Genome-wide association analyses for neuroleptic-induced tardive dyskinesia

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified an association of SNPs in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. By canonical pathway-based analyses with Ingenuity Pathway Analysis software, we also found that genes involved in the GABA receptor signaling pathway were significantly enriched among the genes with gene-based corrected association allelic P values of less than 0.05. The gene expression levels in the postmortem prefrontal brains in those with the risk genotypes for TD were in the opposite direction to those in mouse brains after long-term admiration of haloperidol. These findings indicate that individuals with the susceptibility to TD may have less ability to adapt to long-term exposure of neuroleptics in some gene expression levels.     

Extensive Gray Matter Volume Reduction in Treatment-Resistant Schizophrenia

Background:

Approximately one-third of people with schizophrenia are treatment-resistant and some do not achieve remission with clozapine, the gold-standard antipsychotic medication for treatment-resistant schizophrenia. This study compared global and regional brain volumes between treatment-respondent and treatment-resistant patients with schizophrenia, including a group of patients who were clozapine-resistant.

Methods:

T1-weighted brain MRIs were obtained on a 3T scanner in 20 controls and 52 people with schizophrenia who were selected based on their symptomatic responses to antipsychotic medication: 18 responded well to first-line atypical antipsychotics (FLR), 19 were treatment-resistant but responsive to clozapine monotherapy (TR), and 15 were ultra-treatment-resistant and did not respond to clozapine (UTR). Treatment groups were matched for disease duration and current psychopathology. SIENAX and FSL-VBM were used to investigate differences in the global brain, gray matter (GM), white matter, ventricular cerebrospinal fluid volumes, and regional GM volumes.

Results:

GM volume was significantly reduced in the TR and UTR groups compared with controls and the FLR group (p < 0.05). GM volume was significantly reduced in TR patients compared with FLRs in the superior, middle, and inferior temporal gyri, pre- and post-central gyri, middle and superior frontal gyri, right supramarginal gyrus, and right lateral occipital cortex. UTR patients showed reduced GM compared with FLRs in their right parietal operculum and left cerebellum. No significant volume differences were observed between TR and UTR groups.

Conclusions:

These differences are unlikely to be solely due to medication effects, and reduced GM volume in treatment-resistant schizophrenia may represent an accelerated disease course or a different underlying pathology.     

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal–clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl--aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal–retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40–85 Hz, p=0.006) and reduced low-frequency oscillations (delta band at 1–5 Hz, p<0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal–retardation symptoms experienced during ketamine administration (p=0.02). Ketamine also reduced gating of the theta-alpha (5–12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.     

Variation of Stratum Corneum Biophysical and Molecular Properties with Anatomic Site

Several serine protease enzymes are known to be involved in both normal desquamation and the inflammatory processes of the skin. Alteration in the activity of these proteases should also affect corneocyte maturity and size as well as stratum corneum thickness. The aim of the present work was to characterise the baseline changes in corneocyte size, corneocyte maturity, selected protease activity (specifically, Kallikreins-5 and 7, tryptase), protein content and trans-epidermal water loss (TEWL) as a function of anatomic site. The anatomic sites investigated were: cheek, abdomen, wrist and mid-ventral forearm. TEWL values were highest for the cheek (p < 0.05). The TEWL values were also significantly higher (p < 0.05) for cheek and wrist compared with other sites. Protein content was significantly lower for wrist (p < 0.05) compared with other sites. Corneocyte maturity and surface area were significantly (p < 0.05) lower for cheek and wrist compared with other sites. An excellent correlation (r² = 0.99) was obtained for maturity and surface area measurements. Kallikrein-5 and tryptase activity were significantly higher for the cheek compared with other sites but Kallikrein-7 values were uniform across sites. The findings have significant implications for skin permeability to drugs and other substances such as environmental toxins depending on the anatomic site of delivery or exposure.KEY WORDS: kallikrein, maturity, protease, skin, transepidermal water loss     

Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia

OBJECTIVE: Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. METHODS: Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). RESULTS: Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample). CONCLUSION: The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD.     

Pulse pressure amplification in relation to body fatness

AIMS

Arterial pressure transfer to the periphery is accompanied by pulse pressure amplification (PPA). Pulse pressure is influence by body fat. The purpose of the present study was to evaluate any possible inter-relation between body fatness and PPA in healthy subjects.

METHODS

Haemodynamic and wave reflection indices were estimated by pulse wave analysis. Body fat was measured by bio-impedance.

