GABA Agonist Research Articles

Shankhpushpi (Convolvulus pluricaulis): Exploring its Cognitive Enhancing Mechanisms and Therapeutic Potential in Neurodegenerative Disorders

Shankhpushpi (<i>Convolvulus pluricaulis</i>), also called <i>C. pluricaulis</i> Choisy (<i>C. pluricaulis</i>), is a longstanding shrub also known by the names C. microphyllus Sieb. as well as C. prostratus Forsk and it’s employed as a traditional people’s remedy for a number of illnesses such as memory enhancement in Ayurveda and Conventional Chinese Medicine system. It is primarily utilized as a memory enhancer and brain stimulant for the treatment of central nervous diseases like stress, depression, and sleeplessness. Traditional Indian medications are used. Anxiolytic, neurological (Alzheimer's, Huntington's, Epilepsy, but also Depressant) antioxidants, analgesics, immunomodulatory, antibacterial, antihyperlipidemic, and cardioprotective actions are just a few of the medicinal qualities of this herb that have been linked to them in historical publications. Therefore, identifying and scientifically validating herbal remedies helps advance Ayurvedic/ Unani studies. Various biological phytoconstituents, including the alkaloids (convolamine), flavonoids (kaempferol), and polyphenolic compounds (scopoletin, sitosterol, and ceryl alcohol), have been linked to the therapeutic benefits of this botanical. Several active substances, such as scopoletin, kaempferol phytosterol, as well as -sitosterol, which was extracted from flying sections of <i>C. pluricaulis</i>, have been demonstrated to work as GABAA agonists that might explain the antianxiety and CNS depressant properties of shankhpushpi. To compile data for this article, a Systematic Literature Review on <i>C. pluricaulis</i> was conducted.

Growth of the prefrontal cortical glioblastoma altered cognitive and emotional behaviors via mediating miRNAs and GABA-A receptor signaling pathways in rats.

The present study investigated the impact of GABAergic signaling and miRNA expression on glioblastoma multiforme (GBM) growth within the medial prefrontal cortex (mPFC) and its associated cognitive and emotional impairments. The implantation of C6 cells into the mPFC induced GBM in this brain region (referred to as the mPFC-GBM) in male Wistar rats via stereotaxic surgery, as confirmed by Magnetic Resonance Imaging (MRI), and Hematoxylin and Eosin (H&E) staining. Repeated microinjections of muscimol, a potent GABAA receptor agonist, directly into the mPFC-GBM (1µg/rat/2.5μl) following tumor induction decreased tumor volume and weight, resulting in an increased survival rate. Conversely, a higher dose of muscimol (6µg/rat/2.5μl) increased tumor size and reduced survival. Behavioral alterations induced by GBM, including anxiety-like responses, exploratory behaviors, locomotor activity, and memory formation, were assessed using anxiety-like behavior task, the hole-board test, and the novel object recognition test. Muscimol treatment dose-dependently affected these behaviors in the animals with the mPFC-GBM, bringing their performance with that of the sham group at the dose of 1µg/rat/2.5μl. Changes in specific miRNAs expressions, including miR-208, -290-295, -345, -743 and -802 were associated with the growth of the mPFC-GBM under muscimol treatment. These findings suggest that GBM growth into the mPFC profoundly impacts cognitive and emotional behaviors which can be improved by muscimol treatment. Considering that the expression levels of targeted miRNAs could be influenced by the growth of the mPFC-GBM, both with or without muscimol treatment, these non-coding RNAs might serve as potential biomarkers for GBM.

Antiseizure Medications: Advancements, Challenges, and Prospects in Drug Development.

