Integrated analysis identifies GABRB3 as a biomarker in prostate cancer.

BACKGROUND: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. METHODS: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. RESULTS: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. CONCLUSION: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.

Electroacupuncture-induced activation of GABAergic system alleviates airway inflammation in asthma model by suppressing TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Electroacupuncture (EA) has been shown to attenuate airway inflammation in asthmatic mice; however, the underlying mechanism is not fully understood. Studies have shown that EA can significantly increase the inhibitory neurotransmitter γ-aminobutyric acid (GABA) content in mice, and can also increase the expression level of GABA type A receptor (GABAAR). Furthermore, activating GABAAR may relieve inflammation in asthma by suppressing toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway. Therefore, this study aimed to investigate the role of GABAergic system and TLR4/MyD88/NF-κB signaling pathway in asthmatic mice treated with EA. METHODS: A mouse model of asthma was established, and a series of methods including Western blot and histological staining assessment were employed to detect the level of GABA, and expressions of GABAAR and TLR4/MyD88/NF-κB in lung tissue. In addition, GABAAR antagonist was used to further validate the role and mechanism of GABAergic system in mediating the therapeutic effect of EA in asthma. RESULTS: The mouse model of asthma was established successfully, and EA was verified to alleviate airway inflammation in asthmatic mice. The release of GABA and the expression of GABAAR were significantly increased in asthmatic mice treated with EA compared with untreated asthmatic mice ( P  < 0.01), and the TLR4/MyD88/NF-κB signaling pathway was down-regulated. Moreover, inhibition of GABAAR attenuated the beneficial effects of EA in asthma, including the regulation of airway resistance and inflammation, as well as the inhibitory effects on TLR4/MyD88/NF-κB signaling pathway. CONCLUSION: Our findings suggest that GABAergic system may be involved in mediating the therapeutic effect of EA in asthma, possibly by suppressing the TLR4/MyD88/NF-κB signaling pathway.

Novel spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives as potent anticonvulsant agents: One-pot synthesis, in vivo biological evaluation, and molecular docking studies.

A new series of spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives 4a-m were synthesized via a one-pot method and evaluated for anticonvulsant activities using pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. Obtained results demonstrated that these compounds have not anticonvulsant activity in PTZ test while are active in the MES test. Among the synthesized compounds, the best anticonvulsant activity was obtained with compound 4h. This compound also was not neurotoxic. Given that the title new compounds have the pharmacophore requirement for benzodiazepine (BZD) receptor agonist, the most potent compound was assayed in vivo and in silico as BZD receptor agonist. After treatment with flumazenil as a standard BZD receptor antagonist, anticonvulsant activity of compound 4h decreased. Therefore, the involvement of BZD receptors in anticonvulsant activity of this compound confirmed. Furthermore, docking study of compound 4h in the BZD-binding site of GABAA receptor confirmed that this compound interacted with the important residues.

Probable mechanisms involved in the antiepileptic activity of Clerodendrum polycephalum Baker (Labiatae) leaf extract in mice exposed to chemical-induced seizures.

The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. This study is aimed at evaluating the effects of Clerodendrum polycephalum (CP) leaf extract on chemical-induced seizures in mice and the possible mechanisms of action. Swiss albino mice were pretreated with CP (50, 100, or 500 mg/kg, p.o.) prior to intraperitoneal injection of picrotoxin (PTX) or pentylenetetrazole (PTZ). However, the most effective dose was used to elucidate the role of GABAergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling mechanisms in mice brains. Accordingly, we evaluated the preventive and reversal effects of CP on kainic acid (KA)-induced temporal lobe epilepsy (TLE), oxidative stress, and neuroinflammatory in mice. The pretreatment of mice with CP delayed the latencies to PTX and PTZ-induced seizures and decrement in the period of tonic-clonic attacks. Interestingly, CP (100 mg/kg) completely prevented PTZ-induced tonic-clonic seizures. Contrastingly, flumazenil (benzodiazepine receptor antagonist), NG -nitro-L-Arginine (L-NNA) (10 mg/kg., neuronal nitric oxide synthase inhibitor), and methylene blue (MB) (2 mg/kg, a soluble guanylyl cyclase inhibitor) but not L-arginine (150 mg/kg., nitric oxide precursor) reversed CP-induced anticonvulsant-like effect in PTZ model. Furthermore, KA-elicited TLE was prevented by CP treatment. CP also attenuated KA-induced oxidative stress, cyooxygenase-2 (COX-2), and nuclear factor kappa-B (NF-κB) elevated expressions in the hippocampus. The study revealed that the ethanolic leaf extract of CP produced anticonvulsant actions through enhancement of antioxidant defense, GABAergic, and NO-cGMP signaling pathways as well as attenuation of inflammatory processes. PRACTICAL APPLICATIONS: The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. For this reason, we believe that supplementation of the Clerodendrum polycephalum leaf extract would prevent epileptic-related disorders in mice induced with epileptic conditions using kainic acid and other behavioral phenotypic models. Here, our findings clearly revealed that Clerodendrum polycephalum leaf extract protects against conditions of epileptic-related disorders and thus might be relevant as a dietary supplement in the prevention or delay of the onset of seizures and epileptic behavior.

