Benzodiazepine Receptor Research Articles

Trends in the Prescription of Benzodiazepine Receptor Agonists from 2009 to 2020: A Retrospective Study Using Electronic Healthcare Record Data of a University Hospital in Japan.

In recent years, the prescription trends of benzodiazepine receptor agonists (BZRAs) have not been investigated in Japan despite the publication of guidelines that promote cautious use of BZRAs. The prescription trend of BZRAs was assessed using the electronic healthcare records data of a University Hospital in Japan. The data from April 2009 to March 2021 were used. The following three types of outcomes were set: the proportion of patients who were prescribed with BZRAs within those prescribed hypnotics or anxiolytics; the mean number of the types of prescribed BZRAs, and the mean average daily doses of BZRAs. The same analysis was conducted for benzodiazepines (BZDs) and non-benzodiazepines (Z-drugs). As a result, we found that the proportions of patients prescribed BZRAs within those prescribed hypnotics or anxiolytics began to decrease, particularly from 2015 for patients aged <75 years and those aged ≥75 years. Further, the degree of decrease was larger in patients aged ≥75 years. The proportion for BZDs decreased particularly in the study period, and the proportion for Z-drugs also began to decrease approximately from 2016 in patients aged ≥75 years. The results suggest a possibility that guidelines affected the decreased prescriptions of BZRAs.

Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition.

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor β (TGF-β)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-β-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-β pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers.

Use of Benzodiazepines and Z-Drugs in Nursing Home Residents with Dementia: Prevalence and Appropriateness.

Background:Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia.Objective:To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia.Methods:This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders.Results:The prevalence of BZRA use is 39.2% (95% CI: 36.3%–42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0% of continuous anxiolytic prescriptions and 44.8% of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks.Conclusion:BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use.

Antibiotics and the Nervous System-Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the β-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer’s or Parkinson’s diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities.

'I just thought that it was such an impossible thing': A qualitative study of barriers and facilitators to discontinuing long-term use of benzodiazepine receptor agonists using the Theoretical Domains Framework.

IntroductionExisting interventions to reduce long‐term benzodiazepine receptor agonist (BZRA) use lack theoretical underpinning and detailed descriptions. This creates difficulties in understanding how interventions work and how to replicate them in practice. The Theoretical Domains Framework (TDF) can be used to identify behaviour change determinants to target during intervention development.ObjectiveTo explore barriers and facilitators to discontinuing BZRA use from the perspective of both current and previous long‐term BZRA users.Design/Setting and ParticipantsSemistructured TDF‐based interviews were conducted with community‐based individuals with current or previous experience of long‐term BZRA use. Data were recorded, transcribed and analysed using the framework method.ResultsTwenty‐eight individuals were interviewed. Despite commonalities in perceived barriers/facilitators to discontinuing BZRA use within individual TDF domains, individual participants had different experiences of identified determinants of BZRA discontinuation. For example, both similarities and differences existed within and between each participant group in terms of knowledge of the appropriate duration of BZRA use (‘Knowledge’ domain) and experience of withdrawal symptoms (‘Reinforcement’ domain). Compared to previous users, current users typically anticipated more barriers to discontinuing BZRA use and fewer positive consequences of discontinuation.ConclusionThis study reports on barriers and facilitators to discontinuing BZRA use from the perspectives of current and previous long‐term users. The findings highlight the challenging nature of BZRA discontinuation and a multitude of barriers that impact participants’ behaviour regarding BZRA use. Future work will involve developing a theory‐based intervention to support BZRA discontinuation in primary care.Patient ContributionThe study included patients as participants.

Preparation, characterization, and in vivo biodistribution study of intranasal 131I-clonazepam-loaded phospholipid magnesome as a promising brain delivery system

ObjectiveClonazepam (CP) is a potent long-acting nitrobenzodiazepine derivative that could be used for targeting peripheral benzodiazepine receptors. Phospholipid magnesome is a new vesicular nanosystem recently developed for brain targeting. Improving the uptake of 131I-CP to the brain might be effective for the diagnosis and/or radiotherapy of certain brain diseases and/or tumors. MethodsCP was radiolabeled with 131I using direct electrophilic substitution reaction. Quality control of 131I-CP was performed using different techniques. Different formulas of 131I-CP were prepared and characterized according to particle size and polydispersity index. The structural features of the optimized formula were then interpreted using transmission electron microscopy and scanning electron microscopy, whereas pharmacokinetic and in vivo behaviors were estimated using the intravenous and intranasal delivery routes. ResultsThe heart and blood demonstrated lower uptake of 131I-CP, which inevitably decreased the nontarget effects of radioiodine. Intranasally administered 131I-CP-loaded magnesomes (INMg) had noticeably higher brain uptake (7.1 ± 0.09%ID/g) with rapid onset of action within 5 min and effective pharmacokinetic behavior. INMg had a drug targeting efficiency and nose-to-brain direct transport percentage of 121.1% and 94.6%, respectively as well as a relative bioavailability of 441.04 ± 75.5%. ConclusionThe present study showed that 131I-CP-loaded magnesomes can be a beneficial brain-targeting approach for improving the diagnosis and/or radiotherapy of certain brain diseases.