RESULTS

A total of 367 healthy volunteers (136 men and 231 women) was studied. Pulse pressure amplification correlated significantly with percentage of body fat (r = −0.53, P < 0.0001), age (r = −0.62, P < 0.0001), height (r = 0.43, P < 0.0001), heart rate (r = 0.28, P < 0.0001) and mean blood pressure (r = −0.29, P < 0.0001). The association of PPA with body fat was also significant in a multiple linear regression model. Age was an independent predictor of PPA and analysis of study subjects subdivided into two groups, those <50 years and those >50 years showed that body fatness correlated inversely and significantly with PPA in individuals both younger and older than 50 years (r = −0.44, P < 0.0001, r = −0.37, P < 0.0001 respectively). Augmentation pressure was also associated significantly with percentage of body fat in both subgroups (r = 0.48, P < 0.0001 and r = 0.49, P < 0.0001 respectively).

CONCLUSIONS

This study performed on healthy subjects showed that pulse pressure amplification is related to body fatness over a wide age range. Percentage body fat is significantly associated with augmentation pressure, a component of central pulse pressure.     

Oxidative stress and the antipsychotic-induced vacuous chewing movement model of tardive dyskinesia: evidence for antioxidant-based prevention strategies

Rationale

Despite decades of research, tardive dyskinesia (TD) remains a poorly understood iatrogenic movement disorder with few effective treatments and no known cure. Accordingly, the development of an innocuous strategy to prevent or mitigate antipsychotic (AP)-associated TD would represent an important clinical advance. Supporting evidence for antioxidant (AX)-based treatment regimens can be found in the preclinical literature, where AP-induced vacuous chewing movements (VCMs) in rats are attenuated by the concurrent administration of direct and indirect AXs.

Objectives

Our aim was to review the preclinical literature examining the role of AX-promoting treatments in the prevention of AP-induced VCMs in rats.

Methods

A literature search using Google Scholar and PubMed was performed. Relevant results were qualitatively reviewed.

Results

Studies featuring a variety of naturally occurring and synthetic AX treatments were identified and included in the review. The majority of studies used haloperidol (HAL), a typical AP, to induce VCMs. Studies revealed reduced VCMs in co-treated rats, with favorable changes seen in markers of oxidative stress (OS) and AX status, but were limited by their short durations.

Conclusions

Some preclinical evidence suggests that the inclusion of a naturally occurring and benign AX compound as an adjunct to AP treatment may help guard patients against TD, but additional long-duration studies are needed. This AX-based strategy is further substantiated by accumulating evidence of preexisting OS abnormalities in schizophrenia (SZ).     

Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice

Aim:

To investigate the role of chemokine receptor CXCR3 in cigarette smoking (CS)-induced pulmonary damage.

Methods:

CXCR3 knockout (CXCR3-/-) mice were used. Differences in airspace enlargement, mRNA expression of matrix metalloproteinases (MMPs), transforming growth factor (TGF) β1, CXCL10 in lung homogenates, and CXCL10 content in bronchoalveolar lavage (BAL) fluids and homogenates were compared between CXCR3-/- mice and wild-type (WT) mice three days after three-day CS exposures.

Results:

The linear intercept was significantly less in CXCR3-/- mice than in WT mice (30.1±0.9 μm vs 40.3±2.4 μm, P<0.01). Morphologically, collagen was deposited less around airways and vessels in CXCR3-/- mice. The lung hydroxyproline content was significantly lower in CXCR3-/- mice than in WT mice (6.0±1.0 μg/mL vs 12.0±1.6 μg/mL, P<0.05). Profoundly lower mRNA expression of MMP2, MMP12, TGFβ1, and CXCL10 was seen in lung homogenates from CXCR3-/- mice. CXCL10 concentrations in BAL fluid and lung homogenates were significantly lower in CXCR3-/- mice than in WT mice (BAL fluid: 19.3±1.4 pg/mL vs 24.8±1.6 pg/mL, P<0.05; lung homogenates: 76.6±7.0 pg/mL vs 119.5±15.9 pg/mL, P<0.05).

Conclusion:

CXCR3 is important in mediating lung tissue damage and airway remodeling following a short-term CS insult, possibly through up-regulation of CXCL10 and inducement of mRNA expression of MMPs. Targeting CXCR3 may be helpful for prevention of CS-induced pulmonary pathology.     