Enhancing GABA inhibition is the next generation of medications for essential tremor.

γ-Aminobutyric acid (GABA) is the most prevalent inhibitory CNS neurotransmitter. Activating GABA-A receptors hyperpolarizes cells via Cl- influx, which inhibits action potentials. Although the exact pathophysiologies of tremor are incompletely understood, proposed neuroanatomy extensively implicates GABA pathways. Pathological studies and imaging studies also show GABA abnormalities in patients with ET. Most importantly, medications that activate GABA-A receptors, such as primidone, often improve tremor. Ongoing clinical trials and physiology research should further refine potential future GABAergic targets and treatments, which are currently the most promising targets for pharmacological intervention.

Why won't it stop? The dynamics of benzodiazepine resistance in status epilepticus.

Status epilepticus is a life-threatening neurological emergency that affects both adults and children. Approximately 36% of episodes of status epilepticus do not respond to the current preferred first-line treatment, benzodiazepines. The proportion of episodes that are refractory to benzodiazepines is higher in low-income and middle-income countries (LMICs) than in high-income countries (HICs). Evidence suggests that longer episodes of status epilepticus alter brain physiology, thereby contributing to the emergence of benzodiazepine resistance. Such changes include alterations in GABAA receptor function and in the transmembrane gradient for chloride, both of which erode the ability of benzodiazepines to enhance inhibitory synaptic signalling. Often, current management guidelines for status epilepticus do not account for these duration-related changes in pathophysiology, which might differentially impact individuals in LMICs, where the average time taken to reach medical attention is longer than in HICs. In this Perspective article, we aim to combine clinical insights and the latest evidence from basic science to inspire a new, context-specific approach to efficiently managing status epilepticus.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

Association study of genetic polymorphisms in GABRD with treatment response and dose in methadone maintenance treatment.

Aim: This study determined if gene variants in the GABA receptor delta subunit (GABRD) are associated with treatment response and dose in methadone maintenance treatment (MMT) for heroin addiction. Materials & methods: A total of 286 MMT patients were recruited and divided into response and nonresponse groups based on retention time in therapy. A total of 177 responders were classified into low dose and high dose subgroups according to the stabilized methadone dose. Four (single nucleotide polymorphisms) SNPs (rs13303344, rs4481796, rs2376805 and rs2229110) in GABRD were genotyped using the TaqMan SNP assay. Logistic regression was used to assess the genetic effects of the SNPs in MMT. Results: No significant associations were observed between the SNPs and treatment response or dose, except the frequency of haplotype ACGC at the four SNPs significantly differed between responders and nonresponders. Conclusion: The results indicated that GABRD variants may play a small role in modulating methadone treatment response.

Lay abstract This study determined if gene variants in the GABA receptor delta subunit (GABRD) are associated with treatment response and dose in methadone maintenance treatment (MMT) for heroin addiction. A total of 286 MMT patients were recruited and divided into response and nonresponse groups. A total of 177 responders were classified into low and high dose subgroups. Four single nucleotide polymorphisms (SNPs) (rs13303344, rs4481796, rs2376805 and rs2229110) in GABRD were genotyped and assessed the genetic effects of the SNPs in MMT. No significant associations were observed between the SNPs and treatment response or dose, except the frequency of haplotype ACGC significantly differed between responders and nonresponders. The results indicated that GABRD variants may play a small role in MMT, which may help provide a foundation for personalized solutions for MMT.

Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma.