Epilepsy is a neurological disorder affecting millions of people worldwide. Antiseizure medications (ASM) remain a critical therapeutic intervention for treating epilepsy, notwithstanding the rapid development of other therapies. There have been substantial advances in epilepsy medications over the past three decades, with over 20 ASMs now available commercially. Here we describe the conventional and unique mechanisms of action of ASMs, focusing on everolimus, cannabidiol, cenobamate, fenfluramine, and ganaxolone, the five most recently marketed ASMs. Major obstacles in the development of ASMs are also addressed, particularly drug-resistant epilepsy as well as psychiatric and behavioral adverse effects of ASMs. Moreover, we delve into the mechanisms and comparative efficacy of ASM polytherapy, with remarks on the benefits and challenges in their application in clinical practice. In addition, the characteristics of the ideal ASM are outlined in this review. The review also discusses the development of new potential ASMs, including modifying existing ASMs to improve efficacy and tolerability. Furthermore, we expound on the modulation of γ- aminobutyric acid type A receptor (GABAAR) as a strategy for the treatment of epilepsy and the identification of a GABAAR agonist, isoguvacine, as a potential ASM.

Baclofinding solutions: Baclofen-induced encephalopathy in a peritoneal dialysis patient.

Baclofen is a gamma-aminobutyric acid agonist that is commonly and widely used for the treatment of muscle spasticity. Given its predominant kidney excretion, patients with reduced kidney function are at particular risk of drug accumulation and toxicity, with neurotoxicity in the form of drowsiness, encephalopathy, seizures, and coma being the most reported clinical features. In addition to the importance of early identification of baclofen toxicity and drug discontinuation, dialysis can effectively accelerate baclofen elimination given its small molecule weight, and the relatively low volume of distribution and weak protein binding. While several cases of baclofen-induced toxicity have been reported in hemodialysis patients, the literature on baclofen toxicity in individuals receiving peritoneal dialysis (PD) is limited. Here, we present a case of baclofen-induced encephalopathy in a PD patient following a single dose of baclofen. In this case, our patient was managed by continuous (24 h) automated PD, with complete recovery of neurological status within three days.

Simultaneous detection and quantification of a novel imidazole-derived GABA agonist isopropoxate and etomidate acid from human urines in abused cases by LC-MS/MS

Simultaneous detection and quantification of a novel imidazole-derived GABA agonist isopropoxate and etomidate acid from human urines in abused cases by LC-MS/MS

Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction

Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA's degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund's adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.

Intervention effect of regulating GABA-A receptor activity on the formation of experimental abdominal aortic aneurysm in rats

Abdominal aortic aneurysm is a potentially fatal vascular inflammatory disease characterized by infiltration of various inflammatory cells.The GABA-A receptor is expressed in many inflammatory cells such as macrophages and T cells and has anti-inflammatory and antioxidant effects. Therefore, the GABA-A receptor may become a potential therapeutic target for abdominal aortic aneurysms. The purpose of this study was to investigate the effect of regulating the activity of the GABA-A receptor on the formation of experimental abdominal aortic aneurysm in rats. In this study, the abdominal aortic aneurysm model of rats was established by aorta intracavitary perfusion of elastase combined with aorta extracavitary infiltration of calcium chloride. GABA-A receptor agonist (topiramate) and antagonist (bicuculline) were used to treating the abdominal aortic aneurysm model rats, which were divided into sham operation group, model group, topiramate group, and bicuculline group(n = 10). Histopathology, immunohistochemistry, fluorescence quantitative PCR, Western blotting, ELISA and Gelatine zymogram were used to study. Regulation of GABA-A receptor activity can interfere with the development and severity of abdominal aortic aneurysms in rats. The GABA-A receptor agonist topiramate reduces the infiltration of inflammatory cells, particularly T cells, into the abdominal aortic wall, while also modulating the balance of Th1/Th2 cytokines in peripheral blood, leading to a significant reduction in inflammatory responses. Additionally, topiramate decreases the secretion of matrix metalloproteinases MMP2 and MMP9, thereby inhibiting extracellular matrix degradation and slowing the progression of aneurysms. In contrast, the GABA-A receptor antagonist bicuculline exacerbates inflammation and promotes aneurysm development. At the molecular level, the mechanisms of action of the GABA-A receptor agonist topiramate and the antagonist bicuculline may involve inhibition or activation of the p38 MAPK signaling pathway. Regulation of GABA-A receptor activity can effectively intervene in the occurrence and development of abdominal aortic aneurysms in rats.