Development and acceptability of a decision aid for chronic insomnia considering discontinuation of benzodiazepine hypnotics.

AimTo describe the development and acceptability of a decision aid (DA) for chronic insomnia considering discontinuation of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) hypnotics, and if discontinuing, tapering with or without cognitive behavioral therapy for insomnia (CBT‐I).MethodsWe reviewed relevant literature describing chronic insomnia to identify options. We used the results of the systematic review and meta‐analysis conducted previously to determine the related outcomes of two options: discontinuation of BZD/BZRA hypnotics by gradual tapering alone and discontinuation of BZD/BZRA hypnotics by gradual tapering with CBT‐I. We then developed a prototype of DA following the International Patient Decision Aid Standards. A mixed methods survey was conducted to assess the acceptability among patients and healthcare providers.ResultsThe prototype consisted of a description of insomnia, options of continuing or discontinuing BZD/BRZA hypnotics (if discontinuing, the options of tapering hypnotics with or without CBT‐I), pros and cons of each option, and a value clarification exercise. Patients (n = 24) reported that the DA had acceptable language (79%), adequate information (71%), and well‐balanced presentation (91%). Healthcare providers (n = 20) also provided favorable feedback.ConclusionWe developed a DA for chronic insomnia considering discontinuation of BZD/BRZA hypnotics, which was acceptable for stakeholders. The developed DA was designed to support patients and healthcare providers to make a decision about whether to discontinue BZD/BRZA hypnotics.

Remimazolam reduces sepsis-associated acute liver injury by activation of peripheral benzodiazepine receptors and p38 inhibition of macrophages

BackgroundRemimazolam is a novel ester-type benzodiazepine with ultrafast onset of sedation effect and fast recovery of consciousness. It has potential advantages in the sedation of sepsis-associated acute liver injury (SALI) patients. However, the effect and mechanism of remimazo lam on inflammation in the liver have not yet been elucidated. This study investigated the anti-inflammatory effects and mechanisms of remimazolam on SALI both in vivo and in vitro. MethodsLipopolysaccharide (LPS) plus galactosamine treated rat model and LPS-challenged RAW264.7 cells model were constructed to simulate SALI. Next, the models were used to explore the efficacy of remimazolam treatment on SALI. Benzodiazepine receptor inhibitor, PK11195, was also employed. Hepatic injury was assessed by quantifying levels of transaminases, examining liver pathology, and calculating the number of inflammatory cells in the liver. Inflammatory response was evaluated by determining levels of pro-inflammatory cytokines and chemokines in blood, as well as p38 phosphorylation (p-p38) in the liver. ResultsSALIrat models showed significant liver damage as manifested by increased levels of transaminases, proinflammatory cytokines, chemokines, and p-38. Remimazolam treatment reduced the liver injury and pathological changes, suppressed pro-inflammatory reactions, and elevated p-p38. The protective effect of remimazolam on liver injury was significantly blocked by PK11195. In LPS-stimulated RAW264.7 cells, it was found that treatment with remimazolam reduced the inflammatory response in LPS-treated cells in a time-dependent manner and decreased the level of p-p38. These results suggest that PK11195 can block remimazolam-induced inhibition of proinflammatory cytokine release and p-38 phosphorylation. ConclusionsThis study shows that remimazolam can attenuate inflammatory response in SALI, which may be associated with activation of peripheral benzodiazepine receptors and inhibition of p38 phosphorylation in macrophages.

Risk of long-term benzodiazepine and Z-drug use following the first prescription among community-dwelling adults with anxiety/mood and sleep disorders: a retrospective cohort study

ObjectiveTo measure the incidence of long-term benzodiazepine receptor agonist (BZRA) use among individuals with anxiety, mood and/or sleep disorders. To identify factors associated with long-term use following the first prescription.MethodsThis...

Development of a 3D-Printed Dosing Platform to Aid in Zolpidem Withdrawal Therapy.

