Incremental predictive validity of the Addiction Severity Index psychiatric composite score in a consecutive cohort of patients in residential treatment for drug use disorders

BackgroundThe Addiction Severity Index (ASI) is a widely used assessment instrument for substance abuse treatment that includes scales reflecting current status in seven potential problem areas, including psychiatric severity. The aim of this study was to assess the ability of the psychiatric composite score to predict suicide and psychiatric care after residential treatment for drug use disorders after adjusting for history of psychiatric care.MethodsAll patients treated for drug use disorders in residential treatment centers in Denmark during the years 2000–2010 with complete ASI data were followed through national registers of psychiatric care and causes of death (N = 5825). Competing risks regression analyses were used to assess the incremental predictive validity of the psychiatric composite score, controlling for previous psychiatric care, length of intake, and other ASI composite scores, up to 12 years after discharge.ResultsA total of 1769 patients received psychiatric care after being discharged from residential treatment (30.3%), and 27 (0.5%) committed suicide. After adjusting for all covariates, psychiatric composite score was associated with a higher risk of receiving psychiatric care after residential treatment (subhazard ratio [SHR] = 3.44, p < 0.001), and of committing suicide (SHR = 11.45, p < 0.001).ConclusionsThe ASI psychiatric composite score has significant predictive validity and promises to be useful in identifying patients with drug use disorders who could benefit from additional mental health treatment.     

Psychosocial and metabolic function by smoking status in individuals with binge eating disorder and obesity

Individuals with binge eating disorder (BED) report smoking to control appetite and weight. Smoking in BED is associated with increased risk for comorbid psychiatric disorders, but its impact on psychosocial functioning and metabolic function has not been evaluated. Participants were 429 treatment-seeking adults (72.4% women; mean age 46.2 ± 11.0 years old) with BED comorbid with obesity. Participants were categorized into current smokers (n = 66), former smokers (n = 145), and never smokers (n = 218). Smoking status was unrelated to most historical eating/weight variables and to current eating disorder psychopathology. Smoking status was associated with psychiatric, psychosocial, and metabolic functioning. Compared with never smokers, current smokers were more likely to meet lifetime diagnostic criteria for alcohol (OR = 5.51 [95% CI = 2.46–12.33]) and substance use disorders (OR = 7.05 [95% CI = 3.37–14.72]), poorer current physical quality of life, and increased risk for metabolic syndrome (OR = 1.80 [95% CI = 0.97–3.35]) and related metabolic risks (reduced HDL, elevated total cholesterol). On the other hand, the odds of meeting criteria for lifetime psychiatric comorbidity or metabolic abnormalities were not significantly greater in former smokers, relative to never smokers. Our findings suggest the importance of promoting smoking cessation in treatment-seeking patients with BED and obesity for its potential long-term implications for psychiatric and metabolic functioning.     

Co-morbidity of substance use disorder and psychopathology in women who use methamphetamine during pregnancy in the US and New Zealand

BackgroundMethamphetamine (MA) abuse is a worldwide problem. Little is known about the co-morbidity of substance use disorders (SUD) and other psychiatric disorders of mothers who use MA prenatally. The Infant Development, Environment and Lifestyle (IDEAL) Study is a prospective, investigation of prenatal MA use and child outcome in the United States (US) and New Zealand (NZ). This study examined prenatal MA use and the co-morbidity of SUD and psychiatric disorders at 1-month postpartum.MethodMothers who used MA (US = 127, NZ = 97) were compared to a matched comparison group (US = 193, NZ = 110). The Substance Abuse Subtle Screening Inventory-3 was used to measure the probability of a SUD. The Brief Symptom Inventory (BSI) was used to measure the likelihood of a positive diagnosis of a psychiatric disorder.ResultsIn the US and NZ, MA groups had lower SES, increased single parenting, delayed prenatal care, and increased polydrug use. In the US only, MA mothers had lower income than the comparison group. MA users were 10 times more likely to have a SUD and twice as likely to meet BSI criteria for a diagnosable psychiatric disorder. In NZ, but not the US, MA users were five times more likely to have co-morbidity of both. This disparity may be due to higher quantities of prenatal alcohol use associated with increased psychiatric symptoms.ConclusionThese findings suggest that addressing both substance abuse and psychiatric disorders in mothers who use MA may be required to effectively treat maternal MA use.     

