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BioRxiv : the Preprint Server For... Nov 2023We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly...
We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly and specifically expressed in satellite glia cells (SGCs) of mice, rat and human, but not in sensory neurons or other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without significant effects on other sensory modalities. overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as a partial agonist and positive allosteric modulator at the neuronal GABA receptors, particularly strongly effecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons and these are also more enwrapped with DBI-expressing glia, as compared to other DRG neurons, suggesting a mechanism for specific effect of DBI on mechanosensation. These findings identified a new, peripheral neuron-glia communication mechanism modulating pain signalling, which can be targeted therapeutically.
PubMed: 38045227
DOI: 10.1101/2023.11.20.567848 -
Sleep Science (Sao Paulo, Brazil) Sep 2023Sleep Bruxism (SB) is a common condition in childhood that can cause multiple consequences such as abnormal tooth wear, tensional headaches, masticatory muscle pain,... (Review)
Review
Sleep Bruxism (SB) is a common condition in childhood that can cause multiple consequences such as abnormal tooth wear, tensional headaches, masticatory muscle pain, or fatigue. The literature reports some interventions, however the treatment for SB in children is not well-established. A systematic review was performed to investigate the effectiveness of the treatments described for SB in children and adolescents: pharmacological and psychological treatments; behavioral guidelines; and dental approaches. Randomized clinical trials comparing different SB treatments with a control group were searched in the electronic databases PubMed, Scopus, Web of Science, Cochrane Library, and VHL until August 04, 2021. Two independent reviewers selected the studies, extracted the data, and assessed the risk of bias. After a two-phase selection process, 07 articles were selected. The methodology of the selected studies was analyzed using the Cochrane Risk of Bias Tool. The criteria used to qualify the studies were based on randomization, allocation, blinding of participants and evaluators, and analysis of results. The signs and symptoms of SB were reduced with pharmacotherapy (hydroxyzine/diazepam) and medicinal extracts ( ), but with occlusal splints and physiotherapy, this improvement was not statistically significant when compared to control groups. Some evidence of the efficacy of pharmacotherapy (hydroxyzine/diazepam) and medicinal extracts ( ) was found. However, this systematic review is not enough to establish a protocol for the treatment of SB. Besides, the individualized management of SB in this population should be considered, emphasizing the management of risk factors.
PubMed: 38196770
DOI: 10.1055/s-0043-1772826 -
Neurobiology of Disease Sep 2023Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical...
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAR subunit composition, there was a redistribution of extrasynaptic GABARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
Topics: Mice; Animals; Diazepam; Alcoholism; Substance Withdrawal Syndrome; Receptors, GABA-A; Benzodiazepines; Brain; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37536384
DOI: 10.1016/j.nbd.2023.106248 -
Journal of Clinical Sleep Medicine :... Oct 2023We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant,...
STUDY OBJECTIVES
We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months.
METHODS
Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents.
RESULTS
The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, < .001; 2 mo: -3.20 ± 5.64, < .001; 3 mo: -3.38 ± 5.61, < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, = 0.27), 2 months (0.082 ± 4.62, = .89), or 3 months (-0.64 ± 4.80, = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, = .004), 2 months (-1.05 ± 2.97, = .029), and 3 months (-1.24 ± 3.06, = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, < .001).
CONCLUSIONS
Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced.
CITATION
Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. . 2023;19(10):1753-1758.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Retrospective Studies; Sleepiness; Hypnotics and Sedatives; Orexin Receptor Antagonists; Benzodiazepines; Diazepam
PubMed: 37243798
DOI: 10.5664/jcsm.10668 -
Journal of the American Medical... Aug 2023To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures... (Review)
Review
OBJECTIVES
To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters.
DESIGN
Narrative review.
SETTING AND PARTICIPANTS
People with seizures in long-term care, including group residences.
METHODS
PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care.
RESULTS
Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers or care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus.
CONCLUSIONS AND IMPLICATIONS
Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.
