Gamma-aminobutyric acid-B Research Articles

Low-Dose Baclofen-Induced Encephalopathy in a Patient with End-Stage Renal Disease: A Case Report

Baclofen, a gamma-aminobutyric acid-B receptor agonist, is commonly used for central-origin muscle spasticity and spasm and neuropathic pain. Baclofen toxicity has been reported to cause a range of symptoms including drowsiness, confusion, respiratory depression, seizures, and even coma, particularly with dosage significantly exceeding therapeutic levels. Given that the baclofen is predominantly eliminated through the kidneys, patients with renal failure are at substantial risk for neurotoxic effects. We report a case of baclofen-induced encephalopathy in a patient with end-stage renal disease, characterized by an altered mental state with myoclonus following the consumption of a low dose of baclofen.

Role of GABAB receptors in cognition and EEG activity in aged APP and PS1 transgenic mice

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Recent evidence suggests that gamma-aminobutyric acid B (GABAB) receptor-mediated inhibition is a major contributor to AD pathobiology, and GABAB receptors have been hypothesized to be a potential target for AD treatment. The aim of this study is to determine how GABAB regulation alters cognitive function and brain activity in an AD mouse model. Early, middle and late stage (8–23 months) amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic mice were used for the study. The GABAB agonist baclofen (1 and 2.5 mg/kg, i. p.) and the antagonist phaclofen (0.5 mg/kg, i. p.) were used. Primarily, we found that GABAB activation was able to improve spatial and/or working memory performance in early and late stage AD animals. In addition, GABAB activation and inhibition could regulate global and local EEG oscillations in AD animals, with activation mainly regulating low-frequency activity (delta-theta bands) and inhibition mainly regulating mid- and high-frequency activity (alpha-gamma bands), although the regulated magnitude at some frequencies was reduced in AD. The cognitive improvements in AD animals may be explained by the reduced EEG activity in the theta frequency band (2–4 Hz). This study provides evidence for a potential therapeutic effect of baclofen in the elderly AD brain and for GABAB receptor-mediated inhibition as a potential therapeutic target for AD.

Transcending Traditional Treatment: The Therapeutical Potential of Nanovesicles for Transdermal Baclofen Delivery in Repeated Traumatic Brain Injury.

The repositioning of previously approved drugs is occupying the researchers' plans. Baclofen (Bac) was our candidate for its established neuroprotective capacity, with a proposal of efficient drug delivery as non-ionic surfactant-based nanovesicles (NISNV) formulae against mild repetitive traumatic brain injury (mRTBI) in rats, thus reducing the number of orally or injected medications, especially in severely comatose patients or pediatrics. A (23) factorial design was implemented for confining Bac-loaded NISNV formulae, where a bunch of variables were inspected. An in-vivo experiment was done to test the prepared formula's efficacy transdermally. The following parameters were measured: brain expression of gamma amino butyric acid B (GABAB), protein kinase C- α (PKC-α), focal adhesion kinase (FAK), TNF-α and nuclear factor kappa B (NF-κB) p65, malondialdehyde (MDA), superoxide dismutase (SOD), and histopathology. The particle size (PS) and entrapment efficiency percent (EE%) speckled from 60.40±0.28% to 88.02±0.01% for the former and 174.64±0.93 to 1174.50±3.54 nm for the latter. In vitro release% after 8 hours ranged from 63.25±5.47% to 84.79±3.75%. The optimized formula (F4) illustrated desirability=1, with 630.09±3.53 µg/cm2 of Bac permeated over 8 hours, which equates to 100% of Bac. Bac post-trauma treatment restored brain expression of GABAB and PKC-α, while decreasing FAK. Besides enhancing the histological findings, the anti-inflammatory effect was clear by decreasing TNF-α and NF-κB p65. Consequently, significant antioxidant sequelae were revealed herein by diminishing MDA levels and restoring SOD activity. Transdermal delivery of Bac-loaded niosomes confirmed neuroprotection and succeeded in surpassing skin-to-brain barriers, which makes it a promising therapeutic option for repeated traumas.

