Increased GABA Levels Research Articles

Ferulic Acid-Loaded Nanostructure Maintains Brain Levels of ACh, Glutamate, and GABA and Ameliorates Anxiety and Memory Impairments Induced by the D-Galactose Aging Process in Rats.

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8weeks concurrently with d-Gal (150mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.

Pterostilbene-loaded PLGA nanoparticles alter phenylpropanoid and oxylipin metabolism in Solanum lycopersicum L. leaves

Due to the fast-changing global climate, conventional agricultural systems have to deal with more unpredictable and harsh environmental conditions leading to compromise food production. The application of phytonanotechnology can ensure safer and more sustainable crop production, allowing the target-specific delivery of bioactive molecules with great and partially explored positive effects for agriculture, such as an increase in crop production and plant pathogen reduction. In this study, the effect of free pterostilbene (PTB) and poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) loaded with pterostilbene was investigated on Solanum lycopersicum L. metabolism. An untargeted NMR-based metabolomics approach was used to examine primary and secondary metabolism whereas a targeted HPLC–MS/MS-based approach was used to explore the impact on defense response subjected to anti-oxidant effect of PTB, such as free fatty acids, oxylipins and them impact on hormone biosynthesis, in particular salicylic and jasmonic acid. In tomato leaves after treatment with PTB and PLGA NPs loaded with PTB (NPs + PTB), both NPs + PTB and free PTB treatments increased GABA levels in tomato leaves. In addition, a decrease of quercetin-3-glucoside associated with the increase in caffeic acid was observed suggesting a shift in secondary metabolism towards the biosynthesis of phenylpropanoids and other phenolic compounds. An increase of behenic acid (C22:0) and a remodulation of oxylipin metabolism deriving from the linoleic acid (i.e. 9-HpODE, 13-HpODE and 9-oxo-ODE) and linolenic acid (9-HOTrE and 9-oxoOTrE) after treatment with PLGA NPs and PLGA NPs + PTB were also found as a part of mechanisms of plant redox modulation. To the best of our knowledge, this is the first study showing the role of PLGA nanoparticles loaded with pterostilbene in modulating leaf metabolome and physiology in terms of secondary metabolites, fatty acids, oxylipins and hormones. In perspective, PLGA NPs loaded with PTB could be used to reshape the metabolic profile to allow plant to react more quickly to stresses.

Visual toxicity in zebrafish larvae following exposure to 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), triphenyl phosphate (TPhP), and isopropyl phenyl diphenyl phosphate (IPPP)

TPhP and IPPP, alternatives to PBDEs as flame retardants, have been studied for their developmental toxicity, but their visual toxicities are less understood. In this study, zebrafish larvae were exploited to evaluate the potential ocular impairments following exposure to BDE-47, TPhP, and IPPP. The results revealed a range of ocular abnormalities, including malformation, vascular issues within the eyes, and histopathological changes in the retina. Notably, the visually mediated behavioral changes were primarily observed in IPPP and TPhP, indicating that they caused more severe eye malformations and vision impairment than BDE-47. Molecular docking and MD simulations showed stronger binding affinity of TPhP and IPPP to RAR and RBP receptors. Elevated ROS and T3 levels induced by these compounds led to apoptosis in larvae eyes, and increased GABA levels induced by TPhP and IPPP hindered retinal repair. In summary, our results indicate TPhP and IPPP exhibit severer visual toxicity than BDE-47, affecting eye development and visually guided behaviors. The underlying mechanism involves disruptions in RA signaling, retinal neurotransmitters imbalance, thyroid hormones up-regulation, and apoptosis in larvae eyes. This work highlights novel insights into the need for cautious use of these flame retardants due to their potential biological hazards, thereby offering valuable guidance for their safer applications.

Calorie Restriction Attenuates Memory Impairment and Reduces Neuroinflammation in Obese Aged Rats.

Obesity and aging collectively potentiate inflammatory responses, particularly within the central nervous system. Managing obesity presents a significant challenge, even more so considering the context of aging. Caloric restriction (CR) has been extensively documented in the literature for its multiple health benefits. Motivated by these findings, we hypothesized that CR could serve as a valuable intervention to address the brain alterations and cognitive decline associated with obesity in aged rats. Our investigation revealed that cafeteria diet increased hippocampal and hypothalamic transcripts related to neuroinflammation, along with cognitive deficits determined in the object recognition test in 18-month-old male rats. Western blot data indicate that the obesogenic diet may disrupt the blood-brain barrier and lead to an increase in Toll-like receptor 4 in the hippocampus, events that could contribute to the cognitive deficits observed. Implementing CR after the onset of obesity mitigated neuroinflammatory changes and cognitive impairments. We found that CR increases GABA levels in the hippocampus of aged animals, as demonstrated by liquid chromatography coupled with mass spectrometry analysis. These findings underscore the potential of CR as a therapeutic opportunity to ameliorate the neuroinflammatory and cognitive alterations of obesity, especially in the context of aging.

