The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders.

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement.

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes.

Using machine learning techniques to characterize sleep-deprived driving behavior.

OBJECTIVE: Sleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present study, we extend this approach to sleep deprivation and test the model for characterization of new interventions. We aimed to classify abnormal driving behavior after sleep deprivation, and, by using a machine learning model, we tested if this model could also pick up abnormal driving behavior resulting from other interventions. METHODS: Data were collected during a previous study, in which 24 subjects were tested after being sleep-deprived and after a well-rested night. Features were calculated from several driving parameters, such as the lateral position, speed of the car, and steering speed. In the present study, we used a gradient boosting model to classify sleep deprivation. The model was validated using a 5-fold cross validation technique. Next, probability scores were used to identify the overlap of driving behavior after sleep deprivation and driving behavior affected by other interventions. In the current study alprazolam, alcohol, and placebo are used to test/validate the approach. RESULTS: The sleep deprivation model detected abnormal driving behavior in the simulator with an accuracy of 77 ± 9%. Abnormal driving behavior after alprazolam, and to a lesser extent also after alcohol intake, showed remarkably similar characteristics to sleep deprivation. The average probability score for alprazolam and alcohol measurements was 0.79, for alcohol 0.63, and for placebo only 0.27 and 0.30, matching the expected relative drowsiness. CONCLUSION: We developed a model detecting abnormal driving induced by sleep deprivation. The model shows the similarities in driving characteristics between sleep deprivation and other interventions, i.e., alcohol and alprazolam. Consequently, our model for sleep deprivation may serve as a next reference point for a driving test battery of newly developed drugs.

Gamma-aminobutyric acid attenuates insulin resistance in type 2 diabetic patients and reduces the risk of insulin resistance in their offspring.

The role of gamma-aminobutyric acid (GABA) in attenuates insulin resistance (IR) in type 2 diabetic (T2D) patients and the reduction of the risk of IR in their offspring, and the function of GLUT4, IRS1 and Akt2 genes expression were investigated. T2D was induced by high fat diet and 35 mg/kg of streptozotocin. The male and female diabetic rats were then divided into three groups: CD, GABA, and insulin. NDC group received a normal diet. All the animals were studied for a six-month. Their offspring were just fed with normal diet for four months. Blood glucose was measured weekly in patients and their offspring. Intraperitoneal glucose tolerance test (IPGTT), urine volume, and water consumption in both patients and their offspring were performed monthly. The hyperinsulinemic euglycemic clamp in both patients and their offspring was done and blood sample collected to measure Hemoglobin A1c (HbA1c). IRS1, Akt and GLUT4 gene expressions in muscle were evaluated in all the groups. GABA or insulin therapy decreased blood glucose, IPGTT, and HbA1c in patients and their offspring compared to DC group. They also increased GIR in patients and their offspring. IRS1, Akt and GLUT4 gene expressions improved in both patients in comparison with DC group. GABA exerts beneficial effects on IRS1 and Akt gene expressions in GABA treated offspring. GABA therapy improved insulin resistance in diabetic patients by increasing the expression of GLUT4. It is also indirectly able to reduce insulin resistance in their offspring possibly through the increased gene expressions of IRS1 and Akt.

Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) Associated with SARS-CoV-2 Infection: Post-Infectious Neurological Complication with Benign Prognosis.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is the cause of the COVID-19 pandemic [5]. SARS-Cov-2 demonstrates partial resemblance to SARS-CoV and MERS-CoV in phylogenetic analysis, clinical manifestations, and pathological findings [6, 7]. Reports emerging from China have described ataxia as a neurological symptom of the SARS-CoV-2 infection [5]. Opsoclonus consists of back-to-back multidirectional conjugate saccades without an inter-saccadic interval [8]. Myoclonus is defined as a sudden, brief, "shock-like", nonepileptic involuntary movement [9], which has been described as a symptom of SARS-CoV-2 infection [10]. Opsoclonus-Myoclonus-Ataxia syndrome (OMAS) associated COVID-19 infection has been reported recently [1112].