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.

Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

Introduction: Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-1205.&#x0D; Materials and methods: A probable interaction between RU-1205, morphine and adjuvant drugs in pain behaviors was carried out on the model of somatogenic pain. 95 male mice received either RU-1205 (5 mg/kg, i.p.) and morphine (1 mg/kg, i.p.) separately or in combination with haloperidol (0.45 mg/kg, i.p.); midazolam (0.3 mg/kg, i.p.); diazepam (1 mg/kg, i.p.); metoclopramide (5 mg/kg, i.p.), and clonidine (1 mg/kg, i.p.). The analgesic effect was assessed by tail flick test. Registration of the latent period of the reaction was carried out 30, 60 and 90 minutes after the adjuvant drug administration.&#x0D; Results: When studying the interaction with morphine, it was found that clonidine, haloperidol and metoclopramide enhanced the effects; diazepam offset them, and midazolam had no affect on the analgesic properties. In the course of the studies, RU-1205 showed an increase in analgesic activity when combined with clonidine, a slight increase with midazolam, and a decrease when co-administered with diazepam. Haloperidol had no influence on the effect of RU-1205, while metoclopramide both potentiated and reduced the analgesic effect.&#x0D; Discussion: Pharmacodynamic and pharmacokinetic interactions of RU-1205 with an α2AR agonist, benzodiazepine receptor agonists, D2P antagonist, and σ-receptor blocker were established.&#x0D; Conclusion: The presented data make it possible to more accurately formulate ideas about the localization and action mechanism of the kappa-agonist of opioid receptors, the compound RU-1205.

The Association between Use of Benzodiazepine Receptor Agonists and the Risk of Obstructive Sleep Apnea: A Nationwide Population-Based Nested Case-Control Study.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse. Benzodiazepine receptor agonists (BZRAs) are associated with pharyngeal muscle relaxation, increased apnea duration, and hypoxia, which might worsen OSA. This study aimed to examine the association between the use of BZRAs and the risk of OSA. The study was conducted using data from the National Health Insurance Database of Taiwan between 2002 and 2011. We only included new users who were never exposed to any BZRAs and identified 1848 participants with OSA, and 1848 matched controls. A logistic regression model was used to determine the association between the use of BZRAs and the development of OSA. BZRA exposure was divided into usage patterns, dosage, duration, and pharmacokinetic class. We found an increased risk of OSA in current users and recent past users compared with distant past users. Patients with a higher cumulative dose of BZRAs were more likely to develop OSA compared to those with a lower cumulative dose. We found an increased risk of OSA in patients treated with BZRAs, especially for current users and those with higher cumulative doses. A reduced risk of OSA was found in Z-drug users compared with benzodiazepine users.

The preventative effect of of Ro5-4864 (peripheral benzodiazepine receptor agonist) on spinal epidural fibrosis after laminectomy in a rat model

ABSTRACT Objective To investigate the histopathological effects of a peripheral benzodiazepine receptor agonist (Ro5-4864) on epidural fibrosis (EF) in an experimental study model (post-laminectomy) in rats. Methods A total of 32 albino Wistar rats were randomly divided into four equal groups (n = 8). In Group 1, no treatment was applied after laminectomy (control group). In Group 2, hemostasis was achieved after Laminectomy, and the surgical procedure was terminated by placing a 2-mm absorbable gelatin sponge dipped in saline into the epidural space. In Group 3, low-dose (4 mg/kg) Ro5-4864 was administered 30 minutes before the surgery. In Group 4, high-dose (8 mg/kg) Ro5-4864 was administered 30 minutes before the surgery. A histopathological examination was performed to evaluate arachnoidal invasion and EF. Results Our data revealed the EF was significantly reduced in rats treated with high-dose Ro5-4864 (Group 4) compared to the control and saline-soaked Spongostan groups (p = 0.000 and p = 0.006, respectively). There was no significant difference between the groups treated with high- and low-dose Ro5-4864. Arachnoidal invasion was not seen in any of the rats in the high-dose R05-4864 group. However, the arachnoidal invasion results did not significantly differ between the study groups (p = 0.052 = 0.05). Conclusions Our study showed that Ro5-4864 could be effective in reducing EF in rats after.