Alteration of cardiac cytochrome P450-mediated arachidonic acid metabolism in response to lipopolysaccharide-induced acute systemic inflammation

Cytochrome P450 (CYP) generated cardioprotective metabolites, epoxyeicosatrienoic acids (EETs), and cardiotoxic metabolites, hydroxyeicosatetraenoic acids (HETEs) levels are determined by many factors, including the induction or repression of the CYP enzymes, responsible for their formation. Therefore, we examined the effect of acute inflammation on the expression of CYP epoxygenases and CYP ω-hydroxylases in the heart, kidney, and liver and the cardiac CYP-mediated arachidonic acid metabolism. For this purpose, male Sprague–Dawley rats were injected intraperitoneally with LPS (1 mg/kg). After 6, 12, or 24 h, the tissues were harvested and the expression of CYP genes and protein levels were determined using real time-PCR, and Western blot analyses, respectively. Arachidonic acid metabolites formations were determined by liquid chromatography–electron spray ionization-mass spectrometry LC-ESI-MS. Our results showed that inflammation significantly decreased the CYP epoxygenases expression in the heart, kidney and liver with a concomitant decrease in the EETs produced by these enzymes. In contrast to CYP expoxygenses, inflammation differentially altered CYP ω-hydroxylases expression with a significant increase in 20-HETE formation. The present study demonstrates for the first time that acute inflammation decreases CYP epoxygenases and their associated cardioprotective metabolites, EETs while on the other hand increases CYP ω-hydroxylases and their associated cardiotoxic metabolites, 20-HETE. These changes may be involved in the development and/or progression of cardiovascular diseases by inflammation.     

LC/MS/MS evaluation of cocaine and its metabolites in different brain areas,peripheral organs and plasma in cocaine self-administering rats

BackgroundWe employed a cocaine intravenous self-administration model based on positive reinforcement of animals' instrumental reactions (i.e., lever pressing) rewarded by a dose of the drug. We also carried out simultaneous characterization of the phar-macokinetics of cocaine and its metabolites in rats during withdrawal; in this part of the experiments, we investigated the cocaine (2 mg/kg, iv)-induced changes in the distribution, rate constant, clearance and t_1/2 of the parent drug and its metabolites in different structures of the brain and in peripheral tissues.MethodsBy using liquid chromatography-tandem mass spectrometry (LC/MS/MS) we measured the levels of cocaine and its major metabolites.ResultsOur results demonstrate differences in the levels of cocaine after cocaine self-administration in the rat, with the highest concentration seen in the striatum and the lowest in the cerebellum. Cocaine metabolites determined in the rat brain remained at very low levels (benzoylecgonine), irrespectively of the brain area, whereas the norcocaine concentration varied from 1.56 μg/g (the nucleus accumbens) to 2.73 μg/g (the striatum).ConclusionAtandem LC/MS/MS is a valid method for evaluation of brain and peripheral levels ofcocaine and its metabolites. Our results demonstrate brain area-dependent differences in the levels of cocaine after its self-administration in the rat. There were also differences in pharmacokinetic parameters among the brain areas and peripheral tissues following a bolus iv injection of cocaine to rats withdrawn from cocaine; among brain structures the slowest metabolic rate was detected for the striatum.     

Levels of dialkylphosphate metabolites in urine among general U.S. population

Data from National Health and Nutrition Examination Survey for years 2003–2008 were used to study the factors that affect urinary levels of dialkylphosphate (DAP) metabolites in urine. Separate regression models were fitted for children aged 6–11 years, adolescents aged 12–19 years, and adults aged ≥20 years. Specifically, DAP metabolites that were analyzed were: dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP), and diethylthiophosphate (DETP). Males had statistically significantly lower adjusted levels than females for DMP for adolescents, for DEP for adults, for DMTP for both adolescents and adults, and for DETP for both children and adults. Nonsmokers had statistically significantly higher adjusted levels than smokers for DMTP for adolescents and for DMP and DMTP for adults. Exposure to second hand smoke at home was associated with relatively higher levels of DMP among children (p = 0.01) but the reverse was found to be true for DMTP (p < 0.01) among adolescents as well as adults (p = 0.02). Children had higher levels of DMTP than both adolescents and adults (p < 0.01) and higher levels of DETP than adolescents (p = 0.02). Age was found to be negatively associated with the levels of DMTP (p = 0.01) among children and positively associated (p < 0.01) with the levels of all four metabolites among adults.     

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.     

