovanillic acid - PCA perchloric acid - SN substantia nigra - VTN ventral tegmental nucleus - GF glycerolformal (75% 5-hydroxyl-1,3-dioxan + 25% 4-hydroxymethyl-1,3-dioxolan) - DM deltamethrin     

Cassiae semen,a seed of Cassia obtusifolia,has neuroprotective effects in Parkinson’s disease models

Cassiae semen, a commonly consumed tea and medicinal food, has been shown to have multiple therapeutic actions related to the prevention of dementia and ischemia. In this study, we investigated the effects of extract of Cassiae semen (COE) against neurotoxicities in in vitro and in vivo Parkinson’s disease (PD) models. In PC12 cells, COE attenuated the cell damage induced by 100 μM 6-hydroxydopamine (6-OHDA) stress in MTT assay, and it inhibited the overproduction of reactive oxygen species, glutathione depletion, mitochondrial membrane depolarization and caspase-3 activation at 0.1–10 μg/ml. In addition, COE showed radical scavenging activity in the DPPH and ABTS assays. In mesencephalic dopaminergic (DA) culture, COE protected DA cells against 10 μM 6-OHDA- and 10 μM 1-methyl-4-phenylpyridine-induced toxicities at 0.1–1 μg/ml. We also evaluated the effect of COE in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, COE (50 mg/kg, 15 days) + MPTP (30 mg/kg, 5 days)-treated group had decreased T-turn and T-LA which were longer in MPTP group. Moreover, COE significantly protected DA neuronal degeneration induced by MPTP in the substantia nigra and striatum of these mice. These results demonstrate that COE can prevent DA neurons against the toxicities involved in PD.     

The adenosine A<Subscript>2A</Subscript> antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure

Rationale  Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors. Objective  Previous work showed that adenosine A_2A antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice. The present work used a T-maze choice procedure to assess the effects of adenosine A_2A and A₁ antagonism. Materials and methods  With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical 44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food. Results  Haloperidol produced a dose-related (0.05–0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier arm. Co-administration of the adenosine A_2A receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related choice and latency. Conclusions  Adenosine A_2A and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders.     

Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: molecular mechanisms of action of cobalt chloride

This study reports the efficacy of cobalt preconditioning in preventing hypobaric hypoxia induced vascular leakage (an indicator of cerebral edema) using male Sprague-Dawley rats as model system. Exposure of animals to hypobaric hypoxia led to a significant increase in vascular leakage, reactive oxygen species (ROS), nitric oxide (NO), and vascular endothelial growth factor (VEGF) levels. There was a marked increase in Nuclear Factor κB (NFκB) DNA binding activity and levels of pro-inflammatory cytokines such as Monocyte chemoattractant protein (MCP-1), Interferon-γ (IFN-γ), Interleukin-1 (IL-1), and Tumor Necrosis Factor-α (TNF-α) and cell adhesion molecules such as Vascular Cell Adhesion Molecule-1 (VCAM-1), and P-selectin. Chemical preconditioning by cobalt for 7 days (12.5 mg Co/kg b.w., oral) significantly attenuated cerebral vascular leakage and the expression of inflammatory mediators induced by hypoxia. Administration of NFκB inhibitor, curcumin (50 mg/kg b.w.; i.p.) appreciably inhibited hypoxia induced vascular leakage indicating the involvement of NFκB in causing vascular leakage. Interestingly, cobalt when administered at 12.5 mg Co/kg b.w. (i.p.), 1 h before hypoxia could not prevent the vascular leakage indicating that cobalt per se did not have an effect on NFκB. The lower levels of NFκB observed in the brains of cobalt administered animals might be due to higher levels of antioxidant and anti-inflammatory proteins (hemeoxygenase-1 and metallothionein). To conclude cobalt preconditioning inhibited hypobaric hypoxia induced cerebral vascular leakage by lowering NFκB DNA binding activity and its regulated pro-inflammatory mediators. This is contemplated to be mediated by cobalt induced reduction in ROS/NO and increase in HO-1 and MT.     

Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL_cre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters.     

Sexual excitement and stretching and yawning induced by B-HT 920

The azepine derivative B-HT 920, a putative agonist at dopamine (DA) autoreceptors, injected IP in adult male rats, induced numerous penile erections (PE) and stretching and yawning (SY), considered typical signs of central DA receptor stimulation, without eliciting stereotyped behaviour (SB). Both signs induced by B-HT 920 were dose related and significantly enhanced with respect to controls from 10 to 1,000/micrograms/kg. Pretreatment with the neuroleptics haloperidol (0.025, 0.5 and 1 mg/Kg IP), sulpiride (20 and 40 mg/Kg) and alpha 2-antagonist yohimbine (1 and 3 mg/Kg IP) antagonized the behavioural effect of B-HT 920 whereas the alpha 1-antagonist prazosin (1 mg/Kg IP) had no effect on the response. The impressive activity of B-HT 920 in producing SY and PE, along with its inability to evoke SB, supports the role of DA autoreceptors in the regulation of SY and sexual behaviour.     

Synthesis and Evaluation of Antidepressant-like Activity of Some 4-Substituted 1-(2-methoxyphenyl)Piperazine Derivatives

A series of new derivatives of N-(2-methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant-like activity. They have been evaluated toward receptors 5-HT_1A, 5-HT₆, and 5-HT₇, as well as in vivo in the tail suspension, locomotor activity, and motor co-ordination tests. All the tested compounds proved very good affinities toward 5-HT_1A and 5-HT₇ receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors K_i <1 nm (5-HT_1A) and K_i = 34 nm (5-HT₇). Antidepressant-like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED₅₀ (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD₅₀ (rotarod, mice, i.p.) = 53.2 mg/kg b.w.