Discrimination between leucine-rich glioma-inactivated 1 antibody encephalitis and gamma-aminobutyric acid B receptor antibody encephalitis based on ResNet18.

This study aims to discriminate between leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis and gamma-aminobutyric acid B (GABAB) receptor antibody encephalitis using a convolutional neural network (CNN) model. A total of 81 patients were recruited for this study. ResNet18, VGG16, and ResNet50 were trained and tested separately using 3828 positron emission tomography image slices that contained the medial temporal lobe (MTL) or basal ganglia (BG). Leave-one-out cross-validation at the patient level was used to evaluate the CNN models. The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) were generated to evaluate the CNN models. Based on the prediction results at slice level, a decision strategy was employed to evaluate the CNN models' performance at patient level. The ResNet18 model achieved the best performance at the slice (AUC = 0.86, accuracy = 80.28%) and patient levels (AUC = 0.98, accuracy = 96.30%). Specifically, at the slice level, 73.28% (1445/1972) of image slices with GABAB receptor antibody encephalitis and 87.72% (1628/1856) of image slices with LGI1 antibody encephalitis were accurately detected. At the patient level, 94.12% (16/17) of patients with GABAB receptor antibody encephalitis and 96.88% (62/64) of patients with LGI1 antibody encephalitis were accurately detected. Heatmaps of the image slices extracted using gradient-weighted class activation mapping indicated that the model focused on the MTL and BG for classification. In general, the ResNet18 model is a potential approach for discriminating between LGI1 and GABAB receptor antibody encephalitis. Metabolism in the MTL and BG is important for discriminating between these two encephalitis subtypes.

GABABR IgG Associated Encephalitis: Clinical Presentations and Measures to Improve Diagnostic Assay Specificity

Objective To review the clinical/oncological presentations of gamma aminobutyric acid-B receptor (GABABR)-IgG and evaluate the clinical specificity of antibody testing methodologies. Background GABABR-IgG is an intermediate-risk paraneoplastic autoantibody commonly associated with encephalitis and/or seizures. Design/Methods GABABR-IgG positive patients tested at Mayo Clinic Neuroimmunology Laboratory were identified. Available archived sera were retested by cell-based assay (CBA) at 1:10 and 1:100 dilutions. Results 105 GABABR-IgG seropositive patients with clinical details were identified (females, n = 56; median age 63 [range 8-82]). Most patients had one of three anti-GABABR encephalitis/seizure presentations: focal-onset seizures with altered mental status (n = 39), new-onset refractory status epilepticus (NORSE [n = 23]) or rapidly progressive dementia (n = 14). Fifty-three of 72 patients (74%) with available data had associated malignancy, primarily small cell lung cancer (SCLC). Two P/Q type VGCC-IgG positive patients had isolated Lambert-Eaton Myasthenic Syndrome. Additionally, 27 patients presented with non-specific symptoms or alternate diagnoses (atypical presentation); none had underlying SCLC (13 with malignancy data). Most patients with anti-GABABR encephalitis/seizure presentations had GABABR-IgG detected in CSF (95%, 52/55; of 3 who were negative, 1 had NMDA-IgG and another AMPA-IgG and CRMP5-IgG) and/or GABABR-IgG detected by CBA in serum at a dilution of 1:100 (76%, 31/41). Five encephalitis/seizure patients with GABABR-IgG detected in CSF were CBA positive only at 1:10 dilution in serum. Forty-eight of 76 patients had samples positive on tissue IFA (serum = 17/42, CSF = 40/49). Among 27 patients with atypical presentations, most did not have GABABR-IgG CSF CBA positivity (91%, 21/23) and/or GABABR-IgG 1:100 serum titer by CBA (0/17). None of 27 cases were tissue IFA positive (serum = 0/27, CSF = 0/21). Conclusions GABABR-IgG is associated with autoimmune encephalitis/seizure presentations. Our study highlights the importance of evaluating CSF and testing serum at both 1:10 and 1:100 dilutions, as seropositivity at only the 1:10 dilution by CBA without CSF GABABR-IgG positivity has poor clinical specificity.

