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Diagram of the developing zones where GABA regulates cell development (A) Schematic representation of an embryonic (E) 15 coronal section of the forebrain. Radial glia (RG, green) proliferate in the ventricular zone (VZ) and extend their processes to the pial surface across the ganglionic eminence and the neocortex. Neuronal precursors (blue) migrate along radial glial processes and some proliferate in the SVZ (not shown on the diagram). Both proliferation and migration are regulated by GABA (#1-3). The migration of the precursors of cortical GABAergic interneurons (orange) born in the VZ of the ganglionic eminence is also affected by GABA (#4). S: primordia of septum, H: primordia of hippocampus. (B) Schematic representation of an adult sagittal section of the forebrain illustrating the neurogenic zones, the SVZ along the lateral ventricle and the subgranular zone (SGZ). GABA decreases the proliferation of neural progenitors and neuroblasts in the SVZ (#5), and the speed of migration of neuroblasts (#6) on their way to the olfactory bulb. (C) Simplified lineage summary.
Source publication
GABA, acting via GABA(A) receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptor's properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drug...
Contexts in source publication
Context 1
... description of the developing zones (Fig. 2)-The primary germinative zone is a layer of proliferating neuroepithelial cells all along the neural tube in early phases of neurogenesis. These cells divide symmetrically and generate identical progeny, thus expanding the germinative zone. Later, neuroepithelial cells progressively generate the well-known radial glia that still behave ...
Context 2
... cells all along the neural tube in early phases of neurogenesis. These cells divide symmetrically and generate identical progeny, thus expanding the germinative zone. Later, neuroepithelial cells progressively generate the well-known radial glia that still behave as neural progenitors and divide in the ventricular zone along the ventricles [111] (Fig. 2A). They can divide asymmetrically resulting in equal distribution of genomic DNA, but unequal distribution of cytoplasmic regulatory elements. As a result radial glia generate neuroblasts (still able to proliferate in the embryonic subventricular zone) and neuronal precursors (i.e. postmitotic, committed to become neurons) that migrate ...
Context 3
... wall, the radial glia also progressively transform into astrocytes, which retain the capacity of behaving as neural progenitors [117]. The cell production capacity of this zone, called the subventricular or subependymal zone sandwiched between the lateral ventricle and the striatum, persists until adulthood in mammals, including humans [89,118] (Fig. 2B). SVZ astrocytes generate transit amplifying cells and then neuroblasts that migrate throughout the SVZ and along the rostral migratory stream to reach the olfactory bulb or the piriform cortex [200] where they differentiate into GABAergic and dopaminergic interneurons. SVZ neuroblasts also migrate and integrate into the piriform ...
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Citations
... Certain PAMs, such as barbiturates, neurosteroids, and anesthetics, exhibit GABA-mimetic properties at higher concentrations, thereby directly activating GABAA receptors (Stephens et al., 2017;Alanis et al., 2020). Negative allosteric modulators (NAM) or "inverse agonists" have the contrary effect of PAMs in that they decrease GABA-induced responses ( Figure 6) (Henschel et al., 2008;Rudolph and Knoflach, 2011). Non-selective NAMs, such as picrotoxin, inhibit GABAA receptor activity by binding noncompetitively within the chloride channel pore, resulting in anxiogenic and convulsive effects (Olsen, 2006;Kalueff, 2007;Olsen, 2018). ...
Insomnia, a prevalent health challenge, often requires pharmacological interventions to improve sleep onset, maintenance, and quality. Benzodiazepines and Z-drugs, like other positive modulators, enhance the inhibitory effects of gamma-aminobutyric acid (GABA) by stabilizing the open conformation of the GABAA receptor (GABAAR) chloride ion channels, facilitating the transition to sleep. However, prolonged use raises concerns, including dependence and cognitive issues. Among herbal alternatives, Humulus lupulus (hops) is gaining attention due to its role as a natural relaxant, sleep aid, and brewing component. Neuroactive phytochemicals in hops may modulate GABAARs differently from benzodiazepines. This research uncovers these hop constituents and potential therapeutic mechanisms.