The role of the dorsomedial hypothalamus in the cardiogenic sympathetic reflex in the Sprague Dawley rat.

Myocardial ischemia causes the production and release of metabolites such as bradykinin, which stimulates cardiac spinal sensory afferents, causing chest pain and an increase in sympathetic activity referred to as the cardiogenic sympathetic afferent reflex. While the brain stem nuclei, such as the nucleus tractus solitarius and rostral ventrolateral medulla, are essential in the cardiogenic sympathetic afferent reflex, the role of other supramedullary nuclei in the cardiogenic sympathetic afferent reflex are not clear. The dorsomedial hypothalamic nucleus (DMH) is involved in cardiovascular sympathetic regulation and plays an important role in the sympathetic response to stressful stimuli. In this study, we determined the role of DMH in the cardiogenic sympathetic afferent reflex. To do this we measured arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) responses to epicardial bradykinin (10 μg/mL) in anesthetized Sprague Dawley rats before and after bilateral DMH microinjection (50 nL) of either the GABAA agonist muscimol (0.5 nmol) to inhibit or the antagonist bicuculline (40 pmol) to disinhibit activity. Muscimol inhibition elicited a modest, albeit significant, reduction in basal arterial pressure and heart rate and attenuated the arterial pressure and heart rate reflex response to epicardial bradykinin. However, it did not change the magnitude of the reflex. Bicuculline disinhibition of the DMH increased basal arterial pressure, heart rate, and RSNA but did not augment the response to epicardial bradykinin. These results suggest that sympathetic activity derived from the DMH does not play an important role in the cardiogenic sympathetic afferent reflex in Sprague Dawley rats.

Identification of a novel imidazole-derived GABA agonist isopropoxate: simultaneous detection and quantification of imidazole-derived analogs from human hairs in abused cases by LC-MS/MS.

Distribution and abuse of imidazole-derived γ-aminobutyric acid (GABA) agonists, such as etomidate and metomidate, and their analogs have been encountered frequently especially in China. The aim of this study was to identify etomidate, metomidate, propoxate, and isopropoxate more accurately by establishing a gas chromatography-mass spectrometry (GC-MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) method and applying it to real forensic cases. Onemg of the seized powder was dissolved in 1mL of methanol, and subjected to GC-MS and LC-MS/MS. Hair samples were washed and cut into approximately 2mm sections, then ground to powder by a low-temperature grinder. Twenty mg of the hair powder was extracted with 1mL of methanol, and the supernatant was subjected to LC-MS/MS. Etomidate, metomidate, propoxate, and isopropoxate were chromatographically separated and each mass spectrum was obtained by GC-MS. For LC-MS/MS, tested validation data were all satisfactory. The seized powder samples contained isopropoxate, with an approximate content of 30.9%. Etomidate, etomidate acid, metomidate, and isopropoxate could be determined in the submitted hairs, ranging from 2.89 to 8.09ng/mg, 0.0591-0.177ng/mg, 0.342-2.77ng/mg, and 33.2-130ng/mg, respectively. Mass spectra and ion chromatograms of etomidate, metomidate, isopropoxate, and propoxate were obtained by GC-MS. We have also established a simultaneous and reliable analytical method for etomidate, etomidate acid, metomidate, and isopropoxate in human hair by LC-MS/MS. This is the first report to present analytical results of a novel imidazole-derived GABA agonist isopropoxate in drug abuse cases.

Piriform cortex is an ictogenic trigger zone in the primate brain.

Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures. Focal microinjection of the γ-aminobutyric acid type A (GABAA) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within-subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABAA agonist muscimol suppressed seizures evoked from piriform cortex. We documented a well-defined region highly susceptible to bicuculline-induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated, but not N-methyl-D-aspartate-mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas-evoked seizures. Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use.

Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons.

Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.