0849 Baclofen-induced severe central sleep apnea

Abstract Introduction Baclofen is a gamma-aminobutyric acid-B agonist that targets neurons in the spinal cord and brain. It has skeletal muscle-relaxant properties and is FDA approved to treat spasticity from spinal cord injury (SCI), multiple sclerosis, or traumatic brain injury. Off label use includes treatment of alcohol use disorder, hiccups, and muscle spasms. A rare respiratory side effect of baclofen is apnea, with reports of baclofen-induced central sleep apnea (CSA) in a pediatric patient and four adults with alcohol use disorder. We describe a case of severe CSA in a veteran with T7 paraplegia due to chronic baclofen use. Report of Cases: A 42-year-old veteran with T7 paraplegia was referred to sleep medicine for unrefreshing sleep. He had a remote history of spinal cord injury complicated by spasticity that was being treated with oral baclofen (40 mg TID). Further evaluation of unrefreshing sleep was obtained with baseline polysomnography. A total of 146 apnea and hypopnea events were observed (5 obstructive apneas, 131 central apneas, 4 mixed apneas and 6 hypopneas) for an AHI of 43.2 events/hour. Minimum oxygen saturation was 85% with 0.3 minutes spent <89%. Respiratory pattern was suggestive of crescendo decrescendo breathing but did not meet diagnostic criteria for Cheyne-Stokes respiration (cycle length <40 seconds). Other causes of CSA were investigated but unrevealing. A diagnosis of baclofen-induced central sleep apnea was made. Conclusion Spasticity is a common consequence of SCI and is commonly managed with baclofen. Apnea is a rare respiratory side effect of baclofen but can significantly impact patients’ sleep quality and overall quality of life. Our case highlights how providers should have a high suspicion for sleep-disordered breathing in patients with chronic baclofen use. Support (If Any) 1. Ghanavatian S, Derian A. Baclofen. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 15, 2021.2. Locatelli F, Formica F, Galbiati S, et al. Polysomnographic Analysis of a Pediatric Case of Baclofen-Induced Central Sleep Apnea. J Clin Sleep Med. 2019;15(2):351-354. Published 2019 Feb 15. doi:10.5664/jcsm.76443. Olivier PY, Joyeux-Faure M, Gentina T, et al. Severe Central Sleep Apnea Associated With Chronic Baclofen Therapy: A Case Series. Chest. 2016;149(5):e127-e131. doi:10.1016/j.chest.2015.10.001