Involvement of opioidergic and GABAergic systems in the anti-nociceptive activity of the methanolic extract of Cuscuta Epithymum Murr. in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cuscuta epithymum Murr. (CE) is a parasitic plant used as a traditional medicine to treat various diseases such as muscle and joint pains and headache different parts of the world, Europe in the north, Asia in the east. AIM OF THE STUDY: In this study, we aimed to investigate the anti-nociceptive effect of the methanolic extract of the aerial parts of CE and its probable mechanism(s) in mice. MATERIALS AND METHODS: The anti-nociceptive activity of different doses of CE methanolic extract (2.5, 5, 10, 25, 50 and 100 mg/kg, i.p.) was assessed using tail flick, formalin and writhing tests. Morphine (5 mg/kg, s.c.) was used as positive control drug. The possible mechanisms were evaluated by using naloxone (4 mg/kg, i.p.), ondansetron (4 mg/kg, i.p.), picrotoxin (0.6 mg/kg, i.p.) and MK-801 (0.03 mg/kg, i.p.). RESULTS: GC-MS analysis indicated that one of the main components of CE extract was terpenoid compounds. The CE extract (25-100 mg/kg), like morphine, reduced tail flick latency and nociceptive response in both phases of the formalin test. We also observed that the extract significantly decreased the number of abdominal contractions dose-dependently from 5 to 100 mg/kg. The results of tail flick and the first phase of formalin test proved that unlike ondansetron and MK-801, naloxone and picotroxin were able to reverse the anti-nociceptive effect of CE extract. CONCLUSION: Our observations showed the anti-nociceptive potential of the CE extract, which may be mediated by opioidergic and GABAergic systems.

Protective Effects of Aminooxyacetic Acid on Colitis Induced in Mice with Dextran Sulfate Sodium.

As a known inhibitor of pyridoxal phosphate-dependent transaminase glutamic-oxaloacetic transaminase 1 (GOT1), aminooxyacetic acid (AOAA) has been pointed out to have potential pharmacological effects in antiepileptic, anticonvulsant, antibacterial, cancer cell proliferation inhibition, and acute myocardial infarction (MI) relief. However, its role in inflammatory bowel disease (IBD) has not been reported. Through the in vivo experiment of dextran sulfate sodium- (DSS-) induced colitis in mice, it was found that AOAA significantly attenuated the symptoms, signs, and pathological changes of colitis. In addition, AOAA treatment prevented gut barrier damages by enhancing the expression of zona occludens- (ZO-) 1, occludin, claudin-1, and E-cadherin and recovering the upregulation of the most abundant intermediate filament protein (vimentin). Moreover, the release of interleukin- (IL-) 1ß, IL-6, and tumour necrosis factor- (TNF-) α was suppressed, yet the level of IL-10 was upregulated by AOAA treatment compared to the model group. Furthermore, it was shown that AOAA administration boosted M2-like phenotype and effectively reduced M1 macrophage phenotype in the lamina propria of mouse colonic epithelium. Similarly, the effect of AOAA was verified in vitro. AOAA effectively inhibited the classically activated M1 macrophage phenotype and proinflammatory cytokine (IL-1ß, TNF-α, and IL-6) expression induced by lipopolysaccharide (LPS) and promoted M2-like phenotype. Collectively, this study reveals for the first time that short-term treatment of AOAA can significantly alleviate DSS-induced acute colitis by regulating intestinal barrier function and macrophage polarization, which provides a theoretical basis for the potential use of AOAA in the treatment of IBD.

Combined use of GABA and sitagliptin promotes human ß-cell proliferation and reduces apoptosis.

γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent ß-cell survival and function. In human ß-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic ß-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human ß-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human ß-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ ß-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on ß cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of ß-cell proliferation and a decrease in apoptosis.

New agents and perspectives in the pharmacological treatment of major depressive disorder.