Kamishoyosan potentiates pentobarbital-induced sleep in socially isolated, ovariectomized mice

Ethnopharmacological relevanceSleep disorders are among the most common symptoms in both peri- and post-menopausal women. Kamishoyosan (KSS) is a Kampo medicine prescribed for the treatment of sleep disorders in menopausal women in Japan. However, its precise mechanism of action remains unclear. Aim of the studyIn the present study, we developed a new animal model of menopausal sleep disorders by inducing social isolation stress in ovariectomized mice. Using pentobarbital-induced sleeping time as an index, we aimed to investigate the effects of KSS and involvement of the benzodiazepine receptors. Materials and methodsEight-week-old, female ddY mice were ovariectomized or subjected to a sham operation (control) and housed in social isolation or groups for 9 weeks. The animals were divided into four groups, group-housed sham-operated, isolated sham-operated, group-housed ovariectomized, and socially isolated ovariectomized. Pentobarbital (50 mg/kg) was administered intraperitoneally (i.p.). Sleeping time was considered the period between the loss of righting reflex and its return (up to 180 min). KSS was administered orally (p.o.) 60 min before the test. Diazepam and flumazenil were administered i.p. 30 and 45 min before the test, respectively. On the day after administration, the mice were euthanized, and their uteri were weighed. ResultsSocially isolated, ovariectomized mice had shorter sleeping times than mice in all other groups. In mice with intact ovaries, diazepam (1 mg/kg, i.p.) considerably prolonged the pentobarbital-induced sleeping time, but KSS (30–1000 mg/kg, p.o.) did not. However, KSS (100 mg/kg, p.o.) significantly prolonged the pentobarbital-induced sleeping time in socially isolated ovariectomized mice. The prolongation of sleeping time mediated by KSS was reversed by flumazenil (3 mg/kg, i.p.). ConclusionsKSS potentiated pentobarbital-induced sleep in socially isolated, ovariectomized mice, and the benzodiazepine receptors are possibly involved in its pharmacological mechanism. These findings suggest that KSS is beneficial for the treatment of menopausal sleep disorders.

Intracerebroventricular administration of α-melanocyte-stimulating hormone (α-MSH) enhances thigmotaxis and induces anxiety-like behavior in the goldfish Carassius auratus

α-Melanocyte-stimulating hormone (α-MSH) is a body pigmentation-regulating hormone secreted from the intermediate lobe of the pituitary in vertebrates. It is also produced in the brain, and acts as an anorexigenic neuropeptide involved in feeding regulation. In rodents, intracerebroventricular (ICV) administration of α-MSH has been shown to affect not only feeding behavior, but also psychomotor activity. However, there is still no information regarding the psychophysiological effects of α-MSH on behavior in fish. Therefore, we examined the effect of synthetic α-MSH on psychomotor activity in goldfish. Since this species prefers the edge to the central area of a tank, we used this as a preference test for assessing psychomotor activity. When α-MSH was administered ICV at 1 and 10 pmol g−1 body weight (BW), the time spent in the edge area of a tank was prolonged at 10 pmol g−1 BW. However, α-MSH at these doses did not affect locomotor activity. The action of α-MSH mimicked those of FG-7142 (a central-type benzodiazepine receptor (CBR) inverse agonist with an anxiogenic effect) at 10 pmol g−1 BW and melanotan II (a melanocortin 4 receptor (MC4R) agonist) at 50 pmol g−1 BW, whereas ICV administration of tofisopam (a CBR agonist with an anxiolytic effect) at 10 pmol g−1 BW prolonged the time spent in the central area. The anxiogenic-like effect of α-MSH was abolished by treatment with the MC4R antagonist HS024 at 50 pmol g−1 BW. These data indicate that α-MSH affects psychomotor activity in goldfish, and exerts an anxiogenic-like effect via the MC4R-signaling pathway.

Posttraumatic Stress Disorder Risk and Benzodiazepine Dependence in Older Veterans with Insomnia Symptoms

ABSTRACT Objectives To measure the rate of benzodiazepine receptor agonist (BZA) dependence in older veterans with insomnia symptoms chronically using BZAs and to assess for associations between high posttraumatic stress disorder (PTSD) risk and BZA dependence. Methods A cross-sectional study was conducted among veterans aged 55 years and older with insomnia symptoms (current or historical) and chronic use of BZAs (≥3 months). Measurements included the Primary Care-PTSD screen (score >2 indicates high PTSD risk) and Benzodiazepine Dependence Questionnaire. Logistic regression was used to test for associations between PTSD risk and BZA dependence. Results A high PTSD risk was observed in 40% of the participants (N = 33). One-fifth (21.7%, N = 18) of participants met the criteria for benzodiazepine dependence (score ≥23 on Benzodiazepine Dependence Questionnaire). Veterans with high PTSD risk were significantly more likely to have BZA dependence (odds ratio 10.09, 95% CI [2.39, 42.54], p = .002). Conclusions In older veterans with insomnia symptoms and chronic use of BZAs, high PTSD risk is associated with elevated risk for BZA dependence, which may make discontinuation of these medications difficult. Clinical implications Clinicians should consider the strong association between PTSD symptoms and benzodiazepine dependence when developing plans to taper a BZA in veterans with these symptoms.