0864 Severe Central Sleep Apnea

Abstract Introduction Central sleep apnea (CSA) is a rare form of sleep disordered breathing with repeated apneic episodes with absence of associated respiratory effort. CSA due to medication is well described in literature with opiate therapy. Baclofen which is a gamma-aminobutyric acid-B agonist with muscle relaxant properties has been implicated in CSA. We present a rare case of CSA likely due to chronic baclofen use. Patient underwent a polysomnogram (PSG) while on baclofen therapy which revealed severe central sleep apnea. Patient was weaned off baclofen therapy completely and a subsequent PSG was performed which revealed resolution of the CSA. Methods 28 year old male with cerebral palsy and neurogenic bladder who presented for evaluation of snoring, chronic insomnia and non-refreshing sleep. Overnight PSG was performed for further evaluation of his sleep related complaints while on chronic baclofen therapy, which revealed severe central sleep apnea. Trial of positive airway pressure therapy for treatment of CSA and supplemental oxygen therapy were attempted during the PSG but had to be terminated due to intolerance. Echocardiography and magnetic resonance imaging of the brain were performed to rule out congestive heart failure and Chiari malformation respectively, which revealed no underlying pathology to explaining the CSA. CSA in this patient was thought to be associated with chronic baclofen therapy. Patient was weaned off baclofen with repeat PSG revealing resolution of the CSA. Results 1st diagnostic PSG - on Baclofen: 139 central apneas, 6 obstructive apneas, 3 mixed apnea, and 38 hypopneas. This study showed severe central sleep apnea. The apnea-hypopnea index (AHI) was 51.5, REM index 21.8 and supine index 51.5. Central apnea index 39.5. Respiratory events were associated with moderate oxygen desaturations. The mean oxygen saturation during the study was 92.8%, with a minimum oxygen saturation of 81%. The patient spent 2.9 minutes with an oxygen saturation equal to or less than 88% for the entire study. CPAP titration was attempted and aborted, due to patient having difficulty tolerating CPAP. Supplemental oxygen was briefly added at 0.5 LPM, which was also discontinued due to patient complaining of burning sensation in the nose. Head of the bed was elevated at several levels (20 degrees, 30 degrees and 45 degrees) which did not attenuate the respiratory events. 2nd Diagnostic PSG – patient weaned off baclofen for study – Sleep efficiency reduced at 59.4%. Sleep onset latency 7.5 minutes. REM latency 163 minutes. 100% of total sleep time in supine position Moderate snoring. The apnea-hypopnea index (AHI) was 4.2, REM index 36.5 and supine index 4.2. Respiratory events were mainly noted using REM sleep. Respiratory events were associated with moderate oxygen desaturations. The mean oxygen saturation during the study was 93.9%, with a minimum oxygen saturation of 83%. The patient spent 1.2 minutes with an oxygen saturation equal to or less than 88% for the entire study. Labs and imaging – Workup for severe central sleep apnea after first diagnostic sleep study – Echo and MRI brain, which revealed no underlying pathology explaining his central sleep apnea. Therefore, thought to be due to baclofen. Conclusion 28 year old male, concurrent and past medical history of cerebral palsy, neurogenic bladder. Presented, initially to sleep medicine clinic for complaints of insomnia, snoring, and non-refreshing sleep. Wheelchair bound. Has muscle spasticity, was on baclofen. Underwent initial sleep study, for snoring and insomnia. The initial PSG was on baclofen doses. His initial PSG – showed apnea-hypopnea index (AHI) of 51.5, REM index 21.8 and supine index 51.5, Central apnea index 39.5. Oxygen nadir – 81%. Patient had 139 central sleep apnea events. Patient had MRI and echo, which revealed no pathology to explain his severe central sleep apnea. Baclofen on his medicine list – was the concern for the driving force behind his central sleep apnea. As a result, baclofen was weaned and stopped. Repeat PSG – showed moderate snoring, overall AHI greatly improved from first study to 4.2. Respiratory events were associated with moderate oxygen desaturations. The mean oxygen saturation during the study was 93.9%, with a minimum oxygen saturation of 83%. The patient spent 1.2 minutes with an oxygen saturation equal to or less than 88% for the entire study. In closing – due to the side effect profile of baclofen leading to central sleep apnea in this case, recommend alternative therapy in place of baclofen due to severe central sleep apnea with baclofen use. Support (If Any) 1. Ghanavatian S, Derian A. Baclofen. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 15, 2021.2. Locatelli F, Formica F, Galbiati S, et al. Polysomnographic Analysis of a Pediatric Case of Baclofen-Induced Central Sleep Apnea. J Clin Sleep Med. 2019;15(2):351-354. Published 2019 Feb 15. doi:10.5664/jcsm.76443. Olivier PY, Joyeux-Faure M, Gentina T, et al. Severe Central Sleep Apnea Associated With Chronic Baclofen Therapy: A Case Series. Chest. 2016;149(5):e127-e131. doi:10.1016/j.chest.2015.10.001

A RARE ASSOCIATION OF ANTI- GABA-B RECEPTOR WITH ANTI HU ANTIBODIES IN AUTOIMMUNE ENCEPHALITIS: A CASE REPORT

Antibodies to the gamma aminobutyric acid-B receptor (Anti-GABA-B-R) encephalitis is an uncommon subtype of autoimmune encephalitis (AE) in which IgG antibodies directed against the B1 subunit of the GABA-B-R has been described. Clinically it presents as limbic encephalitis (LE) which is characterized by seizures, psychosis, and memory loss with progression to autonomic dysfunction, altered consciousness and death. We present a case of an elderly male who presented in the ER due to progressive agitation, confusion, and irritability. Immunological workup revealed anti GABA-B-R antibody and anti Hu. After admission his consciousness rapidly deteriorated over the next few days, and he was incubated. The patient developed septic shock and due to poor prognosis, the patient’s family requested withdrawal of ventilatory support.

