Gamma-aminobutyric Acid Research Articles

NE contribution to rebooting unconsciousness caused by midazolam.

The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.

Proton-free induction decay MRSI at 7 T in the human brain using an egg-shaped modified rosette K-space trajectory.

Proton (1H)-MRSI via spatial-spectral encoding poses high demands on gradient hardware at ultra-high fields and high-resolutions. Rosette trajectories help alleviate these problems, but at reduced SNR-efficiency because of their k-space densities not matching any desired k-space filter. We propose modified rosette trajectories, which more closely match a Hamming filter, and thereby improve SNR performance while still staying within gradient hardware limitations and without prolonging scan time. Analytical and synthetic simulations were validated with phantom and in vivo measurements at 7 T. The rosette and modified rosette trajectories were measured in five healthy volunteers in 6 min in a 2D slice in the brain. An elliptical phase-encoding sequence was measured in one volunteer in 22 min, and a 3D sequence was measured in one volunteer within 19 min. The SNR per-unit-time, linewidth, Cramer-Rao lower bounds (CRLBs), lipid contamination, and data quality of the proposed modified rosette trajectory were compared to the rosette trajectory. Using the modified rosette trajectories, an improved k-space weighting function was achieved resulting in an SNR per-unit-time increase of up to 12% compared to rosette's and 23% compared to elliptical phase-encoding, dependent on the two additional trajectory parameters. Similar results were achieved for the theoretical SNR calculation based on k-space densities, as well as when using the pseudo-replica method for simulated, in vivo, and phantom data. The CRLBs of γ-aminobutyric acid and N-acetylaspartylglutamate improved non-significantly for the modified rosette trajectory, whereas the linewidths and lipid contamination remained similar. By optimizing the shape of the rosette trajectory, the modified rosette trajectories achieved higher SNR per-unit-time and enhanced data quality at the same scan time.

Design, Synthesis, and Insecticidal Activity of Novel meta-Diamide Compounds Bearing a Phthalimide as a Potential GABA Receptor Antagonist.

In pursuit of potent and environmentally benign insecticides targeting the γ-aminobutyric acid (GABA) receptor, a series of novel meta-diamide compounds bearing a phthalimide were rationally designed and synthesized. Bioassay studies revealed that most of the target compounds exhibited promising larvicidal activity against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). Notably, the most active compound N15 displayed exceptional potency with LC50 values of 3.82 and 3.42 mg·L-1 against M. separata and P. xylostella, respectively. Electrophysiological studies using Xenopus oocytes confirmed that compound N15 exerted its insecticidal activity by targeting the GABA receptors.

Decoding the Significance of Alpha Cell Function in the Pathophysiology of Type 1 Diabetes.

Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research.

Systemic acquired resistance inducing chemicals mitigate black scurf disease in potato by activating defense-related enzymes.

The potato, being an underground vegetable crop, faces consistent threats from soil- and tuber-borne fungal and bacterial pathogens. Black scurf and stem canker disease caused by the fungal pathogen Rhizoctonia solani Kuhn is a critical global concern in the potato cultivation system. In this study, we evaluated the disease mitigation potential of five systemic acquired resistance-inducing chemicals viz., salicylic acid, jasmonic acid, β-aminobutyric acid, γ-aminobutyric acid and hydrogen peroxide (H2O2). Two common methods, tuber dipping and foliar spray, were utilized in this experiment to evaluate pathogen inhibition on inoculated tubers. The results revealed that all the systemic acquired resistance inducing chemicals were effective in disease suppression in a concentration-dependent manner compared to an inoculated control. Significant differences (P<0.005) were evident among the various treatment combinations, with salicylic acid being the most effective in alleviating black scurf disease. Maximum reduction in disease incidence compared to the control was observed with salicylic acid (57.89% and 73.68%), followed by jasmonic acid (52.63% and 65.78%) and H2O2 (49.99% and 60.52%) under the tuber dipping treatment combinations. Whereas, in the foliar application, the maximum reduction in disease incidence compared to the control was observed with salicylic acid (44.73 and 63.15%), followed by jasmonic acid (42.10 and 60.52%) and H2O2 (39.46 and 52.63%). The tuber dipping treatments were significantly more efficacious (P<0.005) compared to foliar spray for all treatment combinations. The biochemical analysis of defense-related enzymes and metabolites demonstrated the induced resistance activation under these treatments. The activity of peroxidase, polyphenol oxidase, and phenyl ammonia-lyase was significantly higher in treated tubers as compared to inoculated and uninoculated control. The total phenol content was also elevated in treated tubers as compared to the respective control. Altogether, these resistance-inducing chemicals can be successfully included in integrated disease management programs.

