Anxiolytic and antidepressants' effect of Crataegus pinnatifida (Shan Zha): biochemical mechanisms.

Depression and anxiety disorders are highly prevalent. Selective serotonin reuptake inhibitors (SSRIs) are the current first-line treatment for depression, but they have pronounced limitations. Traditional Chinese medicine can serve as a safe and effective alternative to conventional drugs, particularly since many herbal remedies have already been approved for human use as food additives, making the transition from bench to bedside more efficient. We previously demonstrated that a novel herbal treatment (NHT) induces anxiolytic- and antidepressant-like effects. NHT consists of four herbs: Crataegus pinnatifida (Shan Zha), Triticum aestivum (Fu Xiao Mai), Lilium brownii (Baihe), and the fruit of Ziziphus jujuba (Da Zao). In the current study, we examined the antidepressant-like and anxiolytic-like activities of each individual herb on stressed mice and compared those to the effects of NHT and escitalopram. We show here that Shan Zha is sufficient to produce an anxiolytic and antidepressant-like effect similar to NHT or the escitalopram through activation of 5-HT1A receptor and an elevation in BDNF levels in the hippocampus and Pre-frontal cortex (PFC). Chronic treatment with Shan Zha did not alter serotonin transporter levels in the PFC, as opposed to escitalopram treatment. These results were confirmed in vitro, as none of the herbs blocked SERT activity in Xenopus oocytes. Notably, Shan Zha is sold as a nutritional supplement; thus, its transition to clinical trials can be easier. Once its efficacy and safety are substantiated, Shan Zha may serve as an alternative to conventional antidepressants.

Moderation of the transgenerational transference of antenatal stress-induced anxiety.

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring's exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams' and pups' anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams' anxiety. Interestingly though, pups' exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.

Cerebral MAO Activity Is Not Altered by a Novel Herbal Antidepressant Treatment.

Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.

GABAA Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment.

Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.

The Impact of Chronic Early Administration of Psychostimulants on Brain Expression of BDNF and Other Neuroplasticity-Relevant Proteins.

ABSRACT: Frequently, healthy individuals, children, and students are using stimulants to treat attention deficit hyperactivity disorder (ADHD)-like symptoms or to enhance cognitive capacity, attention and concentration. Methylphenidate, the most common treatment for ADHD, similarly to cocaine, blocks the dopamine reuptake, leading to increase in dopamine level in the synaptic cleft. Brain-derived neurotrophic factor (BDNF) and other neuroplasticity-relevant proteins have a major role in cellular plasticity during development and maturation of the brain. Young Sprague Dawley rats (postnatal days (PND) 14) were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70, and 90). We found age-dependent, but stimulant-independent, alterations in the mRNA expression levels of microtubule-associated protein tau, doublecortin, and synaptophysin. The PND 90 rats, treated with methylphenidate at an early age, exhibited increased BDNF protein levels in the prefrontal cortex compared to the saline-treated group. Despite the treatment effects at the biochemical level, cocaine and methylphenidate treatments at an early age had only minor effects on the behavioral parameters measured at older ages. The biochemical alterations may reflect neuroprotective or neuroplastic effects of chronic methylphenidate treatment at an early age.

Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration.

Attention deficit hyperactivity disorder (ADHD) overdiagnosis and a pharmacological attempt to increase cognitive performance, are the major causes for the frequent (ab)use of psychostimulants in non-ADHD individuals. Methylphenidate is a non-addictive psychostimulant, although its mode of action resembles that of cocaine, a well-known addictive and abused drug. Neuronal- and glial-derived growth factors play a major role in the development, maintenance and survival of neurons in the central nervous system. We hypothesized that methylphenidate and cocaine treatment affect the expression of such growth factors. Beginning on postnatal day (PND) 14, male Sprague Dawley rats were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70 and 90). On PND 56, rats treated with cocaine or methylphenidate from PND 14 through PND 35 exhibited increased hippocampal glial-cell derived neurotrophic factor (GDNF) mRNA levels, after 21 withdrawal days, compared to the saline-treated rats. We found a significant association between cocaine and methylphenidate treatments and age progression in the prefrontal protein expression of brain derived neurotrophic factor (BDNF). Neither treatments affected the behavioral parameters, although acute cocaine administration was associated with increased locomotor activity. It is possible that the increased hippocampal GDNF mRNA levels, may be relevant to the reduced rate of drug seeking behavior in ADHD adolescence that were maintained from childhood on methylphenidate. BDNF protein level increase with age, as well as following stimulant treatments at early age may be relevant to the neurobiology and pharmacotherapy of ADHD.