Refractory Gastroesophageal Reflux Disease: A Management Update.

Gastroesophageal reflux disease (GERD) is one of the most frequent gastrointestinal disorders. Proton pump inhibitors (PPIs) are effective in healing lesions and improving symptoms in most cases, although up to 40% of GERD patients do not respond adequately to PPI therapy. Refractory GERD (rGERD) is one of the most challenging problems, given its impact on the quality of life and consumption of health care resources. The definition of rGERD is a controversial topic as it has not been unequivocally established. Indeed, some patients unresponsive to PPIs who experience symptoms potentially related to GERD may not have GERD; in this case the definition could be replaced with “reflux-like PPI-refractory symptoms.” Patients with persistent reflux-like symptoms should undergo a diagnostic workup aimed at finding objective evidence of GERD through endoscopic and pH-impedance investigations. The management strategies regarding rGERD, apart from a careful check of patient's compliance with PPIs, a possible change in the timing of their administration and the choice of a PPI with a different metabolic pathway, include other pharmacologic treatments. These include histamine-2 receptor antagonists (H2RAs), alginates, antacids and mucosal protective agents, potassium competitive acid blockers (PCABs), prokinetics, gamma aminobutyric acid-B (GABA-B) receptor agonists and metabotropic glutamate receptor-5 (mGluR5) antagonists, and pain modulators. If there is no benefit from medical therapy, but there is objective evidence of GERD, invasive antireflux options should be evaluated after having carefully explained the risks and benefits to the patient. The most widely performed invasive antireflux option remains laparoscopic antireflux surgery (LARS), even if other, less invasive, interventions have been suggested in the last few decades, including endoscopic transoral incisionless fundoplication (TIF), magnetic sphincter augmentation (LINX) or radiofrequency therapy (Stretta). Due to the different mechanisms underlying rGERD, the most effective strategy can vary, and it should be tailored to each patient. The aim of this paper is to review the different management options available to successfully deal with rGERD.

Anti-GABAB receptor encephalitis associated with combined small cell lung carcinoma

Autoimmune encephalitis with antibodies against the gamma-aminobutyric acid-B receptor is a relatively rare disease. We report a case with characteristic symptoms of limbic encephalitis associated with combined small cell lung carcinoma. The brain magnetic resonance imaging showed bilateral temporal lesions and the photoemission tomography revealed regional heterogenous metabolism across the brain. The double labeling of anti-gamma-aminobutyric acid-B receptor autoantibodies both in the tissues of neuroendocrine and small cell neoplasia was a unique feature of this patient.

Lateral habenula electrical stimulation with different intensities in combination with GABAB receptor antagonist reduces acquisition and expression phases of morphine-induced CPP

The lateral habenula (LHb) plays a principal role in response to aversive stimuli and negative emotional states. In this study, we have evaluated the effects of unilateral electrical stimulation (e-stim) of the LHb on morphine-conditioned place preference (CPP), before or after bilateral injections of Gamma-aminobutyric acid-B receptor (GABABR) antagonist, phaclofen, in male rats. Morphine (5 mg/kg; s.c.) induced a significant CPP, using a 5-day CPP paradigm. Intra-LHb microinjection of phaclofen or the LHb e-stim decreased only the acquisition of CPP. The 150 μA stimulation plus phaclofen significantly suppressed the expression phase but induced aversion in the acquisition of CPP, and an e-stim of 25 μA in combination with the antagonist, significantly prevented only the acquisition phase. The findings of this study confirm the possible role of GABABRs in the LHb on the acquisition and the expression of CPP. These results show that e-stim of LHb alone or plus phaclofen may change the GABA transmission, involving into CPP. Therefore, the GABAergic system, especially through GABABRs, may play a prominent role in the behavioral responses to morphine-induced CPP by LHb stimulation.

Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury.

Altered neuronal Ca2+ homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α2δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H2O2 production and the H2O2/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI.

Clinical Characteristics of Anti-GABA-B Receptor Encephalitis.