GABAergic signalling in the suprachiasmatic nucleus is required for coherent circadian rhythmicity.

The suprachiasmatic nucleus is the circadian pacemaker of the mammalian brain. Suprachiasmatic nucleus neurons display synchronization of their firing frequency on a circadian timescale, which is required for the pacemaker function of the suprachiasmatic nucleus. However, the mechanisms by which suprachiasmatic nucleus neurons remain synchronized in vivo are poorly understood, although synaptic communication is considered indispensable. Suprachiasmatic nucleus neurons contain the neurotransmitter GABA and express GABA receptors. This has inspired the hypothesis that GABA signalling may play a central role in network synchronization, although this remains untested in vivo. Here, using local genetic deletion, we show that disruption of GABA synaptic transmission within the suprachiasmatic nucleus of adult mice results in the eventual deterioration of physiological and behavioural rhythmicity in vivo and concomitant cellular desynchrony in vitro. These findings suggest that intercellular GABA signalling is essential for behavioural rhythmicity and cellular synchrony of the suprachiasmatic nucleus neural network.

Exogenous GABA-Ca Alleviates Growth Inhibition Induced by a Low-P Environment in Peanuts (Arachis hypogaea).

Phosphorus (P) deficiency is a major global factor constraining peanut production. Exogenous γ-aminobutyric acid (GABA) and Ca2+ are essential to improve stress resilience in peanuts growing under low-P conditions. This study therefore examined the detailed physiological effects of GABA-Ca on restoring peanut growth under low-P conditions. These included the root-shoot ratio, leaf nutrients, photochemical activity, reactive oxygen species (ROS), cyclic electron flow (CEF), ATP synthase activity, and the proton gradient (∆pH), all of which were measured under low-P (LP, 0.5 mM) and optimized-P (1 mM) conditions. Specifically, supplying GABA-Ca under LP conditions regulated the ∆pH by causing adjustments in CEF and ATP synthase activities, buffering the photosystems' activities, restoring the antioxidant enzyme system, and lowering ROS production. Interestingly, exogenous GABA-Ca restored peanut growth under low-P conditions, possibly by the putative signaling crosstalk between GABA and Ca2+. The plausible signal amplification between GABA and Ca2+ suggested that the combination of GABA and Ca, may offer an effective strategy for enhancing peanut adaptation to low-P conditions. Moving forward, the strategic supplementation of GABA-Ca, either during cultivation or through the formulation of novel fertilizers, opens up many possibilities for better and more resilient plant production in soils with low P.

Exploring Ultrasonic Energy Followed by Natural Fermentation Processing to Enhance Functional Properties and Bioactive Compounds in Millet (Pennisetum glaucum L.) Grains

This study explores the effect of ultrasonic treatment followed by fermentation on the in vitro protein digestibility, protein solubility, functional properties, antioxidant activity, total carotenoid content, and gamma-aminobutyric acid (GABA) levels in millet grains. Ultrasonic treatment was applied at different temperatures (20, 40, and 60 °C). The findings indicated significant improvements in phenolic and flavonoid contents and antioxidant activity in terms of the results of the DPPH, FRAP, and ABTS assays of millet grains after ultrasonic treatment alone or combined with fermentation. Moreover, the carotenoid and GABA contents were found to be significantly higher in the ultrasonic-treated grains. The protein solubility functional properties of the millet grains were also improved after the ultrasonic treatment alone or coupled with the fermentation process. Principal component analysis (PCA) revealed that the combined ultrasonic treatment and fermentation of the millet grains could enhance their antioxidant activity, functional characteristics, and vital compounds. Furthermore, the partial least squares (PLS) validation model emphasised that the ultrasonic treatment of millet at 40 °C, followed by fermentation, is the most optimal treatment among the other treatments. Hence, the conclusions highlight the potential of combined ultrasonic (40 °C) and fermentation treatments to improve grains’ nutritional value and functional properties, making millet more suitable for use in health-promoting food products.