Disposition and acute toxicity of imidacloprid in female rats after single exposure

Single dose of imidacloprid (IMI-20 mg/kg bodyweight) was orally administered in female rats. Its disposition along with two metabolites 6-chloro nicotinic acid (6-CNA) and 6-hydroxy nicotinic acid (6-HNA) was monitored in organs (brain, liver, kidney, and ovary) and bodily fluids (blood, urine) at 6, 12, 24 and 48 h and faeces at 24 and 48 h. Maximum concentration (C_max) of IMI and metabolites in each organ and bodily fluid occurred after 12 h. Area under curve (AUC) of IMI ranged from 35 to 358 μg/ml/h; 6-CNA: 27.12–1006.42 μg/ml/h and 6-HNA: 14.98–302.74 μg/ml/h in different organs and bodily fluids. Clearance rate of IMI was maximum in ovary followed by kidney, liver, brain, faeces, blood and urine. Percent inhibition of acetyl-cholinesterase (AChE) was comparable in brain and Red Blood Cells (RBC) at 6–48 h which suggests the RBC-AChE as valid biomarker for assessing IMI exposure. It is evident that IMI was absorbed, metabolized, and excreted showing increased level of serum enzymes like Glutamic oxaloacetic transaminase (GOT), Glutamic pyruvic transaminase (GPT) and biochemical constituents like billirubin and Blood Urea Nitrogen (BUN) at 48 h. These data suggest that IMI is widely distributed, metabolized and induced toxicology effects at 20 mg/kg bodyweight to female rats.     

Exposure and recovery response of isomers of HCH,metabolites of DDT and estradiol-17β in the female catfish,Heteropneustes fossilis

Effects of 40 days of exposure and 20 days of recovery response at sublethal concentration of technical grades of gamma isomer of hexachlorocyclohexane (γ-HCH, 0.025 ppm, 99.8%) and dichlorodiphenyltrichloroethane (DDT, 5.0 ppm) in tissue (liver, brain and ovary) bioconcentrations, gonadosomatic index (GSI) and plasma levels of estradiol-17β (E2) have been estimated during prespawning phase in the catfish Heteropneustes fossilis (Bloch). The results indicated that the tissue bioconcentrations of both HCHs (HCH isomers) and DDTs (metabolites of DDT) in liver, brain and ovary were in preferential order (liver > brain > ovary). The GSI and plasma levels of E2 were declined in response to exposure of γ-HCH and DDT. On withdrawal of exposure of pesticide there was recovery of HCHs in exposed fish for all tissues studied, whereas DDTs exposed fish showed recovery only in liver. Recovery of E2 production was also recorded in γ-HCH exposed fish whereas very little recorded in DDT exposed fish. It is suggested that HCHs and DDTs have preferential order (liver > brain > ovary) of their tissue bioconcentrations and HCH/DDT-withdrawal-dependent recovery during studied phase.     

The impact of sleep and psychiatric symptoms on alcohol consequences among young adults

ObjectiveIndependent lines of research have documented links between psychiatric symptoms and poor sleep quality, psychiatric symptoms and alcohol use, and alcohol use and poor sleep quality. The current study examined the synergistic effect of poor sleep quality and psychiatric symptoms on alcohol-related consequences in heavy-drinking young adults.MethodMatriculating college students reporting at least one heavy drinking episode over the first nine weeks of the semester (N = 385, 52% female) were categorized as experiencing ‘good’ (n = 280) versus ‘poor’ sleep quality (n = 105) and screening ‘positive’ (n = 203) or ‘negative’ (n = 182) for a psychiatric disorder. Sleep quality was assessed using the Pittsburgh Sleep Quality Index; psychiatric diagnosis was assessed using the Psychiatric Diagnostic Screening Questionnaire; and alcohol-related consequences were assessed using the Brief Young Adult Alcohol Consequences Questionnaire. General linear models were used to examine the main effects and interaction between sleep quality and psychiatric symptoms on alcohol-related consequences.ResultsSleep quality moderated the association between psychiatric screen and alcohol-related consequences among heavy-drinking college students, such that psychiatric symptoms were associated with more alcohol-related consequences in the context of poor sleep quality.ConclusionsThe combination of poor sleep quality and psychiatric symptoms is associated with increased alcohol-related consequences among heavy-drinking college students. Given the significant interaction between these symptoms, healthcare providers are encouraged to screen for the presence of sleep and psychiatric disorders among heavy-drinking young adults and to provide empirically-supported treatments as appropriate.     