Escitalopram or novel herbal mixture treatments during or following exposure to stress reduce anxiety-like behavior through corticosterone and BDNF modifications.

Anxiety disorders are a major public health concern worldwide. Studies indicate that repeated exposure to adverse experiences early in life can lead to anxiety disorders in adulthood. Current treatments for anxiety disorders are characterized by a low success rate and are associated with a wide variety of side effects. The aim of the present study was to evaluate the anxiolytic effects of a novel herbal treatment, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram. We recently demonstrated the anxiolytic effects of these treatments in BALB mice previously exposed to one week of stress. In the present study, ICR mice were exposed to post natal maternal separation and to 4 weeks of unpredictable chronic mild stress in adolescence, and treated during or following exposure to stress with the novel herbal treatment or with escitalopram. Anxiety-like behavior was evaluated in the elevated plus maze. Blood corticosterone levels were evaluated using radioimmunoassay. Brain derived neurotrophic factor levels in the hippocampus were evaluated using enzyme-linked immunosorbent assay. We found that (1) exposure to stress in childhood and adolescence increased anxiety-like behavior in adulthood; (2) the herbal treatment reduced anxiety-like behavior, both when treated during or following exposure to stress; (3) blood corticosterone levels were reduced following treatment with the herbal treatment or escitalopram, when treated during or following exposure to stress; (4) brain derived neurotrophic factor levels in the hippocampus of mice treated with the herbal treatment or escitalopram were increased, when treated either during or following exposure to stress. This study expands our previous findings and further points to the proposed herbal compound's potential to be highly efficacious in treating anxiety disorders in humans.

Promiscuous gating modifiers target the voltage sensor of K(v)7.2, TRPV1, and H(v)1 cation channels.

Some of the fascinating features of voltage-sensing domains (VSDs) in voltage-gated cation channels (VGCCs) are their modular nature and adaptability. Here we examined the VSD sensitivity of different VGCCs to 2 structurally related nontoxin gating modifiers, NH17 and NH29, which stabilize K(v)7.2 potassium channels in the closed and open states, respectively. The effects of NH17 and NH29 were examined in Chinese hamster ovary cells transfected with transient receptor potential vanilloid 1 (TRPV1) or K(v)7.2 channels, as well as in dorsal root ganglia neurons, using the whole-cell patch-clamp technique. NH17 and NH29 exert opposite effects on TRPV1 channels, operating, respectively, as an activator and a blocker of TRPV1 currents (EC50 and IC50 values ranging from 4 to 40 µM). Combined mutagenesis, electrophysiology, structural homology modeling, molecular docking, and molecular dynamics simulation indicate that both compounds target the VSDs of TRPV1 channels, which, like vanilloids, are involved in π-π stacking, H-bonding, and hydrophobic interactions. Reflecting their promiscuity, the drugs also affect the lone VSD proton channel mVSOP. Thus, the same gating modifier can promiscuously interact with different VGCCs, and subtle differences at the VSD-ligand interface will dictate whether the gating modifier stabilizes channels in either the closed or the open state.

Rasagiline prevents neurodegeneration in thiamine deficient rats-a longitudinal MRI study.