Medial prefrontal cortex to nucleus reuniens circuit is critical for performance in an operant delayed nonmatch to position task

Working memory refers to the temporary retention of a small amount of information used in the execution of a cognitive task. The prefrontal cortex and its connections with thalamic subregions are thought to mediate specific aspects of working memory, including engaging with the hippocampus to mediate memory retrieval. We used an operant delayed-non match to position task, which does not require the hippocampus, to determine roles of the rodent medial prefrontal cortex (mPFC), the nucleus reuniens thalamic region (RE), and their connection. We found that transient inactivation of the mPFC and RE using the GABA-A agonist muscimol led to a delay-independent reduction in behavioral performance in the delayed non-match to position paradigm. We used a chemogenetic approach to determine the directionality of the necessary circuitry for behavioral performance reliant on working memory. Specifically, when we targeted mPFC neurons that project to the RE (mPFC-RE) we found a delay-independent reduction in the delayed non-match to position task, but not when we targeted RE neurons that project to the mPFC (RE-mPFC). Our results suggest a broader role for the mPFC-RE circuit in mediating working memory beyond the connection with the hippocampus.

A Spatial Memory Deficit in Male But Not Female Rats After Neonatal Diazepam Exposure: A New Model for Developmental Sedative Neurotoxicity

(Anesth Analg. 2024 Apr 1;138(4):856–865. doi: 10.1213/ANE.0000000000006583) Current models show that drugs targeting GABA receptors can be very damaging to neurodevelopment, though results are conflicting in human studies as opposed to animal studies. A robust time period of research in animal models has suggested; however, that some differences in cognition caused by anesthetic drugs can be difficult to detect in a clinically significant way, though their presence is a distinct possibility. Previous studies by these authors have investigated the sex-dependent differences in neurodevelopment and thus in response to neurodevelopmental toxicity and have found that both sex and timing of drug administration have significant impacts on neurodevelopmental deficits in later life. Limitations of previous studies include the specificity of the drugs used and variable mechanisms at work in addition to acting as a GABA agonist. This study aims to address these limitations by assessing a similar model of neurodevelopmental toxicity using a benzodiazepine medication, diazepam, which specifically targets GABA receptors. The primary outcome was the effect of diazepam on postnatal day 7 rats on sex-dependent spatial memory deficit.

GABA Receptors and Kv7 Channels as Targets for GABAergic Regulation of Acetylcholine Release in Frog Neuromuscular Junction.

Effects of gamma-aminobutyric acid (GABA) and some selective GABAergic ligands on the quantal acetylcholine (ACh) release in the frog neuromuscular contacts were investigated using combination of microelectrode technique with fluorescent and immunohistochemical assays. Significant attenuation of ACh release was observed in the presence of GABA as well as selective GABAA and GABAB receptor agonists. Neither GABAA nor GABAB antagonists abolished to full extent this effect of GABA. Fluorescent assay allowed to detect the GABA-induced opening of K+ channels, which was inhibited by XE-991, a selective antagonist of Kv7 type. Electrophysiological recordings of endplate potentials in the presence of XE-991 confirmed the contribution of Kv7 type potassium channels to the effects of GABA on ACh release that was not associated with GABAA and GABAB receptors activation. Note that XE-991 effectively precluded the action of retigabine, neuronal Kv7 channel opener, on ACh release. Immunohistochemical assay revealed that frog mature skeletal muscle fibers contain a significant amount of GABA, and substantial amount of GABA can be released in the extracellular space at the muscle contractions induced by prolonged high-frequency nerve stimulation. Besides, some binding sites for exogenous GABA were detected on the plasma membranes. It is concluded that GABA, in addition to affecting GABAA and GABAB receptors, can directly activate Kv7 channels, thereby negatively modulating the evoked ACh release. Endogenous GABA may serve as a retrograde regulator of neurotransmitter exocytosis.

The lateral habenula regulates stress-related respiratory responses via the monoaminergic system.