Neurotransmitters and neural hormone-based probes for quadruplex DNA sequences associated with neurodegenerative diseases

The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)3 and G4C2, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.

Modulation of GABAergic neurons in acute epilepsy using sonogenetics.

Epilepsy, a neurological disorder caused by hypersynchronous neural disturbances, has traditionally been treated with surgery, pharmacotherapy, and neuromodulation techniques such as deep brain stimulation and vagus nerve stimulation. However, these methods are often limited by invasiveness, off-target effects, and poor resolution. We present a noninvasive alternative utilizing sonogenetics to selectively stimulate γ-aminobutyric acid (GABA)ergic neurons in the amygdala through engineered auditory-sensing protein, mPrestin (N7T, N308S), in a pentylenetetrazole-induced rat model. Activation of GABAergic neurons induced by the sonication with 0.5-MHz transcranial ultrasound can modulate epileptiform activity by 50 %. Electrophysiological recordings confirmed effective neuromodulation and persistent seizure suppression up to 60 min post-treatment without tissue damage, inflammation, or apoptosis. This sonogenetic approach offers a promising, safe method for epilepsy management by targeting GABAergic neurons.

ADVANCEMENTS IN UNDERSTANDING AND MANAGING ALCOHOL WITHDRAWAL SYNDROME: A COMPREHENSIVE REVIEW

Alcohol withdrawal syndrome (AWS) is a clinically significant condition that can arise upon abrupt cessation or reduction of alcohol consumption in individuals with alcohol dependence. This review article provides a comprehensive overview of AWS, encompassing its epidemiology, pathophysiology, clinical manifestations, assessment tools, and management strategies. We discuss the neurobiological mechanisms underlying AWS, including the role of neurotransmitter systems such as gamma-aminobutyric acid (GABA) and glutamate, as well as neuroadaptive changes that occur with chronic alcohol use. Furthermore, we explore the spectrum of clinical manifestations associated with AWS, ranging from mild withdrawal symptoms to severe complications such as delirium tremens and seizures. Diagnostic tools and scoring systems commonly used for assessing AWS severity are examined, along with evidence-based approaches for pharmacological and non-pharmacological management of AWS. Additionally, we highlight emerging research areas and future directions in the field of AWS, including novel treatment modalities and potential biomarkers for predicting withdrawal severity and treatment response. This comprehensive review aims to provide clinicians, researchers, and healthcare professionals with a thorough understanding of AWS to facilitate early recognition, appropriate management, and improved outcomes for individuals affected by this condition.

Mechanism of NACHO-mediated assembly of pentameric ligand-gated ion channels.

Pentameric ligand-gated ion channels (pLGICs) are cell surface receptors of crucial importance for animal physiology 1-4 . This diverse protein family mediates the ionotropic signals triggered by major neurotransmitters and includes γ -aminobutyric acid receptors (GABA A Rs) and acetylcholine receptors (nAChRs). Receptor function is fine-tuned by a myriad of endogenous and pharmacological modulators 3 . A functional pLGIC is built from five homologous, sometimes identical, subunits, each containing a β-scaffold extracellular domain (ECD), a four-helix transmembrane domain (TMD) and intracellular loops of variable length. Although considerable progress has been made in understanding pLGICs in structural and functional terms, the molecular mechanisms that enable their assembly at the endoplasmic reticulum (ER) 5 in a vast range of potential subunit configurations 6 remain unknown. Here, we identified candidate pLGICs assembly factors selectively associated with an unassembled GABA A R subunit. Focusing on one of the candidates, we determined the cryo-EM structure of an assembly intermediate containing two α1 subunits of GABA A R each bound to an ER-resident membrane protein NACHO. The structure showed how NACHO shields the principal (+) transmembrane interface of α1 subunits containing an immature extracellular conformation. Crosslinking and structure-prediction revealed an adjacent surface on NACHO for β2 subunit interactions to guide stepwise oligimerisation. Mutations of either subunit-interacting surface on NACHO also impaired the formation of homopentameric α7 nAChRs, pointing to a generic framework for pLGIC assembly. Our work provides the foundation for understanding the regulatory principles underlying pLGIC structural diversity.