Neuroprotection is a therapeutic approach for the management of neurodegenerative diseases. Experimental thiamine deficiency (TD) in rats provides a model for selective neurodegeneration accompanied by chronic oxidative deficits. Rats exhibit neurological and cognitive impairments, which can be partially reversed by thiamine administration, enabling the study of mechanisms of neurodegeneration as well as neuroprotection. In this magnetic resonance (MR) study we used various techniques to characterize the neuroprotective effects of rasagiline, a selective MAO-B inhibitor. TD was induced by a thiamine-deficient diet and daily injections of the central thiamine antagonist, pyrithiamine. Daily injections of either saline or rasagiline (3mg/kg) were also administered to untreated-TD rats and rasagiline-treated TD rats respectively. With the appearance of neurological symptoms, all injections were terminated and thiamine was restored. MRI scans were performed before induction of TD (control values), on days 10, 12 (before symptoms appear), 14 (symptomatic stage) and during the recuperation period. Both groups were assessed using in-vivo serial T2-weighted imaging and diffusion tensor imaging (DTI), from which apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were calculated. A histopathological evaluation was correlated with the MRI analysis. Thalamic hyperintensities were significantly smaller and less severe in the rasagiline-treated TD rats. Enlargement of the lateral ventricles was significantly less pronounced in the rasagiline-treated TD group. FA values of the untreated-TD group decreased significantly in the thalamic on days 12 and 14 and in the corpus callosum on day 14. These results demonstrate significant neuroprotection by rasagiline which could have implications for clinical neurodegenerative disorders.

A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice.

AIMS: Depression is a chronic, recurring and potentially life-threatening illness. Current treatments for depression are characterized by a low success rate and associated with a wide variety of side effects. The aim of the present study was to evaluate the behavioral and biological anti-depressant effects of a novel herbal treatment (NHT), as well as to assess its potential side effects, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram. MAIN METHODS: Depressive-like behavior was evaluated using the forced swim test (FST) and the tail suspension test (TST). Sexual behavior was evaluated following treatment by measuring latency before first mount and number of total mounts. Brain derived neurotrophic factor (BDNF) levels were evaluated using enzyme-linked immunosorbent assay. Serotonin transporter (SERT) levels in the pre-frontal cortex (PFC) and hypothalamus were evaluated using high affinity binding assay. KEY FINDINGS: (1) The NHT reduced depressive-like behavior in the FST and TST; (2) BDNF levels in the PFC of mice treated both with the NHT and escitalopram were increased; (3) SERT levels in the hypothalamus were significantly higher in the NHT group, in comparison to escitalopram and the control groups, and significantly lower in the PFC of the NHT group in comparison to the escitalopram group; and (4) the NHT led to less sexual dysfunction, compared to treatment with escitalopram. SIGNIFICANCE: Our NHT has the potential of being highly efficacious in treating depression in humans, while causing minimal to no influence on sexual function.

Genome-wide miRNA expression profiling of human lymphoblastoid cell lines identifies tentative SSRI antidepressant response biomarkers.

AIM: Over 30% of patients with major depression do not respond well to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Using genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) CHL1 was identified as a tentative SSRI sensitivity biomarker. This study reports on miRNAs implicated in SSRI sensitivity of LCLs. METHODS: Eighty LCLs were screened from healthy adult female individuals for growth inhibition by paroxetine. Eight LCLs exhibiting high or low sensitivities to paroxetine were chosen for genome-wide expression profiling with miRNA microarrays. RESULTS: The miRNA miR-151-3p had 6.7-fold higher basal expression in paroxetine-sensitive LCLs. This corresponds with lower expression of CHL1, a target of miR-151-3p. The additional miRNAs miR-212, miR-132, miR-30b*, let-7b and let-7c also differed by >1.5-fold (p < 0.05) between the two LCL groups. CONCLUSION: The potential value of these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients.

Anxiolytic effects of a novel herbal treatment in mice models of anxiety.