Despite the important advances in the understanding of the pathophysiology of MDD, a large proportion of depressed patients do not respond well to currently available pharmacological agents. The present review focuses on new targets and future directions in the pharmacological treatment of MDD. Novel agents and their efficacy in the treatment of depression are discussed, with a focus on the respectively target pathophysiological pathways and the level of available evidence. Although it is expected that classic antidepressants will remain the cornerstone of MDD treatment, at least for the near future, a large number of novel compounds is currently under investigation as for their efficacy in the treatment of MDD, many of which with promising results.

Valproic Acid in the Treatment of Migraines.

Migraine headaches can be a disabling condition for patients. Fortunately, most patients can be successfully managed in the outpatient setting, however, there are a number of patients who may not respond to the abortive treatments that they have been prescribed. These patients often present to the emergency department (ED) for further assistance with the management of their condition. Migraines are the fourth most common cause of ED visits and are associated with an estimated annual cost of $17 billion in the United States. Familiarity with abortive treatments is critical for providers in the ED as are treatments, such as valproic acid, that may be considered in patients who do not respond to other treatment options. Many providers are more familiar with the role of valproic acid in the treatment of mood and seizure disorders, but its tolerability and the successes reported in the primary literature make it a reasonable consideration for patients with migraine who fail to respond to other therapies. This article briefly summarizes the therapies considered first line for abortive treatment in the setting of migraines and provides an overview of the primary literature describing the use of valproic acid in these patients.

CYP3A subfamily activity affects the equilibrium concentration of Phenazepam® in patients with anxiety disorders and comorbid alcohol use disorder.

Phenazepam® is prescribed to relieve anxiety and sleep disorders during alcohol withdrawal, although it is associated with undesirable side effects. Aim: To demonstrate changes in the safety and efficacy profiles of Phenazepam in patients with anxiety disorders and comorbid alcohol use disorder. Materials & methods: A total of 94 Russian patients with alcohol use disorder received 4.0 mg of Phenazepam per day in tablets. We used a urinary 6-beta-hydroxycortisol/cortisol ratio to evaluate CYP3A activity. Results: A statistically significant inverse correlation between Phenazepam plasma concentration and CYP3A activity was found (r = -0.340 and p = 0.017). Correlation between the concentration/dose ratio and phenotyping results was also statistically significant (r = 0.301 and p = 0.026). Conclusion: The safety and efficacy of Phenazepam depend on CYP3A genetic polymorphisms.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

The use of off-label medications in substance abuse treatment programs.

Background: Substance use disorder (SUD) treatment centers serve a population of clients who have diverse needs, and may desire or require access to varied treatments while seeking care for their SUDs. While pharmacotherapies have increased in popularity for the treatment of SUDs, adoption rates do remain quite low. But a wider array of pharmacotherapies has become available in recent years which may shift the trend. This article helps shed light on how variations in SUD treatment centers develop and persist with regard to the adoption and delivery of off-label medications. Methods: We use a nationally representative and longitudinal sample of SUD treatment centers in the US (N = 196). We use a logistic regression to analyze the relationship between organizational characteristics and offering any medications, off-label. We also use a negative binomial regression to analyze the relationship between organizational characteristics and the number of medications that were used off-label. Results: Our findings reveal that older centers, accredited centers, and centers that offer mental health screenings are all positively associated with the provision of off-label medication in SUD treatment. We also find a positive relationship between private funding and offering a greater number of off-label medications. Conclusions: Our results suggest that SUD clients who seek treatment from centers that offer medications off-label, may have access to a greater number of medication-assisted treatment options.

Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial.

BACKGROUND: Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents. METHODS: We carried out a randomized double-blind placebo-controlled trial in the Children's Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents. RESULTS: A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: -8.0; 95% confidence interval (CI): -9.3 to -6.6), sodium valproate (difference: -8.3; 95% confidence interval: -9.3 to -7.2), and placebo (difference: -4.4; 95% confidence interval: -5.4 to -3.4) arms. The decrease was statistically greater in cinnarizine (difference: -3.6; 95% confidence interval: -5.5 to -1.6) and sodium valproate (difference: -3.9; 95% confidence interval: -5.8 to -1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: -4.6; 95% confidence interval: -5.2 to -4.0; sodium valproate: -4.0; 95% confidence interval: -4.8 to -3.3; placebo: -2.6; 95% confidence interval: -3.4 to -1.8). The decrease was statistically greater in cinnarizine (difference: -2.0; 95% confidence interval: -3.2 to -0.8) and sodium valproate (difference: -1.5; 95% confidence interval: -2.7 to -0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation. CONCLUSION: Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents. Trial registration: IRCT201206306907N4.