Protein phosphatase 2A inhibitors: a possible pharmacotherapy for benzodiazepine dependence.

Benzodiazepines (BZDs) activate the γ-aminobutyric acid (GABA) subtype A (GABAA) receptors, and thus are widely used medicines for the treatment of anxiety and insomnia. For chronic use, tolerance to BZDs is a major problem. Patients with chronic insomnia that develop tolerance to BZDs lose therapeutic effects but also potentially suffer from BZD dependence resulting in BZD withdrawal. The development of such treatments is important for the appropriate use of BZDs. Research articles regarding investigation of BZD dependencewere searched on PubMed, Embase, and Scopus databases using keywords "benzodiazepine", "dependence", "treatment". When BZDs are taken chronically, continuous GABAA binding results in up-regulation of α-amino-3-hydroxy-5-methyl-4-lisoxazolepropionic acid (AMPA) glutamate receptor function and release of brain-derived neurotrophic factor (BDNF). Released BDNF binds to its specific receptor tropomyosin-related kinase receptor B (TrkB). Enhanced BDNF-TrkB signaling activates protein phosphatase 2A (PP2A). Activated PP2A dephosphorylates GABAA receptors, resulting in the downregulation of the GABAA receptor function. Reduced GABAA receptor function augments long-term potentiation (LTP), AMPA-mediated glutamatergic neuroplasticity, by reducing LTP inhibition by GABAA receptor function. Augmented LTP enhances extreme anxiety, which leads to BZD dependence. Therefore, iInhibiting dephosphorylation of the GABAA receptor by PP2A, PP2A inhibitors could reduce LTP and anxiety, restoring BZD effectiveness and resulting in possible therapeutic effects for BZD dependence.

High Expression of GABAA Receptor β Subunit Genes Is Associated with Longer Overall Survival in Medulloblastoma.

Background/Objectives: Most of the rapid inhibitory neurotransmission in the brain is mediated through activation of the γ-aminobutyric acid (GABA) type A (GABAA) receptor, which is a ligand-gated ion channel. GABAA receptor activation via GABA binding allows for an intracellular influx of Cl- ions, thus inducing cellular hyperpolarization. Each GABAA receptor consists of a combination of five subunits, and several subunits have been proposed as biomarkers and therapeutic targets in cancer. Here, we show the expression of genes encoding β subunits of the GABAA receptor, namely GABRB1, GABRB2, and GABRB3, across the four different molecular subgroups of medulloblastoma (MB), which is the most common malignant pediatric brain tumor. We also show the associations of GABAA receptor β subunits with MB patients' overall survival (OS). Methods: The expression of genes encoding GABAA receptor β subunits was analyzed using a previously described dataset comprising 763 MB tumor samples. Patients were classified into high- and low-gene-expression groups, and the Kaplan-Meier estimate was used to examine the relationship between gene expression levels and patient OS. Results: High GABRB1 expression was associated with better OS within each of the four molecular subgroups. The GABRB2 gene showed higher transcript levels in Group 3 MB compared to all other subgroups, and high expression was associated with better prognosis in Group 3 tumors. GABRB3 expression was significantly higher in Group 3 and Group 4 MB, and high expression of GABRB3 genes was associated with longer OS in the sonic hedgehog (SHH) subgroup. The high expression of GABRB1, GABRB2, and GABRB3 is associated with longer patient OS in a subgroup-specific manner. Conclusions: These results indicate a role for GABAA receptors containing β subunits in influencing MB progression.

A UTILIZAÇÃO DE VALERIANA OFFICINALIS E PASSIFLORA INCARNATA EM PACIENTES COM DEPRESSÃO

Depression, a debilitating mental condition with an increasing impact on quality of life, does not always respond well to conventional treatments, which often have side effects that hinder adherence. In this context, phytotherapeutics like Valeriana officinalis and Passiflora incarnata have emerged as promising therapeutic alternatives. This study aimed to review the effectiveness of these phytotherapeutics in treating depression and anxiety. The methodology involved a systematic literature review of 16 articles published between 2014 and 2024, following PRISMA guidelines. Results indicated that both phytotherapeutics significantly reduced depressive and anxiety symptoms, with fewer adverse effects compared to conventional medications. Valeriana officinalis and Passiflora incarnata were observed to modulate the GABA system, promoting symptom relief. However, inconsistent bioactive compound standardization and preparation variability are limitations for clinical application. It is concluded that, while promising, these phytotherapeutics require further research to ensure consistent efficacy and safety.

