Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Serum testosterone levels in bipolar and unipolar depressed female patients and the role of medication status.

Objective: to compare testosterone levels between female depressed patients and female bipolar patients.Methods: Sixty-one female patients with major depressive disorder (MDD) (n = 23) or bipolar disorder (BD) (n = 38) between 18 and 45 years old were included in the study. Participants were evaluated during a depressive or manic episode with the Hamilton depression rating scale (HDRS) or Young mania rating scale (YMRS), respectively. No patients in the MDD group were taken valproate while in the BD group 14 (36.84%) were taken valproate. Total testosterone (TT) and free testosterone (FT) levels were quantified during the early follicular phase of the cycle, with radioimmunoassay or solid phase enzyme-linked immunoassay. Data were collected from May 2016 to February 2017.Results: Mean TT serum levels were significantly higher in BD patients in comparison to MDD patients. Although age and diagnosis were related to TT levels, however when we added valproate use in the analysis, only the relation between TT and valproate use remained significant.Conclusions: In this sample, TT levels were related to valproate use in patients with BD. More studies regarding the role of testosterone in affective symptoms should be conducted to clarify the relation between testosterone, affective disorders, and medication.KeypointsWe observed that testosterone levels were significant higher in bipolar women compared to women with MDD.The use of valproate could be associated with the testosterone levels in female patients with BD.Evaluation of women suffering BD should include a testosterone levels determination, particularly when they are taking valproate.

Effects of Gaba Derivatives on Anxious and Compulsive Behavior in Offspring of Rats with Experimental Preeclampsia.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

Binding of Glyprolines to L-Arginine Inverts Its Analgesic and Antiagressogenic Effects.

We studied the effects of intraperitoneal administration of L-arginine in doses of 5, 15, and 50 µg/kg and peptides in doses containing equimolar amount of this amino acid on aggressive-defensive behavior of rats (footshock model). The peptides were synthesized by binding of Pro-Gly-Pro sequence to one or both ends of the L-arginine molecule. The analgesic and antiagressogenic effects of L-arginine and opposite effects of arginine-containing peptides (except Pro-Gly-Pro tripeptide) were demonstrated. The combination of arginine with glyprolines yielded peptides with intrinsic regulatory properties. This expands the possibilities of synthesis of drugs for correction of pain and aggression caused by pain.

Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice.

Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-κB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-κB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-κB pathway and neurodevelopmental disorders pathogenesis.

Rapid Tranquilization for Psychiatric Patients with Psychomotor Agitation: What is Known About it?

Rapid tranquilization is an intervention used in control of agitation or aggression in patients with mental disorders. This study synthesized the available evidence regarding efficacy and safety of drugs used for rapid tranquilization in psychiatric patients with psychomotor agitation. It is an overview study of systematic reviews and meta-analysis of randomized controlled trials (RCT) identified in the database MEDLINE, EMBASE, CINAHL, Web of Science, Cochrane Library and LILACS until April 2015. A team of reviewers, in pairs and independently, identified eligible studies and assessed methodological quality using AMSTAR. Data were extracted from four studies (61 RCT, 8021 participants). The association of haloperidol with promethazine (H + P) promoted tranquilization and presented better safety profile, with moderate quality evidence. Olanzapine demonstrated benefit towards tranquilization and good safety profile, but needed additional administration to keep tranquilization. There was no benefit in the use of haloperidol alone or associated to another psychotropic to most outcomes evaluated. The evidence was of low quality to most of the interventions. H + P was considered a good option for rapid tranquilization, however, more RCT are necessary to confirm the efficacy and safety of the available interventions.

Effects of Tripeptide Gly-His-Lys in Pain-Induced Aggressive-Defensive Behavior in Rats.

We studied the effect of Gly-His -Lys tripeptide administered intraperitoneally in doses of 5, 15, 50 and 150 µg/kg on pain-induced aggressive-defensive behavior. A foot-shock model of aggression in rats grouped in pairs in an electrified chamber was used. Analgesic and antiaggresiogenic effects of the peptide were demonstrated. It was found the L-lysine residue plays the key role in these effects, because they were observed under the influence of L-lysine administration in doses close to its equimolar content in the studied tripeptide.

Effects of Oxytocin on the Levels and Metabolism of Monoamines in the Brain of White Outbred Mice during Long-Term Social Isolation.