The α-acid humulone and hop prenylflavonoids (PFs), including xanthohumol/isoxanthohumol, 6/8-prenylnaringenin, enhanced GABA-induced displacement of [3H]EBOB, a GABAAR function marker, in the low micromolar range. These potent effects were flumazenil-insensitive and α6β3δ subtype-selective. Molecular docking at the α1β2γ2 isoform identified the extracellular α+/β− interface as the PF binding site. An additional 6-prenylnaringenin site was recognized at the extracellular α+/γ2− interface, aligning with its inhibition of [3H]flunitrazepam and [3H]Ro 15-4513 binding. Given humulone’s prominence and relatively high potency, its activity was confirmed electrophysiologically, where it enhanced GABA-evoked currents in the sedation-mediating α1β3γ2 subtype. In mice, humulone reduced locomotor activity, shortened sleep onset induced by pentobarbital, and prolonged sleep duration induced by either pentobarbital or ethanol. Moreover, [3H]EBOB binding assays showed synergies between humulone and ethanol, and additive interactions with PFs, suggesting enhanced alcohol intoxication in hop-rich beers.
In summary, we revealed positive modulators of GABAARs that act independently of the classical benzodiazepine site. 6-prenylnaringenin also acts as a silent modulator with the potential to block benzodiazepine responses. Humulone plays a pivotal role in the sedative and sleep-promoting properties of hops. These findings offer novel mechanistic insights into hop neuroactive constituents and potential avenues for sleep aid optimization.
... Additionally, anesthesia-related changes in neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors, have been implicated in cognition deficiency. GABA is the main inhibitory neurotransmitter in the brain, and anesthetics that enhance its activity, like propofol, might disrupt normal neural communication (16). NMDA receptors, involved in learning and memory processes, can also be affected by anesthetics, potentially impairing cognitive function (17,18). ...
General anesthesia is a frequently employed medical intervention that facilitates the induction of a temporary state of unconsciousness, hence facilitating the execution of surgical procedures in patients. Nevertheless, the cognitive capabilities of patients with neurological comorbidities, such as epilepsy or dementia, may be a subject of worry when contemplating the impact of general anesthesia. Studies have indicated that individuals who have pre-existing neurological diseases may encounter negative consequences on their brain function when exposed to anesthesia. These consequences can manifest as a reduction in cognitive abilities or a worsening of their current coexisting medical conditions. Hence, it is imperative for healthcare practitioners to thoroughly assess the potential advantages and disadvantages of general anesthesia in individuals with neurological comorbidities. This evaluation should encompass exploring alternative methodologies or tailoring anesthetic management strategies to mitigate potential complications and enhance patients’ overall results.
... In the mature brain, activation of GABA determines hyperpolarization of neurons thanks to a net influx of Cl − anions, resulting in an inhibitory effect (56). In neuroblasts and immature neurons, the presence of an inwardly directed Na + -K + -Cl − co-transporter 1 (NKCC1) determines a relatively high internal Cl − concentration. ...
Background
Evidence-based data on treatment of neonatal status epilepticus (SE) are scarce. We aimed to collect data on the efficacy and safety of ketamine for the treatment of neonatal SE and to assess its possible role in the treatment of neonatal SE.
Methods
We described a novel case and conducted a systematic literature review on neonatal SE treated with ketamine. The search was carried out in Pubmed, Cochrane, Clinical Trial Gov, Scopus and Web of Science.
Results
Seven published cases of neonatal SE treated with ketamine were identified and analyzed together with our novel case. Seizures typically presented during the first 24 h of life (6/8). Seizures were resistant to a mean of five antiseizure medications. Ketamine, a NMDA receptor antagonist, appeared to be safe and effective in all neonates treated. Neurologic sequelae including hypotonia and spasticity were reported for 4/5 of the surviving children (5/8). 3/5 of them were seizure free at 1–17 months of life.
Discussion
Neonatal brain is more susceptible to seizures due to a shift towards increased excitation because of a paradoxical excitatory effect of GABA, a greater density of NMDA receptors and higher extracellular concentrations of glutamate. Status epilepticus and neonatal encephalopathy could further enhance these mechanisms, providing a rationale for the use of ketamine in this setting.
Conclusions
Ketamine in the treatment of neonatal SE showed a promising efficacy and safety profile. However, further in-depth studies and clinical trials on larger populations are needed.
... Ketamine was used in this study to induce hypnosis. Ketamine is an antagonist of the N-Methyl-D-Aspartate (NMDA) receptor, an excitatory receptor that plays a key role in seizures as well as causing sedation via its GABAA receptors potentiation [38]. This study also showed the sleep latencies and total sleeping time of NHEPA at 100 mg/kg and 150 mg/kg i.p. were comparable to the standard hypnotic agent, diazepam (1 mg/kg, i.p.) used in this study. ...