Objective: Anti-GABA-B (gamma aminobutyric acid-B) receptor encephalitis is an autoimmune disease mediated by GABA-B-related antibodies. To fully understand the disease, we collected clinical data from patients with GABA-B receptor encephalitis and conducted an analysis to draw conclusions.Methods: All patients with GABA-B receptor encephalitis from the Neurology Department of Beijing Tiantan Hospital, affiliated with Capital Medical University, from August 2015 to September 2019 were accepted as study subjects. The clinical data of the patients were analyzed retrospectively and included the general demographic characteristics, clinical manifestations, and auxiliary examinations, including laboratory results, electroencephalograms (EEGs), brain magnetic resonance imaging (MRI), and positron emission tomography (PET-CT) results, as well as treatments.Results: From August 2015 to September 2019, 14 cases of anti-GABA-B receptor encephalitis were diagnosed. Among these patients, middle-aged and elderly men were the main demographic, with an average age of 52 years; moreover, the onset of the disease was relatively sudden, and the time from onset to diagnosis was ~1 month. The main clinical symptoms were frequent epileptic seizures, cognitive dysfunction, and mental behavioral disorders. In seven (50%) patients, the leukocyte in cerebrospinal fluid (CSF) were increased. Five (36%) patients had elevated cerebrospinal fluid protein. In most patients, the oligoclonal bands (83%) of CSF were positive, and 24 h IgG levels (92%) were increased. Anti-Hu or anti-Yo antibodies were positive in two (14%) patients. Tumor markers in 10 (71%) patients indicated that neuron-specific enolase, gastrin-releasing precursor, non-small cell lung cancer-related antigen, or carcinoembryonic antigen levels were increased. EEG results often indicated slow waves, sharp waves, or spike waves in temporal areas. Brain MRI always showed high T2 signals in the medial temporal lobe, hippocampus, and amygdala and swelling in the medial temporal lobe and hippocampus. PET-CT scans almost showed abnormal metabolism in the hippocampus and temporal lobe. Three (21%) patients who underwent systemic PET-CT showed hypermetabolism in pulmonary parenchymal nodules and enlargement of mediastinal lymph nodes. All patients underwent high-dose hormone therapy or immunoglobulin immunotherapy. After treatment, the symptoms of epilepsy, cognitive disorders, and mental behavioral disorders improved to varying degrees. However, one patient died of lung cancer.Conclusion: Anti-GABA-B receptor encephalitis mainly occurred in middle-aged and elderly men, and the disease onset was relatively sudden. Before disease onset, some patients experienced fever and non-specific respiratory symptoms, which mainly manifested as frequent epileptic seizures, cognitive dysfunction, and abnormal mental behavior. MRI and PET-CT revealed abnormal signals and local metabolism, respectively, in the temporal lobe. Moreover, the disease has a close relationship with lung cancer, which requires long-term follow-up observation.

GABAB receptor activation attenuates inflammatory orofacial pain by modulating interleukin-1β in satellite glial cells: Role of NF-[formula omitted]B and MAPK signaling pathways

Orofacial inflammation could activate satellite glial cells (SGCs) in the trigeminal ganglion (TG) to produce interleukin 1β (IL-1β) which plays crucial roles in the development of inflammatory pain. Recent studies have shown that gamma-amino butyric acid-B (GABAB) receptor could modulate the expression of inflammatory cytokines in microglia and astrocytes in the spinal cord. The objective of this study was to investigate whether GABAB receptors in TG SGCs attenuate inflammatory facial pain via mediating IL-1β following inflammation and its mechanisms. Complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce inflammation in vivo. Lipopolysaccharide (LPS) was added to culture medium to activate SGCs in vitro. Behavioral measures showed that microinjection of baclofen (a selective GABAB receptor agonist) into the TG ameliorated the mechanical allodynia of CFA-treated rats. Interestingly, baclofen pretreatment inhibited SGC activation and IL-1β production, however, preserved the decreased expression of GABAB receptors in SGCs activated by CFA in vivo and LPS in vitro. In addition, baclofen suppressed the increased expression of p-NF- κ B p65, p-I κ Bα, and p-p38 MAPK, while reversed the decreased production of I κ Bα, and further enhanced the increased expression of p-ERK(1/2) in LPS-treated SGCs in vitro. Finally, those effects of baclofen were abolished by saclofen (a specific GABAB receptor antagonist) co-administration. Altogether, these results demonstrated for the first time that activation of GABAB receptor might inhibit IL-1β production by suppressing NF- κ B and p38 MAPK signaling pathway activation and restore GABAB receptor expression in SGCs to attenuate inflammatory facial pain

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Activation of GABAB Receptor Suppresses Diabetic Neuropathic Pain through Toll-Like Receptor 4 Signaling Pathway in the Spinal Dorsal Horn.

