Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress

BackgroundIn the present study, antidepressant-like activity of palmatine was evaluated in unstressed and stressed young male Swiss albino mice.MethodsThe animals were subjected to unpredictable mild stress daily for 21 successive days to induce depression-like behavior. Palmatine (0.25, 0.5, 1 mg/kg, ip) was administered for 21 successive days to unstressed and stressed mice. The antidepressant-like activity was evaluated using the tail suspension test, forced swim test and sucrose preference test.ResultsPalmatine (0.5 and 1 mg/kg, ip) significantly decreased immobility periods of unstressed and stressed mice in the forced swim test and tail suspension test, thus indicating its significant antidepressant-like activity. Only the highest dose (1 mg/kg) of palmatine significantly reversed the stress-induced decrease in sucrose preference. There was no significant effect on locomotor activity of the mice by palmatine and fluoxetine. The antidepressant-like activity of palmatine was found to be comparable to fluoxetine (10 mg/kg) administered for successive 21 days. Palmatine (0.5 and 1 mg/kg, ip) significantly reversed the stress-induced increase in brain catalase levels, MAO-A activity, lipid peroxidation, plasma nitrite and corticosterone levels.ConclusionsPalmatine showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of MAO-A activity, decrease in plasma nitrite levels and due to its antioxidant activity. In addition, palmatine also showed antidepressant-like activity in stressed mice probably through decrease in plasma corticosterone levels.     

Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice

BackgroundThe aim of present study was to evaluate antidepressant-like activity of ellagic acid in Swiss young male albino mice; and to explore the possible underlying mechanisms for this activity.MethodsMice were immobilized for 150 min once only for induction of stress. Ellagic acid (8.75, 17.5, 35 mg/kg, po) and fluoxetine (20 mg/kg, ip) per se were administered to unstressed and stressed mice; and immobility periods were recorded using tail suspension test and forced swim test. The plasma nitrite levels were also estimated in unstressed and stressed mice. Effects of 7-nitroindazole (nNOS inhibitor), aminoguanidine (iNOS inhibitor), prazosin (α₁-adrenoceptor antagonist), sulpiride (selective D₂-receptor antagonist), and p-chlorophenylalanine (p-CPA – tryptophan hydroxylase inhibitor) on antidepressant-like activity of ellagic acid were also evaluated.ResultsEllagic acid (17.5 and 35 mg/kg, po) and fluoxetine per se significantly decreased immobility periods of unstressed and stressed mice, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice. Ellagic acid significantly decreased the plasma nitrite levels in stressed mice only. Aminoguanidine significantly potentiated antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid (35 mg/kg) in stressed mice. 7-Nitroindazole did not enhance antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid in unstressed mice. Prazosin and p-CPA significantly attenuated antidepressant-like effect of ellagic acid (35 mg/kg) in unstressed mice only.ConclusionThus, ellagic acid showed antidepressant-like activity in unstressed mice probably by interaction through adrenergic and serotonergic systems. On the other hand, antidepressant-like activity of ellagic acid in stressed mice might be through inhibition of inducible NOS.     

Tolerance liability of diazepam is dependent on the dose used for protracted treatment

BackgroundBehavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated.MethodsWe applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolytic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperito-neal (ip) administration on animal behavior.ResultsTolerance to the sedative effect of 2 mg/kg diazepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. A sensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied.ConclusionThe presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.     

Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine,serotonin and noradrenaline in the rat frontal cortex

BackgroundSeveral clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression.We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex.MethodsAnimals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1 mg/kg and FLU at a dose of 10 mg/kg. The release of DA, 5-HT and NAin the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection.ResultsRIS (0.1 and 1 mg/kg) and FLU (10 mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1 mg/kg and FLU 10 mg/kg. Co-treatment of FLU and RIS 0.1 mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1 mg/kg was stronger than RIS 1 mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone.ConclusionsOur data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.     

Single and 90-day repeated oral dose toxicity studies of fermented Rhus verniciflua stem bark extract in Sprague–Dawley rats

Fermented Rhus verniciflua stem bark (FRVSB) extract, an urushiol-free extract of Rhus verniciflua Stokes (RVS) fermented with Fomitella fraxinea, has various biological activities. The present study was carried out to investigate the potential toxicity of the FRVSB extract following single and repeated oral administration to Sprague–Dawley rats. In the single dose toxicity study, the FRVSB extract was administered orally to male and female rats at single doses of 0, 2500, 5000, and 10,000 mg/kg. No animals died and no toxic changes were observed in clinical signs, body weight, and necropsy findings during the 15-day period following administration. In the repeated dose toxicity study, the FRVSB extract was administered orally to male and female rats for 90 days at doses of 0, 556, 1667, and 5000 mg/kg/day. There were no treatment-related adverse effects in clinical signs, body weight, food and water consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any dose tested. The approximate lethal dose of the FRVSB extract was >10,000 mg/kg in both genders, the oral no-observed-adverse-effect level of the FRVSB extract was >5000 mg/kg/day in both genders, and no target organs were identified.     

Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test

BackgroundSeveral clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression.MethodsThe present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST).ResultsThe obtained results showed that fluoxetine (5 mg/kg), mirtazapine (5 and 10 mg/kg) or risperidone (0.05 and 0.1 mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10 mg/kg) and risperidone (0.1 mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10 mg/kg and risperidone at 0.05 and 0.1 mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT_1a receptor antagonist) at a dose of 0.1 mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST.ConclusionThe obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT_1a receptors may play some role in these effects.     

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT_1A receptor agonist and 5-HT₃ receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT₃ receptor antagonist) or flesinoxan (5-HT_1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1 mg/kg (∼80% 5-HT₃ receptor occupancy; OR) and ≤3.0 mg/kg (5-HT_1A, 5-HT_1B, 5-HT₃ receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0 μg/kg (∼25% 5-HT₃ receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0 mg/kg (∼25% 5-HT_1A receptor occupancy; SA); only 1.0 mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT₃, 5-HT_1B, and 5-HT_1A receptors, respectively. Vortioxetine′s effects on SA performance may involve 5-HT_1A receptor agonism, but not 5-HT₃ receptor antagonism, whereas the effects on OR performance may involve 5-HT₃ receptor antagonism and 5-HT_1A receptor agonism.     

Effects of morphine and methadone treatments on glutamatergic transmission in rat frontal cortex

The effects of repeated administration of morphine and methadone, followed by a challenge dose of either morphine or methadone were examined ex vivo in rat frontal cortical slices that were prepared 1 h after final drug administration. Morphine challenge dose (5 mg/kg), administered 14 days after the end of repeated morphine pretreatment (10 mg/kg, administered 7 times) decreased both the AMPA/kainate and the NMDA components of field potentials that were evoked in cortical layer II/III by electrical stimulation. This effect did not occur either when a methadone challenge dose (2.5 mg/kg) was administered instead of morphine or after repeated morphine treatment. Moreover, after repeated methadone treatment (2.5 mg/kg, administered 7 times), neither morphine nor methadone challenge affected AMPA/kainate or NMDA components of the field potentials. These data indicate a specific effect of repeated morphine followed by morphine challenge on cortical glutamatergic transmission.     

Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: Changes in urinary pyrroles levels and motor activity performance

The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC–MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC.Wistar rats were treated with 4 doses of: 400 mg 2,5-HD/kg bw (group I), 400 mg 2,5-HD/kg bw + 200 mg NAC/kg bw (group II), 200 mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p < 0.01) in urinary DMPN and free 2,5-HD, a significant increase (p < 0.01) in DMPN NAC excretion, and a significant recovery (p < 0.01) on motor activity in rats co-exposed to 2,5-HD + NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione.     

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D₁-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D₁-like receptor antagonist (P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P < 0.05). These results suggest a role for D₁-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.     

Fluoxetine Potentiation of Omega-3 Fatty Acid Antidepressant Effect: Evaluating Pharmacokinetic and Brain Fatty Acid-Related Aspects in Rodents

We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies.     

Mechanism of St. John's wort extract (STW3-VI) during chronic restraint stress is mediated by the interrelationship of the immune,oxidative defense,and neuroendocrine system

Chronic stress is a contributing risk factor for the development of psychiatric illnesses such as anxiety and depression disorders. The aim of the present study was to evaluate the mechanisms of action of the standardized St. John's wort extract (STW3-VI; SJW) in a chronic restraint stress model. Markers of antioxidant capacity such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus and hypothalamus, and plasma levels of ACTH and corticosterone as well as the inflammatory markers IL-6 and TNF-α were determined in rats exposed to chronic restraint stress for 21 consecutive days. In addition, total body and relative organ weights as well as behavioral changes in the open field test were evaluated on the last day. The results show that stressed animals decreased in open field activity compared to unstressed animals, which could be reversed by fluoxetine (10 mg/kg, p.o.) and SJW (125–750 mg/kg, p.o.) treatment. In addition, chronic restraint stress significantly decreased thymus and spleen indices in the stressed control group. However, treating stressed rats with fluoxetine or STW3-VI produced a significant and dose dependent increase in both thymus and spleen indices compared to stressed controls. Additionally, SJW and fluoxetine significantly reduced stress-induced increases in plasma ACTH and corticosterone levels. Furthermore, the administration of SJW significantly reduced the stress-induced increase in TNF-α levels. Our data provide new evidence for the hypothesis that the mechanism of action of STW3-VI is mediated by the interrelationship between the immune, oxidative defense and neuroendocrine system.     

Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver

BackgroundRat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate of testosterone 2α- and 16α-hydroxylation.MethodsThe reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazodone – 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day), in the absence of antidepressants in vitro.ResultsThe investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on CYP2C11 activity, which were moderate (sertraline, nefazodone and clomipramine: K_i = 39, 56 and 66 μM, respectively), modest (fluoxetine and amitriptyline: K_i = 98 and 108 μM, respectively) or weak (imipramine and desipramine: K_i = 191 and 212 μM, respectively). Mirtazapine had no inhibitory effect on CYP2C11 activity. One-day exposure of rats to the antidepressant drugs did not significantly change the activity of CYP2C11 in liver microsomes; however, imipramine, desipramine and fluoxetine showed a tendency to diminish the activity of CYP2C11. Of the antidepressants studied, only desipramine and fluoxetine administered chronically elevated CYP2C11 activity; those effects were positively correlated with the observed increases in the enzyme protein level.ConclusionThree different mechanisms of the antidepressants-CYP2C11 interaction are postulated: 1) a direct inhibition of CYP2C11 shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo inhibition of CYP2C11 produced by one-day treatment with imipramine, desipramine and fluoxetine, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction of CYP2C11 produced by chronic treatment with desipramine and fluoxetine, which suggests their influence on enzyme regulation.     

An antioxidant,N,N′-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: A 28-day repeated dose test and reproduction/developmental toxicity test

A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N′-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42–46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively.     

Effect of fluoxetine on tolerance to the analgesic effect of morphine in mice with skin cancer

Adjuvant drugs that attenuate or inhibit the development of tolerance to morphine may lead to improved management of pain in chronic diseases such as cancer. The aim of this study was to investigate effect of fluoxetine, a specific 5-HT (5-hydroxytryptamine, serotonin) reuptake inhibitor, on tolerance induced to the analgesic effect of morphine in mice with skin cancer. The study was carried out on female Swiss albino mice. For skin tumorigensis, mice were initiated with a single dose of 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by multiple doses of croton oil. Tolerance to morphine analgesia was induced by daily subcutaneous (sc) injections of morphine (5 mg/kg for 30 days) and assayed using the hot plate method. Results obtained from this study showed that pain thresholds in mice with skin cancer were significantly lower. Tolerance to the analgesic effect of morphine (5 mg/kg, sc) appeared at day 15, whereas in normal and skin tumor bearing mice co-treated daily with morphine (5 mg/kg, sc) and three different intraperitoneal (ip) doses of fluoxetine (0.16, 0.32 and 0.64 mg/kg) tolerance was observed at days 20, 25 and 30, respectively. In conclusion, our data indicate that concurrent use of morphine with fluoxetine may produce good cancer pain control and attenuate the development of tolerance.     

In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration

Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(ɛ-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245 ± 10 nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n = 6/group) received a single-dose of saline solution (1.2 ml/kg) or LNC (7.2 × 10¹² LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9 ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4 × 10¹² LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80–treated group (p < 0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p < 0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs.     

Protective effect of HMG CoA reductase inhibitors against running wheel activity induced fatigue,anxiety like behavior,oxidative stress and mitochondrial dysfunction in mice

BackgroundChronic fatigue stress (CFS) is an important health problem with unknown causes and unsatisfactory prevention strategies, often characterized by long-lasting and debilitating fatigue, myalgia, impairment of neuro-cognitive functions along with other common symptoms. The present study has been designed to explore the protective effect of statins against running wheel activity induced fatigue anxiety.MethodsMale albino Laca mice (20–30 g) were subjected to swim stress induced fatigue in a running wheel activity apparatus. Atorvastatin (10, 20 mg/kg, po) and fluvastatin (5, 10 mg/kg, po) were administered daily for 21 days, one hour prior to the animals being subjected to running wheel activity test session of 6 min. Various behavioral tests (running wheel activity, locomotor activity and elevated plus maze test), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels and catalase activity) and mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) were subsequently assessed.ResultsAnimals exposed to 6 min test session on running wheel for 21 days showed a significant decrease in number of wheel rotations per 6 min indicating fatigue stress like behavior. Treatment with atorvastatin (10 and 20 mg/kg) and fluvastatin (10 mg/kg) for 21 days significantly improved the behavioral alterations [increased number of wheel rotations and locomotor activity, and anxiety like behavior (decreased number of entries and time spent in open arm)], oxidative defence and mitochondrial complex enzyme activities in brain.ConclusionPresent study suggests the protective role of statins against chronic fatigue induced behavioral, biochemical and mito-chondrial dysfunctions.     