Paracetamol impairs the profile of amino acids in the rat brain

In our experiment we investigated the effect of subcutaneous administration of paracetamol on the levels of amino acids in the brain structures. Male Wistar rats received for eight weeks paracetamol at two doses: 10 mg/kg b.w. (group P10, n = 9) and 50 mg/kg b.w. per day s.c. (group P50, n = 9).The regional brain concentrations of amino acids were determined in the prefrontal cortex, hippocampus, hypothalamus and striatum of control (Con, n = 9) and paracetamol-treated groups using HPLC. Evaluation of the biochemical results indicated considerable decrease of the content of amino acids in the striatum (glutamine, glutamic acid, taurine, alanine, aspartic acid) and hypothalamus (glycine) between groups treated with paracetamol compared to the control. In the prefrontal cortex paracetamol increased the level of γ-aminobutyric acid (GABA). The present study demonstrated significant effect of the long term paracetamol treatment on the level of amino acids in the striatum, prefrontal cortex and hypothalamus of rats.     

Influences of chronic venlafaxine,olanzapine and nicotine on the hippocampal and cortical concentrations of brain-derived neurotrophic factor (BDNF)

Brain-derived neurotrophic factor (BDNF) is a key neurotrophic factor in the brain. It plays an important role in the etiopathogenesis and pharmacotherapy of mental disorders, such as depression or schizophrenia. In recent years, studies have shown that cognitive processes, which are impaired in the course of mental disorders, significantly change BDNF levels in the brain.Administered to rats at a dose of 20 mg/kg (b.d. for 5 weeks), venlafaxine (VEN) increases BDNF levels in the hippocampus and cortex, compared to controls. Administered at a dose of 0.5 mg/kg (b.d. for 5 weeks), olanzapine (OLA) significantly increases BDNF levels in both the cortex and the hippocampus. Similarly, nicotine (NIC) administered at a dose of 0.2 mg/kg (b.d. for 5 weeks) increases BDNF concentrations in both the hippocampus and the cortex. Combined administration of NIC with VEN or OLA does not increase BDNF levels in the hippocampus or the cortex.Based on our study, it can be claimed that BDNF mediates behavioral responses only to drugs used individually and participates in the antidepressant and procognitive effects of the study compounds. BDNF also initiates plastic changes and modulation of synaptic activity in rat brains.     

The effects of konjac oligosaccharide on TNBS-induced colitis in rats

The purpose of the study was to assess the effects and the protective mechanism of konjac oligosaccharide (KOS) on the ulcerative colitis (UC) model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. KOS (1.0 and 4.0 g/kg/day) was administered for 14 days after the induction of colitis with TNBS. The status of the rats was assessed by morphological and biochemical methods. The effect of KOS on the colonic microflora was also assessed by studying the bacteria profile and short chain fatty acids (SCFAs) production in feces by standard culture techniques and gas chromatography, respectively. KOS administration improved rat weight, colonic length, damage score, structure of gut microbiota, production of SCFA, and reduced colon tissue levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Therefore, our results indicate that KOS is an anti-inflammatory and could be useful as a prebiotic to design functional foods for UC.     

The effect of perfluorododecanonic acid on endocrine status,sex hormones and expression of steroidogenic genes in pubertal female rats

Perfluorododecanoic acid (PFDoA), one of a number of commercially important perfluoroalkyl acids, has been detected in sera from humans and other animals; however, the effects of PFDoA on female reproduction remain unclear. To assess the impact of PFDoA on puberty and endocrine status, we exposed weaned pre-pubertal female rats to PFDoA, administered orally at doses of 0, 0.5, 1.5 and 3 mg/kg-d for 28 days, and measured body weight, reproductive organ weight and morphology, pubertal indicators, endocrine hormones, total serum cholesterol levels and steroidogenic enzyme gene expression. At 3 mg/kg-d, PFDoA significantly decreased body weight and serum estradiol levels, increased cholesterol levels (p < 0.05), and altered ovarian expression of genes responsible for cholesterol transport and steroidogenesis, including steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme and 17-beta-hydroxysteroid dehydrogenase (p < 0.05). PFDoA at the highest dose also reduced estrogen receptor α and β expression levels in the ovary (p < 0.05), whereas a lower concentration of PFDoA (0.5 mg/kg-d) decreased estrogen receptor β mRNA levels in the uterus (p < 0.05). PFDoA treatment did not affect serum follicle-stimulating hormone or luteinizing hormone (LH) levels at any concentration, although PFDoA at 3 mg/kg-d reduced LH receptor mRNA levels. There were no marked changes in sexual organ weight, age and weight at vaginal opening or first estrous cycle, or ovarian/uterine histology at any PFDoA concentration. These data show that PFDoA does not affect the endocrine status of pubertal rats, but at higher doses it does impact estradiol production and the expression of some key genes responsible for estrogen synthesis.     