Psychologic stress induces behavioral and autonomic responses such as acceleration of respiration. The lateral habenula (LHb) is noted to be involved in stress-induced behavioral responses. However, its involvement in stress-induced respiratory responses is unknown. In this study, we aimed to analyze whether and how the LHb regulates respiration. Electrical stimulation of the LHb of anesthetized Wistar male rats increased respiratory frequency and minute ventilation, calculated by respiratory frequency × thoracic movement amplitude. Systemic administration of a dopaminergic receptor antagonist, clozapine, suppressed the LHb-induced respiratory responses. On the other hand, administration of a serotonergic receptor antagonist, methysergide, significantly accelerated the LHb-induced increase in respiratory frequency, together with suppressing the thoracic movement amplitude. To clarify the source of dopaminergic modulation, we inhibited the ventral tegmental area (VTA), which contains dopaminergic neurons and receives inputs from the LHb, by administering microinjections of a GABAA agonist, muscimol. The bilateral inhibition of the VTA almost abolished the LHb-induced respiratory responses. These results suggest that LHb activation causes respiration acceleration, mainly mediated by dopaminergic neurons in the VTA and suppressively modulated by the serotonergic system. Neural circuits originating in the LHb may be a key modulator for respiration during psychological stress.

GABAergic circuit interaction between central amygdala and bed nucleus of the stria terminalis in lipopolysaccharide-induced despair-like behavior

Hyperexcitability of central amygdala (CeA) induces depressive symptoms. The bed nucleus of the stria terminalis (BNST) receives GABAergic input from the CeA. However, it remains unclear whether the GABAergic neurons in the CeA projecting to BNST contribute to major depression. Here, we investigated the roles of GABAergic neurons in CeA and BNST in lipopolysaccharide (LPS)-induced despair-like behavior. We generated adeno-associated virus vectors (AAV) carrying shRNA against Gad67 to knock down GAD67 expression in CeA (Gad67-KD-CeA) or BNST (Gad67-KD-BNST) in C57BL/6J male mice. Despair-like behavior was assessed by tail suspension test (TST) 24 h after LPS administration. Saline-treated Gad67-KD-CeA mice exhibited longer immobility during TST than saline-treated AAV-injected control (AAV-Cont) mice. Although LPS increased immobility time in AAV-Cont mice, it did not affect immobility time in Gad67-KD-CeA mice. While LPS did not affect the immobility time in Gad67-KD-BNST mice, it increased immobility time in AAV-Cont mice. We injected GFP-expressing AAV with a Dlx promoter, specifically expressed in GABAergic neurons, into CeA, and FluoroGold, a retrograde neuronal tracer, into the BNST. GFP signals associated with CeA GABAergic neurons were detected in the BNST, contacting c-fos and GAD67-expressed cells following LPS. We detected the FluoroGold signals in GAD67- and c-fos-expressed neurons in the CeA after LPS administration. Bilateral intra-BNST injection of muscimol (2 pmol), a GABAA receptor agonist, increased immobility time during TST. These findings suggest that LPS-decreased GABAergic activity in the CeA may lead to disinhibition of GABAergic interneurons in the BNST, resulting in GABAA receptor activation and subsequently induces despair-like behavior.

Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure.

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as critical elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here, we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq-mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, the activation of SST neurons in the PLC of male mice and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+ and FosB+ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. The data provide a rationale for the lack of antidepressant efficacy of benzodiazepines and superior efficacy of dendrite-targeting, low-potency GABAA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

Progress in GABAA receptor agonists for insomnia disorder.

Insomnia is the most common sleep disorder in which an individual has trouble falling or staying asleep. Chronic sleep loss interferes with daily functioning and adversely affects health. The main clinical drugs for insomnia are the positive allosteric modulator of the GABA (gamma-aminobutyric acid) A receptors (GABAARs) at the benzodiazepine site with selectivity of the GABA-α1 receptor. They are divided into benzodiazepine drugs and non-benzodiazepine drugs. Most recently, the first partial positive allosteric modulator of GABAAR Dimdazenil was approved by National Medical Products Administration (NMPA) and launched in China. This review summarized the mechanism of actions of current clinical drugs for insomnia, and the clinical applications of these drugs, which may help to understand their involvement in insomnia, and to search for more selective and potent ligands to be used in the treatment of insomnia.

The Role of GABA Receptors in Anesthesia and Sedation: An Updated Review.