The effects of intranasal administration of oxytocin on the levels and metabolism of monoamines in symmetrical structures of the brain of white outbred mice kept under conditions of long-term social isolation were studied by HPLC. Disappearance of initial right-sided asymmetry in the content of dopamine metabolites in the striatum, increased 5-hydroxyacetic acid content in the right striatum, and disappearance of the initial left-sided asymmetry in serotonin level in the cortex were noted; we also found a decrease in norepinephrine content in the left hippocampus with appearance of asymmetry and higher content in the right olfactory tubercle. It can be hypothesized that minor changes in the serotoninergic and dopaminergic systems against the background of high reactivity of noradrenergic system represent specific response of the brain to oxytocin in aggressive animals.

[EFFECT OF MEDIATOR-TYPE DRUGS ON HUMAN PSYCHOPHYSIOLOGICAL STATUS DURING MODEL OPERATOR ACTIVITY].

In a placebo-controlled study, changes in psychophysiological status of operators (38 healthy male volunteers aged 23-35 years) performing 4-hour model operator activity were evaluated after a single oral administration of typical representatives of the different classes of drugs (haloperidol, proroxan, yohimbine hydrochloride, propranolol, mesocarb, isoprenaline, Belladonna extract, anabasine hydrochloride, valproate sodium, and phenazepam), which are used for the treatment, rehabilitation and prophylaxis of common diseases. It was found that all the drugs modified to a greater or lesser extent some components of the model operator activity. Isoprenaline and phenazepam had the most negative effect on the psychophysiological indicators and quality of the modeled operator activity. The results should be considered before administration of such drugs to working operators.

Effects of Phenibut and Citrocard on Non-Competitive and Competitive Behavior during Provoked Aggression in Animals.

Anti-aggressive effects of phenibut (25 mg/kg) and its structural analogue citrocard (50 mg/kg) were revealed in rats under condition of provoked intraspecific aggression. These substances significantly decreased manifestations of aggression in animals: they increased the latency of attacks and reduced their number. Anti-aggressive effects of citrocard were more pronounced than effects of phenibut under conditions of non-competitive aggression induced by fear of inescapable painful exposure or under conditions of competitive aggression reflecting the ability of animals to reveal adaptive social communicative skills in aversive situation.

[Neurogenic copulative dysfunction in men: theoretical aspects, differential diagnosis, and rational therapy].

UNLABELLED: Neurogenic copulative dysfunction (CD) is observed in different diseases and injuries of both the central and peripheral nervous system. CD concurrent with actual nervous system diseases has been established to be an important psychotraumatic factor that significantly reduces quality of life in these patients. AIM: To investigate the effect of aminophenylbutyric acid (Noophen) on male copulative function. SUBJECTS AND METHODS: Forty patients with chronic lumbosacral radiculopathy on an exacerbation and mild and moderate closed head injury were examined. RESULTS: The findings suggest that Noophen is effective in the combination therapy of neurogenic CD. CONCLUSION: The drug can normalize an autonomic control over nerve centers involved in the regulation of copulative function, and improve the psychoemotional status of patients.

[Cognitive and emotional impairments in patients with protracted anxiety-phobic disorders].

AIM: To study cognitive and emotional impairments in patients with anxiety-phobic disorders (APDs), to comparatively analyze the clinical manifestations of acute (less than one-year) and protracted (1-to-5-year) forms of this disease, and to evaluate the efficacy of noofen used to treat this pathology. SUBJECTS AND METHODS: Sixty-two patients aged 18 to 50 years with APDs were examined. The investigators collected clinical history data, performed neurological examination, and assessed autonomic disorders in accordance with the questionnaire to reveal their signs, anxiety using the Hamilton anxiety rating scale, memory impairment employing the methods developed by A.R. Luria, attention disorders applying the test of variables of attention, and diagnosed emotional intelligence using the Mayer-Salovey-Caruso emotional intelligence test. Noofen 1000 mg/day was used to treat the patients. RESULTS: Protracted APDs were shown to be characterized by the higher degree of psychosomatic symptoms and by more pronounced impairments in attention, memory, and emotional intelligence. The data of posttreatment clinical and psychological studiesare indicative of improvements in 73.3% of cases. CONCLUSION: The findings may lead to the conclusion that noofen is highly effective in the treatment of patients with protracted APDs.

Effect of perphenazine enanthate in Pyrenean chamois (Rupicapra pyrenaica).

Perphenazine enanthate was used to allow adaptation to captivity in 11 Pyrenean chamois (Rupicapra pyrenaica). At the time of capture, all animals received 0.10 mg/kg of acepromazine maleate and 2.5 mg/kg of perphenazine enanthate intramuscularly. The effect was evaluated by means of three behaviors: alertness, defecation, and flight distance. The tranquilization and lack of fear of humans of all animals were determined and the usefulness of this long-acting tranquilizer for chamois adaptation to captivity was confirmed.

[On the mechanism of ikaron-1 anti-naupathia action].