AIMS: Anxiety and stress disorders are currently among the ten most important public health concerns, and in recent years, have reached epidemic proportions. The current success rate of treatments for anxiety disorders is not high, reaching 50% at most. These treatments are also associated with a wide variety of side effects. The aim of the present study was to investigate the anxiolytic properties of a novel herbal treatment produced in our laboratory compared to a conventional treatment for anxiety disorders, namely SSRIs. MAIN METHODS: Anxiety-like behavior was evaluated in adult mice exposed to stress during childhood following 1, 2 and 3 weeks of treatment with the novel herbal treatment or escitalopram, using the novel open field and the elevated plus maze paradigms. The behavioral evaluation in these mice was followed by a biochemical assessment of their brain hippocampal BDNF levels and blood corticosterone levels. KEY FINDINGS: The study showed that (1) the novel herbal treatment reduced anxiety-like behaviors in both behavioral tests. Interestingly, this reduction was observed only following a 3-week treatment; (2) following the novel treatment, corticosterone levels in the plasma of treated mice were reduced and this reduction was similar to the one observed following escitalopram treatment; and (3) BDNF levels in the hippocampus of mice treated both with the novel herbal treatment and escitalopram were increased. SIGNIFICANCE: These behavioral and biological findings indicate that our novel herbal compound has the potential of being highly efficacious in treating anxiety disorders.

Decreased serotonin content and reduced agonist-induced aggregation in platelets of patients chronically medicated with SSRI drugs.

BACKGROUND: Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) reduces the risk and severity of cardiovascular diseases. SSRIs block the serotonin transporter, thereby inhibiting serotonin (5-HT) uptake into presynaptic neurons as well as into platelets where 5-HT is stored in dense granules. When 5-HT is released in response to agonists it enhances platelet aggregation induced by injury-related signals. Chronic administration of SSRIs may thus reduce platelet aggregability secondary to depletion of platelets' serotonin stores. METHODS: The study included ten DSM-IV-TR major depression (MDD) and four obsessive compulsive disorder (OCD) patients and fourteen healthy untreated age- and sex-matched controls. The patients were chronically medicated (6-108 months) with various SSRIs. Platelet serotonin content was assessed in fresh samples of platelet rich plasma (PRP) using radioimmunoassay. ADP, collagen, arachidonic acid and epinephrine were used as inducers of platelet aggregation measured in PRP by turbometric method in a microplate reader. RESULTS: Lower platelet serotonin content (66%; p<0.05) and lower ADP, collagen or epinephrine-induced platelet aggregation (10-52%; p<0.05) were detected in PRP of SSRI-medicated patients, while no such effect was obtained with arachidonic acid. LIMITATIONS: The small sample size and the co-treatment with non-SSRI drugs such as benzodiazepines. CONCLUSION: Patients chronically medicated with SSRIs exhibit lower platelet 5-HT content and reduced platelet aggregation induced by ADP, collagen and epinephrine, but not by arachidonic acid. Our observations may explain the increased bleeding risk associated with chronic SSRI treatment as well as the reported beneficial effect of SSRIs in prevention of recurrent myocardial infarction.

Platelet vesicular monoamine transporter 2 density in the disruptive behavior disorders.

In a former study, we reported decreased platelet vesicular monoamine transporter 2 (VMAT2) density (Bmax) in patients with ADHD. The current study aimed at measuring platelet VMAT2 in the disruptive behavior disorders (DBDs) to assess whether this finding is specific to ADHD or generalizable to the broader DBD concept. The study included 13 patients with DBDs aged 10-12 years and 16 healthy volunteers aged 8-17 years. All participants underwent a thorough clinical evaluation using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version for diagnosis, the Nisonger Child Behavior Rating Form, the Clinical Global Impressions Scale-Severity version, and the DSM-IV ADHD Scale (DAS). The study group's DAS scores did not differ from those of the control group. There was no significant difference between the patients with DBDs and the control group either in VMAT2 density (Bmax) or affinity (Kd) as measured by high-affinity [(3)H]TBZOH binding. We conclude that the formerly reported decreased platelet VMAT2 Bmax in patients with ADHD may be specific to ADHD and not present in DBDs. Larger-scale replication is needed.