The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury.

The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for α2/3-containing GABAA receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED50 = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the α1ß3γ2L GABAA receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with α1His102, providing a structural rationale for its low affinity for α1-containing GABAA receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy.

[GABAergic approach of postpartum depression: A translational review of literature]. / Approche GABAergique de la dépression du post-partum : une revue critique translationnelle.

INTRODUCTION: Prevalence of postpartum depression (PPD) ranges from 10 to 15 % of parturients. The impact of the PPD is major on the maternal bond and the health of both mother and child. Its physiopathological mechanisms appear to differ from other types of depression. Today, pharmacotherapy is based on nonspecific treatment, and recent therapeutic advances in this field require a comprehensive approach of the implication of the GABAergic system in the development of PPD. Neurosteroid levels during pregnancy and after parturition and the GABA-A-r modulation are thought to be involved in PPD. OBJECTIVE: To evaluate if the GABAergic approach is relevant in postpartum depression management. METHODS: We conducted a systematic review of literature based on the MEDLINE database with the following Medical Subject Headings (MeSH): "postpartum depression", "GABA", "ganaxolone", "brexanolone", "allopregnanolone", prior to September 2019. We selected articles in English: preclinical and clinical studies, literature review, observational and therapeutic studies. RESULTS: Preclinical models (mouse and rat) show changes in GABAergic inhibition in the peripartum period and correlation between allopregnanolone and GABA-A-r plasticity. This plasticity in the peripartum period maintains levels of inhibition adapted despite increased neurosteroid levels. KO models for the GABA-A-r δ subunit develop depression and anxiety symptoms in the postpartum period, and a change in the expression of the gene coding for the GABA-R alpha-4 subunit was found. Artificial inhibition of progesterone metabolism during post-partum increased depression symptoms. GABAergic fluctuation seems to be interrelated with other systems such as those of oxytocins. A synthetic neurosteroid (SGE-516) was tested on mouse models of PPD, KO for δ-GABA-A-r or KCC2, and showed decreased depressive symptoms and better mothering. Clinical studies confirm neurosteroid fluctuation and changes in the GABAergic system during the peripartum period. Allopregnanolone is the neurosteroid the most studied in PPD, and it is elevated in the brain during the pregnancy. Studies disagree on the presence of significant differences in allopregnanolone plasma levels during pregnancy or postpartum between women with PPD or not. Women with a history of PPD have greater susceptibility to neurosteroid withdrawal. Imagery and genetical data also show a link between allopregnanolone and PPD. The GABA-A-r may not recover in time following a reduced number during pregnancy, and this mismatch between neurosteroid levels and their receptor may trigger PPD. Several randomized controlled trials investigated brexanolone administrated IV, a synthetic formulation of allopregnanolone, and demonstrated a rapid and well tolerated reduction in depressive symptoms. In March 2019 brexanolone obtained FDA approval in PPD indication under the name Zulresso. However, there are differences in the time of beginning of PPD, which could constitute different subgroups of this disease, and which physiopathology could respond to different mechanisms. Prenatal depression does not respond to a GABAergic approach, but women without any risk factor or previous mood disorder developing PPD in the weeks following childbirth could be particularly responsive to this kind of treatment. CONCLUSION: Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease.

Bioactive nanoparticle embedded microcapsules for improving the efficacy of type I diabetes therapy.