Possible influence of neurosteroids in the anxiolytic effects of alpha-casozepine

Alpha-casozepine (α CZP), a tryptic hydrolysate of milk casein is a decapeptide shown to promote sleep and produce anxiolytic or anticonvulsant activity. Intriguingly, studies indicate structural similarities to benzodiazepine (BZD)-like molecules (e.g., diazepam), resulting in positive modulation of γ-aminobutyric acid A type (GABAA) receptors. However, some unexplained anomalous behaviour of α-CZP includes 1) 1000 times less affinity for BZD site on GABAA receptor in vitro conditions, whereas in vivo it showed 10-fold increased affinity when compared to diazepam; 2) anxiolytic effects were observed only in stressed conditions and 3) unlike diazepam, it failed to exhibit dependence or habituation. Interestingly, neurosteroids like allopregnanolone or its analogues that are synthesized de novo have both genomic and non-genomic actions. The rapid nongenomic neuronal inhibition of these compounds is mediated by GABAA receptors through autocrine and paracrine actions. Studies have shown that changes in the levels of neurosteroids during acute (rise) and chronic stress (decreased), consequently, altering the senetivity of GABAA receptor subunits. Neurosteroids even at low concentration (nanomolar range) potentiate the response of GABA indirectly, while at higher concentrations they directly activate the receptor-channel complex. Interestingly, coadministration of neurosteroids and BZPs has shown not only to prevent the development of tolerance of BZP and augmented recovery from BZP withdrawal anxiety and hyperactivity in mice. The combination also produced synergetic anxiolytic effects. Taken together, the evidence suggests possible implications of neurosteroids in the actions of CZP via BZD receptors. The present hypothesis brings out the possible role of neurosteroids and the various factors that might participate in CZP-induce anxiolytic effects.

Effects of benzodiazepine and orexin receptor antagonist on cognitive function revealed by auditory event-related potentials.

Cognitive decline after oral administration of sedatives, such as benzodiazepines, is a serious side effect. Suvorexant, an orexin receptor antagonist, has a favorable tolerability and a limited side-effect profile. The purpose of this study was to estimate the cognitive decline 1 day after oral medication with lormetazepam, a benzodiazepine, and suvorexant by comparing mismatch negativity (MMN) and P300 reflecting auditory discrimination function. Sixty healthy subjects (42 males) were randomly assigned to three groups receiving suvorexant 20 mg, lormetazepam 2 mg, or placebo in this double-blind, randomized control study. Event-related potential recordings during an auditory oddball task and a digit symbol substitution test (DSST) were performed 1 day after oral administration. MMN, on the day after oral administration, was significantly attenuated in the lormetazepam group compared with the other two groups, but there was no difference between the suvorexant and placebo groups. No significant difference was found in P300 amplitudes and DSST scores among the three groups. These findings suggest that suvorexant, unlike benzodiazepine, is not associated with cognitive deficits, as revealed by MMN but not P300. This study shows a neurophysiological difference in the effects of suvorexant and benzodiazepine on cognitive function.

Anti-seizure effects of walnut peptides in mouse models of induced seizure: The involvement of GABA and nitric oxide pathways

Epilepsy is one of the foremost medical disorders. Oxidative stress is a well-known mechanism in epileptogenesis, and many studies suggest that oxidative stress affects the onset and evolution of epilepsy. Here we evaluated the walnut peptide extracts’ anti-seizure property in three different mouse seizure models including pentylenetetrazole-induced clonic seizure, chemical kindling, and maximal electroshock. Walnut peptides (20 mg/Kg) were administered by intraperitoneal (IP) injection of mice 60 min before seizure induction in the three models. To delineate the mechanisms of walnut peptides anti-seizure activity, we evaluated the impact of diazepam, flumazenil, and a NOS inhibitor on this activity. Intraperitoneal administration of walnut peptides significantly increased the seizure threshold. Our results also demonstrated that walnut peptides exert their anti-seizure properties through the modulation of benzodiazepine receptors. Thus, walnut peptides may be considered as a new anti-convulsion agent, which can reduce seizure occurrence and slow down seizure progression.

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Translocator protein 18 kDa [TSPO or peripheral-type benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.