Altered affinity of the platelet vesicular monoamine transporter 2 to dihydrotetrabenazine in children with major depression.

Platelet vesicular monoamine transporter (VMAT2) binding characteristics were assessed, using high affinity dihydrotetrabenazine ([(3)H]TBZOH) binding, in 14 children with major depression (MDD) and 16 matched controls. All participants underwent a thorough diagnostic evaluation and the levels of depression and anxiety were measured. K (d) values were significantly lower in children with MDD versus controls (2.93 ± 0.84 vs. 3.63 ± 0.56 nM, respectively, t = 2.4, df = 18.4, p = 0.025). B (max) values did not differ significantly. This preliminary finding indicates a possible structural change in platelet VMAT2 in children with MDD.

Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker.

AIMS: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants for treating major depression. However, approximately 30% of patients do not respond sufficiently to first-line antidepressant drug treatment and require alternative therapeutics. Genome-wide studies searching for SSRI response DNA biomarkers or studies of candidate serotonin-related genes so far have given inconclusive or contradictory results. Here, we present an alternative transcriptome-based genome-wide approach for searching antidepressant drug-response biomarkers by using drug-effect phenotypes in human lymphoblastoid cell lines (LCLs). MATERIALS & METHODS: We screened 80 LCLs from healthy adult female individuals for growth inhibition by paroxetine. A total of 14 LCLs with reproducible high and low sensitivities to paroxetine (seven from each phenotypic group) were chosen for genome-wide expression profiling with commercial microarrays. RESULTS: The most notable genome-wide transcriptome difference between LCLs displaying high versus low paroxetine sensitivities was a 6.3-fold lower (p = 0.0000256) basal expression of CHL1, a gene coding for a neuronal cell adhesion protein implicated in correct thalamocortical circuitry, schizophrenia and autism. The microarray findings were confirmed by real-time PCR (36-fold lower CHL1 expression levels in the high paroxetine sensitivity group). Several additional genes implicated in synaptogenesis or in psychiatric disorders, including ARRB1, CCL5, DDX60, DDX60L, ENDOD1, ENPP2, FLT1, GABRA4, GAP43, MCTP2 and SPRY2, also differed by more than 1.5-fold and a p-value of less than 0.005 between the two paroxetine sensitivity groups, as confirmed by real-time PCR experiments. CONCLUSION: Genome-wide transcriptional profiling of in vitro phenotyped LCLs identified CHL1 and additional genes implicated in synaptogenesis and brain circuitry as putative SSRI response biomarkers. This method might be used as a preliminary tool for searching for potential depression treatment biomarkers.

N-methyl-citalopram: A quaternary selective serotonin reuptake inhibitor.

We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [(3)H]citalopram and uptake studies with [(3)H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10(-7)M as well as [(3)H]ketanserin binding to rat brain membranes at 10(-5)M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.

Lack of modulatory effect of short-term repeated electroconvulsive therapy on platelet vesicular monoamine transporter 2 (VMAT2) in depressed patients.

We investigated the effect of electroconvulsive therapy (ECT) on platelet vesicular monoamine-transmitter-transporter 2 (pVMAT2) using high-affinity [(3)H]dihydrotetrabenazine binding to platelet VMAT2 in 11 women and 7 men, aged 53.7 +/- 15.8. The Hamilton Depression Rating Scale (HAM-D) and the binding characteristic of pVMAT2 were assessed before and after six ECTs, administered over 21 days. A significant reduction (4.5 +/- 0.46; 20.8%) was obtained in HAM-D scores (p < 0.01) following the ECTs. The pVMAT2 density (B (max)) and affinity values (K (d)) remained unaltered. Six ECTs are not sufficient for modulation in pVMAT2 expression. Long-term studies are needed to clarify the relationship between full remission and possible alterations in platelet/brain VMAT2 characteristics.