Inhibition of serotonin reuptake in the prepubertal rat ovary by fluoxetine and effects on ovarian functions

Fluoxetine (FLX), a selective serotonin reuptake inhibitor is an antidepressant in the treatment of mood disorders. Its impact on reproductive processes is incompletely known. The present study analyzed the reproductive effects of FLX in prepubertal female rats. Two experiments were conducted. First (acute administration), 30-day-old female rats were injected intraperitoneally with 5 mg/kg of fluoxetine-hydrochloride, and were terminated 24, 48 or 72 h after the treatment. Second (subchronic administration), FLX was injected on days 30-33 of age, and the animals were terminated the day of first estrus. In acute treatment estradiol concentration increased to 72 h. In subchronic treatment increased serotonin concentration in ovaries and decreased the number of ova shed. An increase in number of atretic follicles and oocyte fragmentation was observed in these animals. The results suggest that FLX acts on the ovary or hypothalamus–pituitary axis resulting in modifications of the follicular development and ovulation.     

Predictors of acute kidney injury associated with intravenous colistin treatment

Colistimethate sodium (CMS) was recently re-introduced into clinical practice as a last resort for the treatment of nosocomial infections caused by multiresistant bacteria. This retrospective cohort study was designed to identify predictors of acute kidney injury (AKI) associated with intravenous (i.v.) CMS treatment. From March 2007 to July 2008, 71 adult patients receiving CMS for ≥72 h were enrolled. AKI was defined using Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) criteria according to serum creatinine. The median total dose of CMS was 54.3 mg/kg (range 27.5–94.5 mg/kg). AKI developed in 38 patients (53.5%). Cox regression analysis based of cumulative CMS dose (mg/kg) identified four independent predictors of AKI: male sex [hazard ratio (HR) = 3.55, 95% confidence interval (CI), 1.47–8.55]; concomitant use of a calcineurin inhibitor (HR = 6.74, 95% CI 2.49–18.24); hypoalbuminaemia (serum albumin level <2.0 g/dL) (HR = 6.29, 95% CI 2.04–19.39); and hyperbilirubinaemia (total bilirubin level >5 mg/dL) (HR = 3.53, 95% CI 1.17–10.71). In conclusion, AKI was a common complication of i.v. CMS treatment. Male sex, concomitant use of calcineurin inhibitors, hypoalbuminaemia and hyperbilirubinaemia were independent predictors of AKI. The effect of AKI on patient outcomes was not determined.     

1,2,3,4-Tetrahydroisoquinoline as the potential antidepressant compound in forced swimming test in rat

1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo- and endogenous amine present naturally in mammalian brain and may be the natural regulator of monoaminergic systems with a visible neuroprotective potency [Antkiewicz-Michaluk et al., J Neurochem, 2006]. In our study we tested the potential antidepressant properties of TIQ in comparison with a classic antidepressant drug, imipramine by using forced swimming test in rats (FST). Further, we measured the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT), and their metabolites, as well as the rate of monoamines metabolism in different rats brain structures by HPLC methodology with ED. The locomotor activity test was used to check motor function of rat after investigated drugs administration. All experiments were performed on male Wistar rats weighing 220 –240 g.ResultsFST has shown that TIQ (10 , 25 , 50 mg/kg, ip) significantly reduced immobility time similarly to imipramine (30 mg/kg, ip). TIQ significantly elevated swimming activity (p < 0.01) while imipramine increased climbing time (p < 0.01). Additionally, TIQ (25 mg/kg, ip) and imipramine (15 mg/kg, ip) injected simultaneously decreased immobility time, increased the swimming and did not affect the climbing activity. The biochemical analysis showed that TIQ increased the levels of monoamines: DA, NA and 5-HT in rat brain structures. Moreover, the factor of DA re-uptake inhibition, calculated as the ratio [3-MT]/[DOPAC], was significantly elevated by TIQ administration. The rate of serotonin metabolism was strongly decreased (p < 0.01) while, the rate of noradrenaline metabolism was increased (p < 0.05) after injection of TIQ and imipramine. TIQ did not change the locomotor activity in rats.ConclusionsThe obtained data indicate that TIQ produced antidepressant-like effect in FST with potency comparable to imipramine. Thus, in that light and taking into account its neuroprotective potential of action in the brain TIQ may be useful in clinical practice for therapy of depression.