Rice bran oil prevents neuroleptic-induced extrapyramidal symptoms in rats: Possible antioxidant mechanisms

Tardive dyskinesia (TD) is one of the serious side effects of long-term antipsychotic treatment. Chronic treatment with neuroleptic leads to the development of abnormal oral movements called vacuous chewing movements (VCMs). The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of this hypothesis indicate that neurotoxic free radical production is likely to be a consequence of antipsychotic medication and is related to occurrence of TD. Oxidative stress is implicated in the pathophysiology of TD. Rats chronically treated with haloperidol orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs, which increased in a time-dependent manner as the treatment continued for 5 weeks. Motor coordination impairment started after the 1^st week and was maximally impaired after 3 weeks and gradually returned to the 1^st week value. Motor activity in an open field or home cage (activity box) not altered. Administration of rice bran oil (antioxidant) by oral tubes at a dose of 0.4 mL/ day prevented the induction of haloperidol-elicited VCMs as well impairment of motor coordination. The results are discussed in the context of a protective role of antioxidant of rice bran oil in the prevention of haloperidol-induced extrapyramidal symptoms.     

Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol-induced atherosclerosis

BACKGROUND AND PURPOSE

Erectile dysfunction correlates with cardiovascular disease and its common risk factors due to the development of endothelial dysfunction. Positive effects on endothelial and erectile function have been described for substances inhibiting the renin-angiotensin-system. Here, we investigated in an atherosclerosis model, whether telmisartan (angiotensin receptor blocker) and ramipril (angiotensin converting enzyme inhibitor) are equivalent or the combination of both is superior in improving endothelial function in the aorta and the corpus cavernosum and in reducing atherosclerosis.

EXPERIMENTAL APPROACH

Wild-type (WT, C57/B6) and apolipoprotein-E-deficient (ApoE^−/−) mice were treated with a cholesterol-rich diet for 8 weeks. ApoE^−/− mice were supplemented with either telmisartan (20 mg·kg⁻¹·day⁻¹), ramipril (2.5 mg·kg⁻¹·day⁻¹) or the combination thereof.

KEY RESULTS

Systolic blood pressure significantly decreased in treatment groups (P < 0.001), with significantly smaller reduction under ramipril monotherapy (P < 0.05). Endothelial function (assessed by pharmacological stimulation of aortic rings and corpus cavernosum in organ bath chambers) was impaired in ApoE^−/− mice compared to WT animals, which was improved by all three treatments to a comparable extent (P < 0.05). Atherosclerotic lesion size in the ascending aorta and aortic sinus (P < 0.001), the amount of lipid peroxides in cavernosal and aortic tissue (P < 0.05) and free radical load (dihydroethidium-stain) (P < 0.05) were enhanced in untreated ApoE^−/− mice in comparison to WT animals and were significantly reduced by either treatment. In penile tissue, expression of eNOS could be restored by renin-angiotensin-aldosterone system blockade.

CONCLUSIONS AND IMPLICATIONS

Telmisartan and ramipril significantly improved endothelial function of aortic and cavernosal tissues in ApoE^−/− via reduction of oxidative stress. Combination of both agents does not enhance beneficial effects significantly.     

Long-term Alcohol Consumption Increases Pro-Matrix Metalloproteinase-9 Levels via Oxidative Stress

Matrix metalloproteinases (MMPs) play an important role in alcoholic liver disease. In this study, we evaluated the relationship between pro MMP-9 (pMMP-9) and oxidative stress in plasma of rat exposed to chronic alcohol consumption. Twenty four rats were divided into four groups. Rats in the control group (n = 6) were subjected to physiologic saline by intragastric (i.g.) route. Group Ethanol (n = 6) was given 1 ml of 80% ethanol (v/v) in distilled water through i.g. route. Group Vitamin E (Vit E), (n = 6) was given vitamin E (100 mg kg⁻¹ day⁻¹) by intra peritonealy. Group Vitamin E + Ethanol (n = 6) was given vitamin E 2 h before the administration of ethanol. At the end of 4 weeks, blood samples were taken and plasma malondialdehyde (MDA), protein carbonyls (PCs), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α) and pMMP-9 levels were measured. Chronic ethanol administration increased the AST, MDA, PCs, TNF-α and pMMP-9 levels when compared to those in control group (p < 0.05, p < 0.01, p < 0.01, p < 0.05, p < 0.05, respectively). Vitamin E treatment was found to decrease lipid peroxidation and protein oxidation (p < 0.01, p < 0.01, respectively). Also TNF-α and pMMP-9 levels returned to normal by vitamin E treatment. Within all subjects, there was positive correlation between pMMP-9 levels and MDA, PCs levels (p = 0.045, r = 0.454; p = 0.004, r = 0.574, respectively). We conclude that since antioxidant supplementation decreases the alcohol-induced pMMP-9 levels, oxidative stress could be one of the mediators of the generation of MMP-9.     