BACKGROUND: Benzodiazepines have a direct bronchodilatory effect. Methacholine is a non-selective muscarinic receptor agonist causing bronchoconstriction. AIM: To examine the effects of inhaled benzodiazepines, modulating bronchoconstriction induced by methacholine in patients with asthma. PATIENTS AND METHODS: Twelve patients with well controlled asthma were studied. On the first day, after determining the initial values of pulmonary function, a dose response curve was carried out with progressive doses of methacholine. After the last dose, when at least a 20% drop of the initial forced expiratory volume in the first second (FEV1) was achieved, vital capacity (VC) and FEV1 were measured at 7, 15 and 30 minutes after provocation. On the second day a diazepam aerosol was inhaled by the patients prior to the same protocol with methacholine. RESULTS: In the first day of testing, methacholine inhalation (6 mg/mL) led to a significant drop in FEV1 from 2.98 to 1.69 L. On the second day of study, in the same patients, previous inhalation with diazepam reduced the changes of FEV1 after inhalation of methacholine. This parameter decreased from 2.48 to 2.21 L. CONCLUSIONS: Inhalation of benzodiazepines reduce bronchoconstriction after a methacholine challenge in patients with asthma.

Treatment options for insomnia--pharmacodynamics of zolpidem extended-release to benefit next-day performance.

BACKGROUND: Insomnia can manifest as difficulty in falling asleep, in maintaining sleep throughout the night, or waking up too early, with symptoms often unpredictably changing over time. Pharmacologic options for insomnia treatment include prescription hypnotics, such as gamma-amino butyric acid-receptor agonists, sedating antidepressants, over-the-counter antihistamines, melatonin-receptor agonists, and alternative therapies. A concern with insomnia medications is the risk of next-day residual effects, which can impair memory and ability to perform certain tasks, such as driving, and may increase the risk of accidents and falls, especially in the elderly. OBJECTIVES: To describe the impact of current insomnia treatments on next-day performance. RESULTS: The longer-acting benzodiazepines are associated with next-day "hangover" effects and, as a result, have been largely replaced by agents in the nonbenzodiazepine class, which typically have shorter half-lives. The hypnotic, sedative activities of these classes of drugs depend on variations in binding characteristics to the alpha1 subunit of the gamma-amino butyric acidA-receptor, which inhibits neuronal activity in broad areas of the brain and is found in areas of the brain responsible for sleep/wakefulness and sedation. However, nonbenzodiazepines with a rapid onset of action and short half-life have shown limited efficacy for maintaining sleep throughout the night. These properties have contributed to the development of modified-release formulations. Zolpidem extended-release is a bilayer tablet that retains the fast onset of action of its parent compound zolpidem while extending the duration of hypnotic activity, owing to a slower-release portion of the tablet. CONCLUSIONS: Based on clinical evidence, the risk of residual next-day effects of zolpidem extended-release is limited, mainly due to the similarly short half-life in its extended-release formulation.

Designing new treatments for depression and anxiety.

Depression and anxiety are disabling disorders that affect many individuals. Drugs that interfere with the reuptake and/or metabolism of biogenic amines have been used to treat depression for more than four decades. An important development in the treatment of depression has been the emergence of triple reuptake inhibitors (SNDRIs), which inhibit the reuptake of serotonin, norepinephrine and dopamine. Preclinical and clinical research indicates that drugs inhibiting the reuptake of all of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants. Allosteric modulation of GABAA receptors can produce anxiolytic, sedative/hypnotic and anesthetic effects, presumably from enhancing the inhibitory neurotransmission of GABAA through a facilitation of receptor function. Benzodiazepines have been used with great success as anxiolytics, but the use of these drugs is limited because of their addictive potential and sedative side effects. This feature review discusses the design and synthesis of antidepressants based on the monoamine hypothesis of depression, and presents the current status of research on GABAA receptor modulators as a potential treatment for anxiety disorders.

GABA(A) receptor subtypes: dissecting their pharmacological functions.

The enhancement of GABA-mediated synaptic transmission underlies the pharmacotherapy of various neurological and psychiatric disorders. GABA(A) receptors are pluripotent drug targets that display an extraordinary structural heterogeneity: they are assembled from a repertoire of at least 18 subunits (alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, rho1-3). However, differentiating defined GABA(A) receptor subtypes on the basis of function has had to await recent progress in the genetic dissection of receptor subtypes in vivo. Evidence that the various actions of allosteric modulators of GABA(A) receptors, in particular the benzodiazepines, can be attributed to specific GABA(A) receptor subtypes will be discussed. Such discoveries could open up new avenues for drug development.