Pneumomicroinjection of vestibuloprotector ikaron-1 (Russia) in specific neurons of the medial vestibular nucleus (MVN) was studied in cats immobilized by muscle relaxants using microelectrode devices. The original preparation had a direct effect on the majority of MVN neurons (95 %). Thirty four neurons of 37 cells (92 %) developed an inhibitory response, only one cell (3 %) was activated and 2 neurons (5 %) were areactive. Therefore, the inhibitory reaction to the preparation was 34 times more often than excitatory. An investigation of the MVN neurons activity evoked by adequate stimulation of the vestibular apparatus showed that ikaron-1 attenuates the evoked response in 92 % cells. This phenomenon could be behind the ikaron-lantinaupathia action.

[Effect of GB-115 dipeptide on anxiety in rats with model benzodiazepine withdrawal syndrome].

The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

N-Acetylcysteine Augmentation for Patients With Major Depressive Disorder and Bipolar Depression.

Major depressive disorder (MDD) and bipolar depression (BD) can often be difficult to treat. N-acetylcysteine (NAC) is a nutraceutical product that has been trialed in a large number of neuropsychiatric and medical disorders, with mixed results. Many randomized controlled trials (RCTs) have studied NAC augmentation as an intervention in MDD and BD. These RCTs were pooled in 2 recent meta-analyses. One meta-analysis with 7 RCTs (pooled N = 728) conducted in patients with MDD or BD found that NAC was not superior to placebo in the attenuation of depression ratings in either main or sensitivity analyses. The other meta-analysis with 6 RCTs (pooled N = 248) conducted in patients with BD found a small, imprecise effect size for NAC (standardized mean difference, 0.45; 95% confidence interval, 0.06-0.84). The advantage for NAC in this meta-analysis would almost certainly have been lost had the authors excluded from analysis 2 RCTs, both of which had problematic characteristics and findings and both of which also obtained a large and statistically significant advantage for NAC. At present, therefore, evidence does not encourage the use of NAC as an augmentation treatment for patients with MDD or BD. It remains to be seen whether NAC augmentation benefits depressed subpopulations, such as those with higher levels of inflammatory biomarkers at baseline.

Ganoderma lucidum promotes sleep through a gut microbiota-dependent and serotonin-involved pathway in mice.

Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified. Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics. Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.

ß-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice.

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent ß-sitosterol as a promising candidate. ß-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. ß-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of ß-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of ß-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

How can drug discovery for psychiatric disorders be improved?

Psychiatric disorders such as depression, anxiety and schizophrenia are leading causes of disability worldwide, and have a huge societal impact. However, despite the clear need for better therapies, and major advances in the understanding of the molecular basis of these disorders in recent years, efforts to discover and develop new drugs for neuropsychiatric disorders, particularly those that might revolutionize disease treatment, have been relatively unsuccessful. A multidisciplinary approach will be crucial in addressing this problem, and in the first Advances in Neuroscience for Medical Innovation symposium, experts in multiple areas of neuroscience considered key questions in the field, in particular those related to the importance of neuronal plasticity. The discussions were used as a basis to propose steps that can be taken to improve the effectiveness of drug discovery for psychiatric disorders.

Etizolam: A rapid review on pharmacology, non-medical use and harms.

ISSUES: Etizolam is a thienodiazepine derivative, with high affinity for the benzodiazepine site of GABAA receptors. It is often referred to as a new (or novel) psychoactive substance, a 'designer' benzodiazepine or a 'street benzodiazepine'. Increasing reports of non-medical use, identification of etizolam as an ingredient in counterfeit medications and the common identification of etizolam in drug-related deaths, highlight the need for a greater understanding of etizolam. APPROACH: A rapid narrative review was conducted using PubMed and Google Scholar to synthesise what is known about etizolam to answer two research questions: (i) Does the pharmacological or toxicological profile of etizolam differ from other benzodiazepines?; and (ii) What is the nature and context of non-medical use and harms related to etizolam? KEY FINDINGS: Etizolam has a higher potency as an anxiolytic but lower lethality compared with diazepam. Few harms are documented with the therapeutic use of pharmaceutical products. Harms appear to be predominantly related to the use of etizolam in illicitly manufactured pills and occur almost exclusively in the context of mixed-drug toxicity. CONCLUSION: In therapeutic doses, there is little to suggest that etizolam is more harmful than other benzodiazepines. Most harms with etizolam appear to be related to the wide availability of illicitly manufactured pills, which are taken in unknown doses and combined with other substances. Current harm reduction advice, including avoiding combining opioids and benzodiazepines, remains relevant and increasingly important within an emerging culture of non-medical use.