Biochemical and histopathological effects on liver due to acute oral toxicity of aqueous leaf extract of Ecliptaalba on female Swiss albino mice

Background:

Limited data is available about the toxicity of herbal remedies used for self-medication. Since a popular medicinal plant Ecliptaalba contains various bioactive molecules, the present study aimed to observe the biochemical and histological changes in liver associated with acute oral toxicity (LD₅₀) of aqueous extract of E. alba (L.) Hassk. in female Swiss albino mice.

Materials and Methods:

For the acute oral toxicity study, the animals were divided into six groups of 6 mice each. Group– I was normal control and the treatment groups were administered aqueous leaf extract of E. alba orally at different doses of 500 mg (group – I),1750 mg (group–III), 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg/ kg/b.wt.(group- VI) for seven consecutive days. The mice were sacrificed on the eighth day and blood was collected for the analysis of ALP (alkaline phosphatase), SGPT (serum glutamic pyruvic transferase), total protein and albumin. The liver was dissected, weighed, and processed for histopathological analysis.

Results:

The LD₅₀ was found to be 2316.626 mg/kg /body weight in female mice. Serum SGPT, total protein and albumin increased in treated group- IV (P < 0.05), V (P < 0.01), and VI (P < 0.01) as compared to the control (group- I). ALP level significantly decreased in the treated group- IV (P < 0.05), V (P < 0.01) and VI (P < 0.01). Histopathological changes were observed at dose of 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg (group- VI).

Conclusion:

It was concluded that oral administration of aqueous leaf extract of E. alba had detrimental effects on biochemical parameters and induced histopathological alterations in liver of female Swiss albino mice at doses higher than 2000 mg/kg/day indicating that its indiscriminate use should be avoided.KEY WORDS: Biochemical, Ecliptaalba, hepatotoxicity, histopathological     

Efficacy of North American Crotalid Antivenom Against the African Viper Bitis gabonica (Gaboon Viper)

Envenomations by exotic snakes occur from zoological collections and private individual collectors. Antivenoms to these snakes may not be readily available. The objective of this study is to determine the efficacy of North American crotalid antivenin in treating mice envenomated with venom of the African viper Bitis gabonica (Gaboon viper). The subjects of the study were Swiss Webster mice weighing approximately 30 g. The study was conducted in the University research laboratory. B. gabonica venom was obtained from Venom Supplies Pty Ltd (Tanunda, South Australia) and reconstituted in sterile water. North American Crotalid Fab2 antivenin (Anavyp®, Instituto Bioclon, Mexico) was donated by the manufacturer. The experimental groups were: Group I received two times an intraperitoneal LD₅₀ dose of venom, 2.58 mg/kg. Group II received the same dose after incubation for 1 h with 10 mg of antivenin. Time to onset of toxicity defined as respiratory rate <10/min or absence of response to prodding. t test and Chi square with p < 0.05 considered significant. Time to onset of toxicity was 7.040 ± 4.334 h in group I, and 20.665 ± 2.074 in group II (p = 0.0064, 95% confidence interval of difference of means −22.694 to −4.556). Antivenin was efficacious to statistical significance at 4, 8, 12, and 16 h (p values of 0.062, 0.0067, 0.0067, and 0.0253, respectively). Improvement at 20 and 24 h (p values of 0.0673 and 0.0673, respectively) did not achieve statistical significance. North American Crotalid antivenin (Anavyp®, Instituto Bioclon, Mexico) demonstrated efficacy in increasing time to onset of distress in mice poisoned with B. gabonica (Gaboon viper) venom. Based on this result, treatment of humans envenomated with B. gabonica with North American Croatlid antivenin could be considered for severe envenomations if specific B. gabonica antivenin is unavailable.     

A Controlled, Evidence-Based Trial of Paliperidone Palmitate, A Long-Acting Injectable Antipsychotic, in Schizophrenia

Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p⩽0.006) and PANSS negative and positive symptom Marder factor scores (p⩽0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5–6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.     

Neuroleptic-induced vacuous chewing movements in rodents: incidence and effects of long-term increases in haloperidol dose

Rats treated chronically with neuroleptics develop vacuous chewing movements (VCMs), similar in some respects to tardive dyskinesia (TD) in man. The VCM syndrome was used as a model of TD to examine the ability of increased neuroleptic doses to produce long-term suppression of dyskinetic movements. The incidence and persistence of the VCM syndrome in individual rats were also assessed to look for affected and unaffected subgroups. Rats were initially treated for 15 weeks with haloperidol decanoate. For the next 21 weeks, half the group received a 50–150% increase in dose while the other half continued to receive the same dose. Animals were also followed during a 28-week withdrawal period. Total VCM ratings showed a skewed distribution, with some rats exhibiting few movements while others developed marked and persistent movements. Increasing doses did not suppress VCMs, nor did they exacerbate movements during the withdrawal period. To the extent that the VCM syndrome models TD, the absence of long-term suppression of the VCM syndrome suggests that, at this dosage range, increasing depot neuroleptic doses may not be a useful long-term strategy for TD suppression.     