Human lymphoblastoid cell line panels: novel tools for assessing shared drug pathways.

AIMS: While powerful in silico tools are emerging for predicting drug targets and pathways, general in vitro tools for assessing such predictions are lacking. We present a novel in vitro method for distinguishing shared versus distinct drug pathways based on comparative cell growth inhibition profiles across a small panel of human lymphoblastoid cell lines (LCLs) from individual donors. MATERIALS & METHODS: LCLs from unrelated healthy donors were examined in parallel for growth inhibition profiles of various drugs, including antidepressants (paroxetine, fluoxetine, fluvoxamine, citalopram, amitriptyline and imipramine); anticancer drugs (5-fluorouracil, 6-mercaptopurine, azathioprine, methotrexate and resveratrol); steroid drugs (dexamethasone, beclomethasone and prednisolone); and antipsychotic drugs (haloperidol and clozapine). Cell growth was assessed by the colorimetric 2,3-bis(2-methoxy-4-nitro-5-sulfophenly)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide method following 72 h of drug exposure. RESULTS: LCLs from unrelated individuals exhibited a wide range of sensitivities to growth inhibition by a given drug, which were independent of basal cell replication rates. Yet, each individual cell line demonstrated a consistent sensitivity to multiple drugs from the same family. High goodness-of-fit values (R(2) > 0.6) were consistently observed for plots comparing the growth-inhibition profiles for paired drugs sharing a similar pathway, for example antidepressants, steroid drugs, antipsychotics, or 6-mercaptopurine compared with azathioprine, but not for drugs with different pathways. The method's utility is demonstrated by the observation that chlorpheniramine, an antihistamine drug long suspected to also possess antidepressant-like properties, exhibits a growth-inhibition profile very similar to antidepressants. CONCLUSION: Comparing the growth-inhibition profiles of drugs (or compounds) of interest with the profiles of drugs with known pathways may assist in drug pathway classification. The method is useful for in vitro assessment of in silico-generated drug pathway predictions and for distinguishing shared versus distinct pathways for compounds of interest. Comparative transcriptomics analysis of human lymphoblastoid cell lines exhibiting 'edge' sensitivities can subsequently be utilized in the search for drug response biomarkers for personalized pharmacotherapy. The limitations and advantages of the method are discussed.

Neurodegeneration in thiamine deficient rats-A longitudinal MRI study.

Selective neurodegeneration accompanied by mitochondrial dysfunction characterizes neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Thiamine deficiency (TD) in rats is a model for the study of cellular and molecular mechanisms that lead to selective neuronal loss caused by chronic oxidative deficits. Neurodegeneration in TD-rats develops over a period of 12 to 14 days and can be partially reversed by thiamine administration. The aim of this study was to characterize the in-vivo progression of neurodegeneration and the neuronal rescue processes in TD using T(2) magnetic resonance mapping and diffusion tensor imaging (DTI). Each rat was scanned prior to TD induction (day 0), before the appearance of neurological symptoms (day 10), during the symptomatic stage (days 12 and 14) and during the recuperation period (days 31 and 87). Time-dependent lesions were revealed mainly in the thalamus and the inferior colliculi. Early decrease in the fractional anisotropy (FA) was found on day 10 in the inferior colliculi and to a lesser degree in the thalamus, while the earliest detectable changes in the T(2) parameter occurred only on day 12. FA values in the thalamus remained significantly low after thiamine restoration, suggesting irreversible disarrangement and replacement of neuronal structures. While T(2) values in the frontal cortex demonstrated no lesions, FA values significantly increased on days 14 and 31. An enlargement of the lateral ventricles was observed and persevered during the recovery period. This longitudinal MRI study demonstrated that in TD MRI can detect neurodegeneration and neuronal recovery. DTI is more sensitive than T(2) mapping in the early detection of TD lesions.