Diabetic neuropathic pain (DNP) is a prevalent complication in diabetes patients. Neuronal inflammation and activation of Toll-like receptor 4 (TLR4) are involved in the occurrence of DNP. However, the underlying mechanisms remain unclear. Downregulation of gamma-aminobutyric acid B (GABAB) receptor contributes to the DNP. GABAB receptor interacts with NF-κB, a downstream signaling factor of TLR4, in a neuropathic pain induced by chemotherapy. In this study, we determined the role of TLR4/Myd88/NF-κB signaling pathways coupled to GABAB receptors in the generation of DNP. Intrathecal injection of baclofen (GABAB receptor agonist), LPS-RS ultrapure (TLR4 antagonist), MIP (MyD88 antagonist), or SN50 (NF-κB inhibitor) significantly increased paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) in DNP rats, while intrathecal injection of saclofen (GABAB receptor blocker) decreased PWT and PWTL in DNP rats. The expression of TLR4, Myd88, NF-κBp65, and their downstream components IL-1 and TNF-α was significantly higher in the spinal cord tissue in DNP rats compared to control rats. Following inhibition of TLR4, Myd88, and NF-κB, the expression of IL-1 and TNF-α decreased. Activation of GABAB receptors downregulated the expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. Blockade of GABAB receptors significantly upregulated expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. These data suggest that activation of the TLR4/Myd88/NF-κB signaling pathway is involved in the occurrence of DNP in rats. Activation of GABAB receptor in the spinal cord may suppress the TLR4/Myd88/NF-κB signaling pathway and alleviate the DNP.

The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy

ABSTRACTPurpose: We report 11 patients diagnosed with GABAB receptor (GABABR) antibodies encephalitis in China and aim to analyze the clinical characteristics, laboratory and imaging findings, therapeutic modalities and outcomes.Methods: Clinical data from patients diagnosed with anti-GABAB receptor encephalitis in the Second Affiliated Hospital of Hebei Medical University from February 2016 to October 2016 January were retrospectively collected and evaluated.Results: Of the 11 patients, seven were males, and a mean age at presentation of 63 years (range: 47–79 years). The major clinical features include cognitive decline (9/11), epilepsy (10/11), mental and behavioral disorders (6/11), involuntary movement (4/11), sleep disorders (2/11), hearing loss (1/11), disturbance of consciousness (4/11) and fever (3/11). GABA-B receptor antibody was positive in serum and/or cerebrospinal fluid in 11 patients. Small-cell lung cancer was detected in five patients. Electroencephalogram monitoring demonstrated abnormal discharge in 10 cases. Epileptiform activities were found in five patients. Four patients showed abnormality in hippocampal region, parahippocampal gyrus, temporal and occipital lobe on magnetic resonance imaging. Ten patients accepted first-line immune therapy. Five patients with small-cell lung cancer received oncologic treatment. During a median follow-up of 11 months, eight patients showed a good outcome, two patients (cases 8 and 9) with tumors had a poor one and one patient (case 10) died of status epilepticus.Conclusion: Anti-GABAB receptor encephalitis is an uncommon autoimmune disease, which has been known to be often associated with cancer. Generally, patients associated with GABABR GABA-B receptor antibody encephalitis respond well to immunotherapy, especially if started early.