The Application of 1-MCP in Combination with GABA Reduces Chilling Injury and Extends the Shelf Life in Tomato (Cv. Conquista)

Tomatoes have a short shelf life, and refrigeration is commonly used to extend tomato quality. However, suboptimal temperatures can lead to chilling injury (CI), reducing their marketability. In this study, the combined application of 10 mM γ-aminobutyric acid (GABA) and 0.5 µL L−1 of 1-methylcyclopropene (1-MCP) were used as strategies to reduce postharvest CI and prolong storability during tomato commercialization. Both treatments have individually demonstrated their effectiveness in lowering physiological disorders in tomatoes. When applied, the combined treatment resulted in the lowest CI and rot incidence levels compared with the control and individual treatments. Additionally, the combined application effectively delayed weight loss, fruit softening, respiration rate, ethylene production, and increased chlorophyll and flavonoid content. The synergistic application of these substances improved the postharvest quality during storage, reducing quality losses. For this reason, the combination of GABA and 1-MCP could be an effective tool to minimize tomato waste during commercialization by increasing resilience to cold storage and extending the overall fruit shelf life during refrigerated storage.

The Physiological and Pharmacological Roles of Melatonin and Pregabalin

Melatonin and pregabalin are two important compounds that are broadly used in the fields of physiological and medicinal sciences. Melatonin is a primary hormone mainly secreted by the pineal gland and plays an important role in regulating circadian rhythms, sleep-wake cycles, and neuroimmune processes. Its strong antioxidant anti-inflammatory and anti-apoptotic properties have protected it against a wide range of diseases, from cancer to neurological disorders. In this study, the synthesis of melatonin will be widely studied, mainly regarding its role in regulating circadian rhythms and sleep, and its possible therapeutic use in treating neurological diseases and inflammation-related disorders. Pregabalin is an analog of the neurotransmitter gamma-aminobutyric acid (GABA), with anticonvulsant, analgesic, and anxiolytic actions. Clinical practice has widely utilized it because studies indicate that it is useful in treating a variety of conditions: fibromyalgia, epilepsy, neuropathic pain, and generalized anxiety disorder. This article reviews aspects of the pharmacokinetics of pregabalin, its useful functions in pain treatment, and its impact on calcium channel regulation. The review also discusses indications of pregabalin in therapy, along with its possible side effects. This review article aims to consider the molecular processes underlying the activities of melatonin and pregabalin and their therapeutic potential for the management of sleep disorders, inflammation, and neurological diseases to future use of these compounds clinically.

Efficacy and utility of isocycloseram a novel isoxazoline insecticide against urban pests and public health disease vectors.

Isoxazolines inhibit γ-aminobutyric acid chloride channels in insects and acarids by binding to postsynaptic receptors. This prevents chloride influx, leading to depolarization/hyperexcitation, paralysis, and death. Here, we evaluated the potential utility of a novel isoxazoline, isocycloseram, against several urban insect pests. Isocycloseram was active at low doses against the German cockroach, Blattella germanica (L.)[median lethal dose (LD50) 5-15 ng per insect at 72 h, topical assays]; Argentine ant (Linepithema humile Mayr), Pharaoh ant (Monomorium pharaonis (L.), common bed bug (Cimex lectularius (L.) (approximately 40 mg m-2, residual surface spray); Eastern subterranean termite (Reticulitermes flavipes (Kollar)and Formosan subterranean termite (Coptotermes formosanus Shiraki) (5 μg g-1 w/w, tunneling assays); and mosquito, Anopheles stephensi Liston (120 and 150 mg m-2 treated surfaces, aged indoors for 9 months). Additionally, cockroach gel bait at 1% isocycloseram (w/w) caused 95-100% mortality in German, American (Periplaneta americana (L.), and oriental (Blatta orientalis (L.) cockroaches within 5-14 days. Isocycloseram proved to be active against both laboratory and field populations of German cockroaches at doses lower or equal to those of other chemicals. Ants, bed bugs, and mosquitoes readily acquired lethal doses of isocycloseram from different surfaces treated with formulated products. Given its non-repellent nature, delayed effects, and activity at low rates, isocycloseram can be a very effective compound against subsocial, social, and other human disease vector insect pests. © 2024 Society of Chemical Industry.