In order to overcome the side effects of pancreatic transplantation and insulin injection treatment for type I diabetes, we established a drug delivery system employing nanoparticle embedded microcapsules (NEMs). The system co-encapsulated chitosan nanoparticles with γ-aminobutyric acid and ß-TC-6 cells for combined drug and cell therapy in diabetes mellitus (DM). The NEMs, which were formed via high-voltage electrostatic method, had an excellent sphericity with a smooth surface. The average size NEM was 245.52 ± 22.00 µm, which indicated a good size for cell encapsulation. Haemolysis rate of NEMs at concentrations of 100, 200 or 300 mg/mL were all below 5%. Relative viability rates of L929 cells with the same concentrations at 24, 48 or 72 h were all above 80%. We implanted bioactive NEMs into type 1 DM mice to evaluate the effect of the combined therapy. The level of blood glucose in the group receiving the combined therapy decreased during the first 2 weeks of treatment. During the next week, the level of blood glucose stayed in a safe range. Body weight continuously increased during the postoperative period after combined therapy group. Oral glucose tolerance test (OGTT) performed after 24 d showed that the level of blood glucose combined therapy reached the maximum peak of 13.04 mmol/L, lower than 16.56 mmol/L for the cell therapy group. This primary study indicated that microencapsulation technology and combined therapy are promising for the treatment of type I diabetes mellitus.

The Impact of Surgical Amputation and Valproic Acid on Pain and Functional Trajectory: Results from the Veterans Integrated Pain Evaluation Research (VIPER) Randomized, Double-Blinded Placebo-Controlled Trial.

OBJECTIVE: To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Academic, military, and veteran medical centers. SUBJECTS: One hundred twenty-eight patients undergoing amputation or amputation revision surgery at Duke University Hospital, Walter Reed National Military Medical Center, or the Durham Veterans Affairs Medical Center for either medical disease or trauma. METHODS: Patients were randomized to placebo or valproic acid for the duration of hospitalization and treated with multimodal analgesic care, including regional anesthetic blockade. Primary outcome was the proportion of patients with chronic pain at three months (average numeric pain score intensity of 3/10 or greater). Secondary outcomes included functional trajectories (assessed with the Brief Pain Inventory short form and the Defense and Veterans Pain Rating Scale). RESULTS: The overall rate of chronic pain was 68.2% in the 107 patients who completed the end point assessment. There was no significant effect of perioperative valproic acid administration, with a rate of 65.45% (N = 36) in the treatment group and a rate of 71.15% (N = 37) in the placebo group. Overall, pain scores decreased from baseline to follow-up (median = -2 on the numeric pain scale). Patients additionally experienced improvements in self-perceived function. CONCLUSIONS: The rate of chronic pain after amputation surgery is not significantly improved with the perioperative administration of valproic acid. In this cohort treated with multimodal perioperative analgesia and regional anesthetic blockade, we observed improvements in both pain severity and function.

Treating Alcohol Use Disorder in U.S. Veterans: The Role of Traumatic Brain Injury.

OBJECTIVE: The authors examined the efficacy of valproate to reduce relapse to heavy drinking among veterans with alcohol use disorder (AUD) and neuropsychiatric comorbidities and whether antecedent traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) affected treatment response. METHODS: Participants were male veterans 18-60 years old with an AUD and no other substance use besides nicotine or cannabis. Sixty-two patients were randomly assigned to receive either valproate or naltrexone. Participants were evaluated at baseline and followed weekly for 24 weeks. All participants received standardized psychosocial interventions as well as treatment for coexistent psychiatric conditions. RESULTS: During the follow-up period, nine study subjects in the naltrexone group and 14 in the valproate group relapsed to heavy drinking, but the difference did not reach statistical significance. Participants with a history of moderate to severe TBI were more likely to relapse to heavy drinking compared with those with no TBI (hazard ratio=4.834, 95% CI=1.103-21.194, p=0.033). PTSD status did not significantly affect outcome. CONCLUSIONS: Intensive outpatient programs are efficacious alternatives to treat AUD in veterans, although the role of pharmacological treatment is not completely elucidated. Glutamatergic agents appear to be less effective than opiate antagonists to prevent relapse to heavy drinking and to increase cumulative abstinence. Future studies should examine novel pharmacological and nonpharmacological options.