GABA (γ-aminobutyric acid) receptors are constituents of many inhibitory synapses within the central nervous system. They are formed by 5 subunits out of 19 various subunits: α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Two main subtypes of GABA receptors have been identified, namely GABAA and GABAB. The GABAA receptor (GABAAR) is formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel. Other subunits are γ, δ, ε, π, and ϴ. GABAAR has many isoforms, that dictate, among other properties, their differing affinities and conductance. Drugs acting on GABAAR form the cornerstone of anesthesia and sedation practice. Some such GABAAR agonists used in anesthesia practice are propofol, etomidate, methohexital, thiopental, isoflurane, sevoflurane, and desflurane. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors-mainly NMDA receptors. Inspite of its many drawbacks such as pain in injection, quick and uncontrolled conversion from sedation to general anesthesia and dose-related cardiovascular depression, propofol remains the most popular GABAR agonist employed by anesthesia providers. In addition, being formulated in a lipid emulsion, contamination and bacterial growth is possible. Literature is rife with newer propofol formulations, aiming to address many of these drawbacks, and with some degree of success. A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility. Inhalational anesthetics are also GABA agonists. The binding sites are primarily located within α+/β- and β+/α- subunit interfaces, with residues in the α+/γ- interface. Isoflurane and sevoflurane might have slightly different binding sites providing unexpected degree of selectivity. Methoxyflurane has made a comeback in Europe for rapid provision of analgesia in the emergency departments. Penthrox (Galen, UK) is the special device designed for its administration. With better understanding of pharmacology of GABAAR agonists, newer sedative agents have been developed, which utilize "soft pharmacology," a term pertaining to agents that are rapidly metabolized into inactive metabolites after producing desired therapeutic effect(s). These newer "soft" GABAAR agonists have many properties of ideal sedative agents, as they can offer well-controlled, titratable activity and ultrashort action. Remimazolam, a modified midazolam and methoxycarbonyl-etomidate (MOC-etomidate), an ultrashort-acting etomidate analog are two such examples. Cyclopropyl methoxycarbonyl metomidate is another second-generation soft etomidate analog that has a greater potency and longer half-life than MOC-etomidate. Additionally, it might not cause adrenal axis suppression. Carboetomidate is another soft analog of etomidate with low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Alphaxalone, a GABAAR agonist, is recently formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile.

6-Methoxyflavone improves anxiety, depression, and memory by increasing monoamines in mice brain: HPLC analysis and in silico studies

Abstract 6-Methoxyflavone (6-MOF) is a flavonoid that has been reported to be a GABA-A receptor agonist and reverses cisplatin-induced hyperalgesia and allodynia. Considering the varied neuropharmacological profile of 6-MOF, this study was intended to determine the pharmacological effects of 6-MOF on locomotion, anxiety, novel object recognition (NOR), depression, spatial memory, socialization behavior, nest-building behavior, and depression in various groups of mice. Selected groups of mice were injected with 25, 50, and 75 mg/kg 6-MOF. Using HPLC-UV, the frontal cortex, striatum, and hippocampus of the sacrificed mice were analyzed for the levels of vitamin C, dopamine, serotonin, noradrenaline, adenosine, and its metabolites. Statistical analysis showed significant results in socialization behavior and elevated plus maze with 75 mg/kg. In Y-maze, NOR 6-MOF showed significant results at all three doses, while in tail suspension test (TST), 50 and 75 mg/kg showed significant results; however, no statistical significance was observed in nest-building behavior; 50 and 75 mg/kg 6-MOF showed significant results in the Morris water maze. 6-MOF raised vitamin C levels in the frontal cortex and hippocampus. Serotonin, dopamine, and nor-adrenaline levels were raised in the hippocampus and striatum. It has also imparted region-specific neuroprotection by improving adenosine and its metabolite levels. In silico studies performed using PyRx have shown that the minimum binding energy of 6-MOF with antioxidant enzyme is −7.1 k/cal/mol. The binding energy showed that 6-MOF was successfully docked with an anti-oxidant enzyme. In conclusion, in silico and behavioral studies showed that 6-MOF can be a potential candidate for the treatment of cognitive decline, anxiety, and depression.