The influence of amitriptyline and carbamazepine on levomepromazine metabolism in human liver: An in vitro study

BackgroundJoint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the present study was to investigate possible effects of the tricyclic antidepressant drug amitriptyline and the anticonvulsant drug carbamazepine on the metabolism of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver.MethodsThe experiment was performed in vitro using human liver microsomes. The rates of levomepromazine 5-sulfoxidation and N-demethylation (levomepromazine concentrations: 5, 10, 25 and 50 μM) were assessed in the absence and presence of amitriptyline or carbamazepine added in vitro (drug concentrations: 1, 2.5, 5, 10, 25 μM).ResultsA kinetic analysis of levomepromazine metabolism carried out in the absence or presence of carbamazepine showed that the anticonvulsant drug potently inhibited levomepromazine 5-sulfoxidation (K_i = 7.6 μM, non-competitive inhibition), and moderately decreased the rate of levomepromazine N-demethylation (K_i = 15.4 μM, mixed inhibition) at therapeutic drug concentrations. On the other hand, amitriptyline weakly diminished the rate of levomepromazine 5-sulfoxidation (K_i = 63 μM, mixed inhibition) and N-demethylation (K_i = 47.7 μM, mixed inhibition).ConclusionRegarding the central and peripheral effects of levomepromazine and some of its metabolites, the observed metabolic interaction between this neuroleptic and carbamazepine may be of pharmacological and clinical importance.     

Evaluation of 8-hydroxy-2-deoxyguanosine and NFkB activation,oxidative stress response,acetylcholinesterase activity,and histopathological changes in rainbow trout brain exposed to linuron

Linuron is a widely used herbicide to control grasses and annual broad leaf weeds. It is known that linuron has toxic effects on different organisms. However, the toxic effects of linuron on aquatic organisms, especially fish, is completely unknown. Thus, we aimed to investigate changes in 8-hydroxy-2-deoxyguanosine (8-OHdG) and nuclear factor kappa B (NFkB) activity, histopathological changes, antioxidant responses and acetylcholinesterase (AChE) activity in rainbow trout brain after exposure to linuron. Fish were exposed to 30 μg/L, 120 μg/L and 240 μg/L concentrations of linuron for twenty-one days. Brain tissues were taken from fish for 8-OHdG and NFkB activity, histopathological examination and determination of superoxide dismutase (SOD), catalase (CAT) enzyme activity, lipid peroxidation (LPO), and reduced glutathione (GSH) levels. Our data indicated that high linuron concentrations caused a decrease in GSH levels, SOD and CAT activities in brain tissues (p < 0.05). LPO levels were significantly increased by 240 μg/L linuron. All concentrations caused a significant inhibition in brain AChE enzyme activity (p < 0.05). Immunopositivity was detected for 8-OHdG and NFkB, and linuron exposure caused histopathological damage to the brain tissues. The results of this study can provide useful information for understanding of linuron-induced toxicity.     

Difficulties in emotion regulation in treatment-seeking alcoholics with and without co-occurring mood and anxiety disorders