TMET-16. GABA PRODUCTION INDUCED BY IMIPRIDONES IS A TARGETABLE AND IMAGEABLE METABOLIC ALTERATION IN DIFFUSE MIDLINE GLIOMAS

Abstract Diffuse midline gliomas (DMGs) are lethal brain tumors in children. The imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients, but efficacy as monotherapy is limited. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment. Here, using 1H-magnetic resonance spectroscopy (1H-MRS), which is a non-invasive method of quantifying metabolite pool sizes, we show that imipridones induce accumulation of gamma-aminobutyric acid (GABA) in patient-derived (BT245, SF8628) and syngeneic (26-B7, 26-C2) cells. Importantly, in vivo1H-MRS detects a significant increase in GABA within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic BT245, SF8628 or 26-B7 xenografts. Mechanistic studies show that imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, the enzyme that synthesizes GABA, and downregulates GABA transaminase, which degrades GABA, leading to GABA accumulation in DMG cells and orthotopic tumors. Since GABA is known to regulate oxidative stress signaling and since imipridones induce oxidative stress, we assessed whether GABA influences oxidative stress in DMG cells. Our studies indicate that GABA induces expression of superoxide dismutase (SOD1), which scavenges superoxide radicals and, thereby, curbs apoptosis induced by imipridones. The biological effects of GABA are mediated via signaling cascades triggered by GABA receptors and we find that GABA acts in an autocrine manner via the GABAB receptor to upregulate SOD1. Importantly, the clinically translatable GABAB receptor antagonist SGS742 and the SOD1 inhibitor ATN-224 exacerbate oxidative stress and synergistically induce apoptosis in combination with imipridones in DMG cells. Furthermore, SGS742 is brain-penetrant and potentiates ONC206-induced apoptosis in mice bearing orthotopic SF8628 xenografts in vivo. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for imaging drug-target engagement and for enhancing response to therapy. Clinical translation of our studies will enable precision therapy and imaging for DMG patients.

Pharmacology and Articular Cartilage Regeneration: A New Strategy for Osteoarthritis

ABSTRACT Background: Osteoarthrosis is a slowly progressive, multifactorial, and non-inflammatory degenerative disease affecting synovial joints and is typically associated with aging or previous joint damage. Method: Fifty male Sprague Dawley rats were utilized in the study and divided into five groups, with ten rats in each group. The experiment was divided into two phases: in Phase 1, ten animals received 50 μL of saline in the left tibiotarsal joint and served as the control group (SAL), while the other four groups (n = 40) received a single dose of 50 μL complete Freund’s adjuvant (CFA) to induce monoarthritis. In Phase II, after the induction of monoarthritis, from the fourth week onward, the rats in the four CFA-induced monoarthritis groups were treated with 20 μl of gamma-amino butyric acid (GABA), serotonin (SERO), or a neurotransmitter cocktail (NTC) which were given intra-articularly once for three consecutive weeks, while one group was kept as an experimental control. The animals were monitored throughout the experiment, for ankle diameter, gait, and radiological assessment, and were then euthanized and subjected to histopathological evaluation at the conclusion of the study. Results: The study found that there were statistically significant differences in the degree of inflammation between the CFA group and the groups treated with GABA, SERO, and NTC. The CFA group exhibited the most severe and persistent inflammation, whereas the NTC group showed a milder and shorter inflammatory response than the control group (SAL). In terms of gait score, the NTC treatment resulted in a significant reduction in score compared to the treatments with GABA and SERO administered separately. The radiological scores revealed that NTC was the most effective treatment in mitigating radiographic evidence of joint damage, with a significant decrease in bone destruction. The histopathological examination showed that the NTC group had minimal tissue damage or inflammation and had a regenerative effect compared to the other treatment groups. Conclusions: In conclusion, the local administration of neurotransmitters was found to be effective in reversing inflammation, improving gait score, and mitigating radiological changes in CFA-induced arthritis in the murine model.