Evaluation of Anxiolytic effect of Erythrina mysorensis Gamb. in mice

Aim and Objectives:

To evaluate anxiolytic effect of stem bark ethanol and chloroform extracts of Erythrina mysorensis in mice.

Materials and Methods:

The anxiolytic activity was examined by using the elevated plus maze (EPM) and open field test (OFT), and motor coordination by rotarod test (RRT). Twenty four Swiss albino male mice were divided into four groups of six mice each. Group 1 received vehicle (normal saline); group 2 received diazepam (1 mg/kg); groups 3 and 4 received ethanolic and chloroform extract of Erythrina mysorensis, 200 and 400 mg/kg p.o., respectively.

Results:

Mice treated with diazepam (1 mg/kg, p.o.) showed significant (P < 0.001) increase ini the percentage of open arms entries and time spent whereas, in closed arm the number of entries and time spent were significantly (P < 0.05) decreased. Oral administration of chloroform and ethanol extract of E. mysorensis exhibited significant (P < 0.05) increase in the number of open arm entries and time spent with significant (P < 0.05) reduction in number of entries and time spent in the closed arm as compared to group 1. Chloroform and ethanol extracts treated mice also produced significant increase in the number of rearings (P < 0.05), assisted rearings and number of squares crossed (P < 0.01). Rotarod test showed significant (P < 0.01) reduction in motor activity at 45 min with diazepam and E. mysorensis extracts (400 mg/kg) as compared to groups 3 and 1.

Conclusion:

Erythrina mysorensis possess significant anxiolytic activity in the mice. It can be a promising anxiolytic agent.KEY WORDS: Elevated plus maze test, Erythrina mysorensis, open field test, Rotarod test     

Genetic Association of Recovery from Eating Disorders: The Role of GABA Receptor SNPs

Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill'') or absence (n=115 no symptoms in the past year, ie, ‘recovered'') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10⁻⁶, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10⁻⁶, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.     

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg⁻¹ day⁻¹. Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol’s utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-013-9490-6) contains supplementary material, which is available to authorized users.Key words: galactose single-point method, hepatotoxicity, isoniazid, kaempferol, rifampicin     

Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.     

Differential role of dopamine D1 and D2 receptors in isoniazid-induced vacuous chewing movements

Tardive dyskinesia (TD) is a syndrome of potentially irreversible and involuntary hyperkinetic disorders that occurs during chronic neuroleptic therapy and is a major limitation of such therapy. Vacuous chewing movements (VCMs) in rats have been widely accepted as an animal model of tardive dyskinesia. In the present study isoniazid (1, 2 and 5 microM i.c.v.) dose-dependently produced VCMs in rats. The response produced by a 10-microM dose was lower than that of earlier doses but was statistically significant when compared to a saline-treated group. Diazepam (1 and 4 mg/kg i.p.) and progabide (50 and 100 mg/kg i.p.) dose-dependently reversed the isoniazid-induced VCMs. Haloperidol (0.5 and 1 mg/kg i.p.) and SCH-23390 (0.25 and 0.5 mg/kg i.p.) reversed the isoniazid-induced VCMs in a dose-dependent manner. Sulpiride (25 and 50 mg/kg i.p.), a dopamine D2 receptor antagonist, had no effect on isoniazid-induced VCMs. SKF-38393 (10 and 15 mg/kg i.p.) dose-dependently augmented the isoniazid-induced VCMs. Quinpirole 0.02 mg/kg i.p. had no effect on isoniazid-induced VCMs but a higher quinpirole dose (0.05 mg/kg) significantly reduced isoniazid-induced VCMs. Isoniazid (2 microM i.c.v.) produced stereotypy (grooming and rearing) in rats. Haloperidol (0.5 and 1 mg/kg i.p.), SCH-23390 (0.25 and 0.5 mg/kg i.p.) and sulpiride (25 and 50 mg/kg i.p.) decreased the severity of isoniazid-induced stereotypy. SKF-38393 (10 and 15 mg/kg i.p.) dose-dependently augmented the isoniazid-induced grooming behavior more prominently as compared to quinpirole (0.02 and 0.05 mg/kg i.p.); on the other hand quinpirole potentiated isoniazid-induced rearing behavior. In conclusion, the results of the present study demonstrated the differential involvement of dopamine D1 and D2 receptors in isoniazid-induced VCMs.