Topics: United States; Humans; Aged; Anticonvulsants; Long-Term Care; Diazepam; Status Epilepticus; Epilepsy
PubMed: 37253432
DOI: 10.1016/j.jamda.2023.04.015 -
Aging Cell Sep 2023Acyl coenzyme A binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is a phylogenetically ancient protein present in some eubacteria and the entire... (Review)
Review
Acyl coenzyme A binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is a phylogenetically ancient protein present in some eubacteria and the entire eukaryotic radiation. In several eukaryotic phyla, ACBP/DBI transcends its intracellular function in fatty acid metabolism because it can be released into the extracellular space. This ACBP/DBI secretion usually occurs in response to nutrient scarcity through an autophagy-dependent pathway. ACBP/DBI and its peptide fragments then act on a range of distinct receptors that diverge among phyla, namely metabotropic G protein-coupled receptor in yeast (and likely in the mammalian central nervous system), a histidine receptor kinase in slime molds, and ionotropic gamma-aminobutyric acid (GABA) receptors in mammals. Genetic or antibody-mediated inhibition of ACBP/DBI orthologs interferes with nutrient stress-induced adaptations such as sporulation or increased food intake in multiple species, as it enhances lifespan or healthspan in yeast, plant leaves, nematodes, and multiple mouse models. These lifespan and healthspan-extending effects of ACBP/DBI suppression are coupled to the induction of autophagy. Altogether, it appears that neutralization of extracellular ACBP/DBI results in "autophagy checkpoint inhibition" to unleash the anti-aging potential of autophagy. Of note, in humans, ACBP/DBI levels increase in various tissues, as well as in the plasma, in the context of aging, obesity, uncontrolled infection or cardiovascular, inflammatory, neurodegenerative, and malignant diseases.
Topics: Animals; Humans; Mice; Acyl Coenzyme A; Aging; Autophagy; Carrier Proteins; Diazepam Binding Inhibitor; Mammals; Saccharomyces cerevisiae
PubMed: 37357988
DOI: 10.1111/acel.13910 -
Journal of Affective Disorders Oct 2023College students are vulnerable to suffering from anxiety and depression. Moreover, mental disorders can contribute to drug consumption or inappropriate use of...
BACKGROUND
College students are vulnerable to suffering from anxiety and depression. Moreover, mental disorders can contribute to drug consumption or inappropriate use of prescribed drugs. Studies on this topic in Spanish college students are limited. This work analyses anxiety and depression and psychoactive drug intake pattern in the post-COVID era in college students.
METHODS
An online survey was conducted among college students from UCM (Spain). The survey collected data including demographic, academic student perception, GAD-7 and PHQ-9 scales, and psychoactive substances consumption.
RESULTS
A total of 6798 students were included; 44.1 % (CI95%: 42.9 to 45.3) showed symptoms of severe anxiety and 46.5 % (CI95%: 45.4 to 47.8) symptoms of severe or moderately severe depression. The perception of these symptoms did not change after returning to face-to-face university classes in the post-COVID19 era. Despite the high percentage of cases with clear symptoms of anxiety and depression, most students never had a diagnosis of mental illnesses [anxiety 69.2 % (CI95%: 68.1 to 70.3) and depression 78.1 % (CI95%: 77.1 to 79.1)]. Regarding psychoactive substances, valerian, melatonin, diazepam, and lorazepam were the most consumed. The most worrying issue was the consumption of diazepam, 10.8 % (CI95%: 9.8 to 11.8), and lorazepam, 7.7 % (CI95%: 6.9 to 8.6) without medical prescription. Among illicit drugs, cannabis is the most consumed.
LIMITATIONS
The study was based on an online survey.
CONCLUSIONS
The high prevalence of anxiety and depression aligned with poor medical diagnosis and high intake of psychoactive drugs should not be underestimated. University policies should be implemented to improve the well-being of students.