Gamma-aminobutyric acid-B limbic encephalitis and asystolic cardiac arrest: a case report

BackgroundGamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavioral disturbance, and may coexist with other autoantibodies. Many are paraneoplastic, most commonly associated with small cell lung cancer. Until now there have been no reports of cardiac dysrhythmias in these patients.Case presentationA 65-year-old Caucasian man presented with multiple seizures, dysarthria and behavioral disturbance of unclear etiology, with associated asystolic cardiac arrest. Antibody testing showed anti-Gamma-aminobutyric acid-B receptor and anti-Hu antibodies in serum and Gamma-aminobutyric acid-B receptor autoantibodies in cerebrospinal fluid. The diagnosis of small cell lung cancer was subsequently made after lung biopsy, and the patient showed improvement with chemotherapy and intravenous immunoglobulin.ConclusionsWe present the case of a patient with Gamma-aminobutyric acid-B receptor limbic encephalitis associated with asystolic cardiac arrest, an association not previously described. This case illustrates how difficult it is to make the diagnosis on clinical grounds alone. We therefore propose more routine antibody testing in patients with similar symptomatology who remain undifferentiated after initial workup. We also recommend that in the acute setting, patients with Gamma-aminobutyric acid-B receptor encephalitis should receive cardiac monitoring, as further research is required to clarify its possible link with cardiac dysrhythmias.

Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABAB receptor-mediated inhibition of L-type calcium channels

Spontaneous activity of serotonergic neurons of the dorsal raphe nucleus (DRN) regulates mood and motivational state. Potentiation of serotonergic function is one of the therapeutic strategies for treatment of various psychiatric disorders, such as major depression, panic disorder and obsessive-compulsive disorder. However, the control mechanisms of the serotonergic firing activity are still unknown. In this study, we examined the control mechanisms for serotonergic spontaneous activity and effects of chronic antidepressant administration on these mechanisms by using modified ex vivo electrophysiological recording methods. Serotonergic neurons remained firing even in the absence of glutamatergic and GABAergic ionotropic inputs, while blockade of L-type voltage dependent Ca2+ channels (VDCCs) in serotonergic neurons decreased spontaneous firing activity. L-type VDCCs in serotonergic neurons received gamma-aminobutyric acid B (GABAB) receptor-mediated inhibition, which maintained serotonergic slow spontaneous firing activity. Chronic administration of an antidepressant, citalopram, disinhibited the serotonergic spontaneous firing activity by weakening the GABAB receptor-mediated inhibition of L-type VDCCs in serotonergic neurons. Our results provide a new mechanism underlying the spontaneous serotonergic activity and new insights into the mechanism of action of antidepressants.

A randomized, open-label, standard controlled, parallel group study of efficacy and safety of baclofen, and chlordiazepoxide in uncomplicated alcohol withdrawal syndrome

BackgroundAlcohol withdrawal syndrome (AWS) is a distressing condition, generally controlled by benzodiazepines (BZD's). Baclofen, a gamma-aminobutyric acid-B (GABAB) agonist, has also shown promising results in controlling AWS. As there are few studies comparing the efficacy and tolerability of chlordiazepoxide with baclofen, the present study was taken up. The objective of this study was to compare efficacy and tolerability of baclofen with chlordiazepoxide in uncomplicated AWS. MethodsSixty subjects with uncomplicated AWS were randomized into two groups of 30 each, to receive baclofen (30 mg) or chlordiazepoxide (75 mg) in decremented fixed dose regime for 9 days. Clinical efficacy was assessed by Clinical Institute Withdrawal Assessment for Alcohol-Revised Scale (CIWA-Ar) and tolerability by the nature and severity of adverse events. Lorazepam was used as rescue medication. Secondary efficacy parameters were Clinical Global Impression scores, symptom-free days, and subject satisfaction as assessed by visual analog scale. This study was registered with Clinical Trial Registry-India (CTRI/2013/04/003588), also subsequently registered with WHO's ICTRP clinical trial portal. ResultsBoth baclofen and chlordiazepoxide showed a consistent reduction in the total CIWA-Ar scores. However, chlordiazepoxide showed a faster and a more effective control of anxiety and agitation requiring lesser lorazepam supplementation, and also showed a better subject satisfaction compared to baclofen. Both the drugs showed good tolerability with mild self-limiting adverse events. ConclusionThe present study demonstrates that baclofen is not as good as chlordiazepoxide in the treatment of uncomplicated AWS. However, baclofen might be considered as an alternative.