Emotion regulation difficulties (ERD) are known to underlie mental health conditions including anxiety and depressive disorders and alcohol use disorder (AUD). Although AUD, mood, and anxiety disorders commonly co-occur, no study has examined the association between these disorders and ERD among AUD outpatients. In the current study, emotion regulation (ER) scores of AUD individuals with no co-occurring mental health condition were compared to the ER scores of individuals who met diagnostic criteria for co-occurring mood and/or anxiety disorders. Treatment-seeking AUD individuals (N = 77) completed measures of emotion regulation, alcohol use and psychological functioning prior to beginning a 12-week outpatient cognitive-behaviorally oriented alcohol treatment program. Individuals were classified as having no co-occurring mood or anxiety disorder (AUD-0, n = 24), one co-occurring disorder (AUD-1, n = 34), or two or more co-occurring disorders (AUD-2, n = 19). Between-group differences in emotion regulation, quantity/frequency of alcohol consumption, positive and negative affect, affective drinking situations, negative mood regulation expectancies, distress tolerance, alexithymia, trait mindfulness, and psychological symptom severity were examined. Compared with the AUD-0 group, the AUD-2 group reported significantly greater ERD, psychiatric distress and alcohol consumption, more frequent drinking in response to negative affect situations, greater interference from negative emotions, and less use of mindfulness skills. The AUD-1 group differed from AUD-0 group only on the DERS lack of emotional awareness (Aware) subscale. Emotion regulation scores in the AUD-0 group were comparable to those previously reported for general community samples, whereas levels of ERD in the AUD-1 and AUD-2 were similar to those found in other clinical samples. Implications for the inclusion of ER interventions among AUD patients who might most benefit from such an intervention are discussed.     

Nephroprotective effect of date fruit extract against dichloroacetic acid exposure in adult rats

The aim of this study was to investigate the protective effects of aqueous date extract (ADE) on dichloroacetic acid (DCA)-induced nephrotoxicity. In vitro, total phenolic content estimated in the ADE were 417.71 mg gallic acid equivalents/100 g fresh weights (FW), while total flavonoid and tannins contents were 285.23 and 73.65 mg catechin equivalents/100 g FW, respectively. The ADE has strong scavenging activity. Ferulic, caffeic and p-coumaric acids are the major’s compounds. Nephrotoxicity was induced in male Wistar rats by the administration of 0.5 and 2 g/L DCA as drinking water. Some of these rats received also by gavage ADE (4 mL/kg) before the administration of DCA. After two months of experiment, DCA administration caused elevated levels of renal MDA, significant depletion of GSH levels, altered the antioxidant enzyme activities and deteriorated the renal functions as assessed by the increased plasma urea, uric acid and creatinine levels compared to control rats. The treatment with the ADE significantly normalized the increased plasma levels of creatinine, urea and uric acid, reduced the elevated MDA levels, significantly normalized the antioxidant enzyme activities and GSH level and restored the altered kidney histology in rats treated with DCA. Therefore, it was speculated that ADE protects rats from kidney damage through its antioxidant capacity.     

Behavioural and neurochemical comparison of chronic intermittent cathinone,mephedrone and MDMA administration to the rat

The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10 mg/kg) or MDMA (10 mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2 h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10 mg/kg) and MDMA (10 mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10 mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10 mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and failed to induce neurotoxic damage when administered intermittently over 3 weeks.     

Sulfation of melatonin: Enzymatic characterization,differences of organs,species and genders,and bioactivity variation

Exogenous melatonin (Mel) is widely used in clinic for multiple therapeutic purposes. In metabolism pathways of Mel, 6-hydroxymelatonin-sulfate (S-O-Mel) and N-acetylserotonin sulfate (S-NAS) are the most abundant metabolites account for over 90% of total Mel metabolites in humans, indicating that sulfation plays an important role in reflecting the functions and clearance of Mel in vivo. In the present study, we characterized Mel sulfation using various human organ cytosols (liver, lung, kidney, small intestine and brain), liver cytosols from five different animal species, and cDNA-expressed human sulfotransferase (SULT) for the first time. Our results demonstrated that liver, lung, kidney and small intestine of humans had high catalytic efficiency for Mel sulfation, however, brain contained a very low reaction rate. Interestingly, organ cytosols prepared from females exhibited higher sulfation activity than those of males. SULT isoforms 1A1, 1A2, 1A3, 1B1 and 1E1 exhibited metabolic activities toward Mel. According to kinetic parameters (K_m and V_max), chemical inhibition, correlation analysis, molecular docking and sulfation assays with recombinant human SULTs isoforms, SULT1A1 was determined as the major enzyme responsible for Mel sulfation. Furthermore, considerable species differences in Mel sulfation were observed, and the total intrinsic clearance rate of Mel sulfation was as follows: monkey > rat > dog > human > pig > mouse. Additionally, the anti-inflammatory effects of Mel and its sulfated metabolites were evaluated by inhibiting nitric oxide (NO) production in RAW264.7 cells, and S-O-Mel as a bioactive form, exhibited potent bioactivity. Our investigation provided a global view of the enzyme-dependent sulfation of Mel that can guide biomedical research on Mel.