Topics: Humans; Mental Health; COVID-19; Lorazepam; Depression; Anxiety; Substance-Related Disorders; Students; Universities
PubMed: 37245551
DOI: 10.1016/j.jad.2023.05.080 -
Orvosi Hetilap Sep 2023Alcohol withdrawal syndrome is one of the most important consequences of alcohol use disorder, a complex neuropsychiatric disorder, which is firstly treated in... (Review)
Review
Alcohol withdrawal syndrome is one of the most important consequences of alcohol use disorder, a complex neuropsychiatric disorder, which is firstly treated in non-specific and secondly in psychiatric/addictive in- or outpatient units. On the other hand, alcohol withdrawal syndrome is one of the most important outcomes of the severity of alcohol use disorder, further, it can lead to the development of alcohol-related seizure and delirium tremens. Hence, early recognition and optimal treatment of alcohol withdrawal syndrome have a critical importance. Therefore, the main goal of the present review was - by systematically summarizing the scientific data published during the past two decades - to form a unique diagnostic and therapeutic algorithm. During the recognition and the course of alcohol withdrawal syndrome, the Clinical Institute Withdrawal Assessment for Alcohol, Revised scale, while in the risk assessment the Prediction of Alcohol Withdrawal Severity Scale are the recommended psychometric tools. Benzodiazepines are the key elements of the pharmacotherapy of alcohol withdrawal syndrome. Many studies have evaluated that diazepam, chlordiazepoxide, lorazepam and oxazepam with distinct indications have sufficient evidence in the treatment of alcohol withdrawal syndrome. However, in the past few years some authors have recommended the importance of non-benzodiazepine medications. The efficacy of propofol, phenobarbital, carbamazepin, oxcarbamazepin and alpha-2 receptor agonists in the treatment of alcohol withdrawal syndrome have been revealed. Furthermore, it has been evaluated that benzodiazepines are recommended in the treatment of alcohol-related seizure and delirium tremens. In the present review, our aim was to construct a unique, up-to-date diagnostic and therapeutic algorithm by summarizing the related papers published during the past two decades. Hence this scheme may be useful in the optimal treatment of patients diagnosed with alcohol use disorder and it could help to conduct further clinical researches. Orv Hetil. 2023; 164(38): 1487-1496.
Topics: Humans; Alcoholism; Substance Withdrawal Syndrome; Alcohol Withdrawal Seizures; Alcohol Withdrawal Delirium; Benzodiazepines
PubMed: 37742220
DOI: 10.1556/650.2023.32847 -
Neurology Aug 2023The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory convulsive status epilepticus (RSE) in children.
METHODS
An observational case-control study was conducted comparing pediatric patients (1 month-21 years) with convulsive SE whose seizures stopped after benzodiazepine (BZD) and a single second-line antiseizure medication (ASM) (responsive established status epilepticus [rESE]) with patients requiring more than a BZD and a single second-line ASM to stop their seizures (RSE). These subpopulations were obtained from the pediatric Status Epilepticus Research Group study cohort. We explored clinical variables that could be acquired early after presentation to emergency medical services with univariate analysis of the raw data. Variables with < 0.1 were retained for univariable and multivariable regression analyses. Multivariable logistic regression models were fit to age-matched and sex-matched data to obtain variables associated with RSE.
RESULTS
We compared data from a total of 595 episodes of pediatric SE. Univariate analysis demonstrated no differences in time to the first BZD (RSE 16 minutes [IQR 5-45]; rESE 18 minutes [IQR 6-44], = 0.068). Time to second-line ASM was shorter in patients with RSE (RSE 65 minutes; rESE 70 minutes; = 0.021). Both univariable and multivariable regression analyses revealed a family history of seizures (OR 0.37; 95% CI 0.20-0.70, = 0.0022) or a prescription for rectal diazepam (OR 0.21; 95% CI 0.078-0.53, = 0.0012) was associated with decreased odds of RSE.
DISCUSSION
Time to initial BZD or second-line ASM was not associated with progression to RSE in our cohort of patients with rESE. A family history of seizures and a prescription for rectal diazepam were associated with a decreased likelihood of progression to RSE. Early attainment of these variables may help care for pediatric rESE in a more patient-tailored manner.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that patient and clinical factors may predict RSE in children with convulsive seizures.
Topics: Humans; Child; Anticonvulsants; Case-Control Studies; Retrospective Studies; Status Epilepticus; Benzodiazepines; Seizures; Drug Resistant Epilepsy; Diazepam
PubMed: 37295955
DOI: 10.1212/WNL.0000000000207472 -
Biomedicine & Pharmacotherapy =... Dec 2023Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular...
Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.
Topics: Rats; Animals; Basolateral Nuclear Complex; Anti-Anxiety Agents; Lipoylation; Motor Activity; Anxiety; Diazepam
PubMed: 37948993
DOI: 10.1016/j.biopha.2023.115859