Background: Petiveria alliacea L. (Phytolaccaceae) ethnomedically is known for its sedative property and beneficial treatment of other central nervous system (CNS) disorders. However, the neuropharmacological properties of the n-hexane extract of this aromatic plant leaf have not been reported, hence this study. Objective: To determine the acute toxicity profile (LD50) and some CNS activities of the n-hexane extract of fresh leaf of P. alliacea (NHEPA) in mice. Method: The fresh leaf of Petiveria alliacea was collected and the n-hexane extract obtained using appropriate technique. The LD50 was determined for both the oral and intraperitoneal (i.p.) route. All treatments were administered via i.p. route. Behavioural activity was evaluated using the novelty-induced behaviour (NIB) to assess rearing, grooming and locomotion; sedative activity was tested on ketamine-induced hypnosis while the anticonvulsant potential was assessed using chemo-convulsants. The mechanism of action was determined using amphetamine as agonist and flumazenil as an antagonist. Results: The LD50 values obtained for the extract was 2450 and 346 mg/kg for oral and intraperitoneal routes respectively. The extract displayed significant CNS depressant activity on all NIB parameters. NHEPA significantly prolonged sleep latency and total sleeping time at 100 and 150 mg/kg. i.p. The extract also offered some mild protection against convulsion across the model used. The probable mechanism of action may include inhibition of monoamine pathways and augmentation of the GABAA-benzodiazepine complex pathway. Conclusion: NHEPA showed CNS depressant activity, exhibited significant sedative activity and mild anticonvulsant activity.
... The sleep-promoting neurons located in the anterior hypothalamus release gamma-aminobutyric acid (GABA) to suppress activity of wakeinducing areas of the brain [18]. Ketamine has been established to exhibit agonist properties on GABAA receptors [19] hence, it suggests a possible involvement of the GABAergic pathway in the eliciting of the sedative activity of the extracts [20]. ...
This study evaluated the sedative, and anticonvulsant activities of the aqueous (AESM) and ethanol (EESM) dried leaf extracts of Solenostemon monostachyus. The sedative effect of the extracts was evaluated with ketamine-induced hypnosis (100 mg/kg, i.p.). Also, the anticonvulsant activity was evaluated using pentylenetetrazole (PTZ)-induced convulsion (85 mg/kg, i.p.), strychnine-induced convulsion (2 mg/kg, i.p.) and maximal electroshock (MES)-induced convulsion models. The AESM (200 mg/kg, p.o.) gave 66.67% protection, while EESM (800 mg/kg, p.o.) gave 100% protection against the hind limb tonic extension on the MES. The AESM only at 200 mg/kg, p.o. caused a significant change (p < 0.01) in the convulsion latency and time of death in PTZ-induced convulsion. The AESM and EESM (200, 400 and 800 mg/kg, p.o.) significantly (p < 0.05-0.01) shortened sleep latency. At 400 and 800 mg/kg, p.o., AESM prolonged (p < 0.05) total sleeping time while EESM at 800 mg/kg, p.o. significantly (p < 0.05) prolonged total sleeping time relative to vehicle. The study concluded that the aqueous leaf and ethanol dried leaf extracts of S. monostachyus possessed sedative and mild anticonvulsant activities.
... The characteristics of ligands that contribute to receptor activation are usually used as anxiolytic, anticonvulsant, sedative, and muscle relaxant drugs. On the other side, ligands that inhibit receptor function usually have opposite pharmacological effects such as convulsion and anxiogenesis [78,79]. Interestingly, some subtypes of NAM (ex., α5IA) are being studied for their nootropic properties as well as potential therapies for GABAergic medication adverse effects [80]. ...
Background
γ-Aminobutyric acid sub-type A receptors (GABA A Rs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications.
Main body
GABA A Rs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABA A Rs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABA A receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development.
Conclusion
To date, few reviews have discussed GABA A receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABA A Rs, as well as shedding light on the most common associated disorders.
... This biological Seizure is one of the frequently occurring neurologic condition in African countries including Nigeria (1). It cause changes in awareness, behavior and associated with accumulating brain damage and neurological deficits (2). The temporal and frontal lobes of the brain are the most frequently affected due to impaired GABA synthesis by GABAnergic neurons as in epilepsy. ...
Seizure is one of the frequently occurring neurologic condition in African countries including Nigeria. Advances in the regulatory mechanisms of the circadian rhythm and astrocytes involvement in the detoxification of chemicals have provided beneficial insights in the management of diseases. This study investigates the role of melatonin (a known circadian regulator) in the co-administration of anticonvulsants and melatonin in the treatment of status epilepticus. Status epilepticus model was induced chemically using Isoniazid (INH, 300mg/kg, i.o, single dose), at the post-induction the rats were treated with carbamezapine (CBZ), melatonin (MT), and co-treatment (CBZ + MT), then sodium valproate (VPA) and melatonin (MT) monotherapy, and co-treatment (VPA + MT). The saline and INH untreated served as the controls. The immunoperoxidase method using GFAP was use to highlight astrocytes morphologic expressions in the prefrontal and temporal cortices. The untreated revealed marked astrogliosis, mild astrocytic retraction were seen in the monotherapy treated section particularly with melatonin. However, following melatonin co-treatment with CBZ and VPA in either cortex, it revealed prominent astrocytes with retracted features. Melatonin enhanced the therapeutic efficacy of the anticonvulsants, a vital role of an adjuvant in the management of epilepsy.
... It exerts an inhibitory effect on the AMPA subtype glutamate receptor and also binds to the fast-inactivated state of the voltage-gated sodium channel (Lasoń et al., 2013). Furthermore, TPM is thought to act by GABA A receptors (Shank et al., 2000;Henschel et al., 2008). Mechanisms underlying TPM's effects on the locomotor activity of fish and rodents are unknown, although the possibility that species differences may influence this parameter should be examined. ...
Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. The results showed that LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI–SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected anxiety behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish.
... The essential oil of P. aegyptiacus (EOPA) (50-150 mg/kg) and diazepam (1 mg/kg) showed a significant [p<0.05-0.01; F(4, 25 Table 2). ...
... Based on these results, it can be suggested that the oil of P. aegyptiacus demonstrated a significant anxiolytic activity in this model. Sedatives are known for their inhibitory effect on the CNS, which is caused by either augmentation of GABA inhibitory effect by binding to GABAA receptor like benzodiazepines, or antagonizing the effect of glutamate by blocking glutamate receptors such as N-methyl-Daspartate (NMDA) AMPA, kainate, glycine or metabotropic receptors [24][25][26]. The oil (50 -150 mg/kg) significantly (p<0.001) ...
... The sedative-hypnotic action of phenobarbitone and other barbiturates is due to their interaction on the GABAA receptors which enhances GABAA transmission [21]. The binding site is distinct from that of benzodiazepines. ...
... The result of phenobarbitone-induced sedation for VAEE revealed that VAEE possesses strong Ketamine-induced sedation is one of the models used extensively in screening of sedatives and anaesthethics [25]. The model exploits both the uncompetitive antagonistic ability of ketamine to N-methyl-D-aspartate (NMDA) type of excitatory receptor system [26,27] and the sedative effect of ketamine by gamma-amino butyric acid-A (GABAA) receptor potentiation [21]. In this study, 50, 100, 200, 400 and 800 mg/kg of VAEE was used to potentiate ketamine-induced sedation in mice in a dosedependent manner. ...
Background: Traditional plants have been good sources of alternatives for conventional drugs in recent years. The search for alternatives for conventional drugs becomes imperative most especially because of their high cost demand and side effects. The search for alternatives from traditional medicinal plants sources has been fruitful for many ailments and this has led to intense research on the potentials of many other plants that are used traditionally in different part of the world. This study assessed the sedative potentials of ethanol extract of Voacanga africana leaf (VAEE) as well as its toxicity. Methods: Toxicity of the Voacanga africana leaf was examined using Lorke’s method while its sedative activity was evaluated using phenobarbitone and ketamine-induced sleeping time models in mice. The doses used in this study were 50, 100, 200, 400 and 800 mg/kg, administered intra-peritoneal. Results: Results revealed that the LD50 of VAEE was greater than 5 g/kg. Using phenobarbitone-induced sedation, the sleep latency was found to be dose dependent and significantly decreased at higher dose when compared with normal saline while the total sleeping time was found to be significantly in-creased (p<0.05) as dosage increases. Conclusion: The increase in total sleeping time using the two models showed that VAEE possesses marked sedative ability and can serve as a good alternative to conventional sedatives.