Therapeutic Potential of Fingolimod on Psychological Symptoms and Cognitive Function in Neuropsychiatric and Neurological Disorders.

Neuropsychiatric and neurological disorders pose a significant global health burden, highlighting the need for innovative therapeutic approaches. Fingolimod (FTY720), a common drug to treat multiple sclerosis, has shown promising efficacy against various neuropsychiatric and neurological disorders. Fingolimod exerts its neuroprotective effects by targeting multiple cellular and molecular processes, such as apoptosis, oxidative stress, neuroinflammation, and autophagy. By modulating Sphingosine-1-Phosphate Receptor activity, a key regulator of immune cell trafficking and neuronal function, it also affects synaptic activity and strengthens memory formation. In the hippocampus, fingolimod decreases glutamate levels and increases GABA levels, suggesting a potential role in modulating synaptic transmission and neuronal excitability. Taken together, fingolimod has emerged as a promising neuroprotective agent for neuropsychiatric and neurological disorders. Its broad spectrum of cellular and molecular effects, including the modulation of apoptosis, oxidative stress, neuroinflammation, autophagy, and synaptic plasticity, provides a comprehensive therapeutic approach for these debilitating conditions. Further research is warranted to fully elucidate the mechanisms of action of fingolimod and optimize its use in the treatment of neuropsychiatric and neurological disorders.

Short-chain fatty acid valerate reduces voluntary alcohol intake in male mice

BackgroundDespite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied.ResultsHere, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome.ConclusionOur findings suggest that sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms.4EUMY4VU8ayPcKT8VYWNUCVideo

Analysis of the functional role and mRNA expression of GABA B R in the nucleus accumbens of cocaine-addicted rats.

Drug addiction is a social and medical problem that must be urgently addressed. The nucleus accumbens (NAc) is closely related to addiction-related learning memory, and γ-aminobutyric acid type B receptor (GABA B R) is a potential target for the treatment of drug addiction. However, the role of GABA B R activity levels in the NAc in cocaine addiction is unclear. In this study, we established an animal model of cocaine dependence, modulated the level of GABA B R activity, applied a conditioned place preference assay (CPP) to assess the role of the NAc in reconsolidation of addiction memory, evaluated learning and memory functions by behavioral experiments, examined the expression of GB1, GB2, cyclic adenosine monophosphate response element binding protein (CREB), p-CREB, protein kinase A (PKA), protein kinase (ERK), and Brain-derived neurotrophic factor (BDNF) in the NAc by molecular biology experiments, and screened differentially significantly expressed genes by transcriptome sequencing. Our study showed that the GABA B receptor agonist baclofen (BLF) had a significant effect on locomotor distance in rats, promoted an increase in GABA levels and significantly inhibited the PKA and ERK1/2/CREB/BDNF signaling pathways. Moreover, transcriptome sequencing showed that GABA B R antagonist intervention identified a total of 21 upregulated mRNAs and 21 downregulated mRNAs. The differentially expressed (DE) mRNA genes were mainly enriched in tyrosine metabolism; however, further study is needed. GABA B R activity in the NAc is involved in the regulation of cocaine addiction and may play an important role through key mRNA pathways.

Bombax costatum Pellegr. & Vuillet attenuates pentylenetetrazol-induced seizure and cognitive impairment in rats via inhibition of oxidative stress

ObjectivesEpilepsy is a neurological disorder resulting from excessive electrical discharge in the brain. Bombax costatum (BC) is an herb being used in African traditional medicine for the treatment of seizures. This study evaluated the possible anti-convulsant potential of stem bark ethanolic extract of BC on PTZ-induced kindling in rats.MethodsThirty-five Wistar rats were grouped into five (n = 7) and received normal saline, 35 mg/kg of PTZ, 5 mg/kg diazepam followed by 35 mg/kg PTZ after 30 min and BC stem back ethanolic extract at 125 mg/kg and 250 mg/kg followed by 35 mg/kg of PTZ intraperitoneally after 30 min. BC was administered orally daily while normal saline and PTZ were given intraperitoneally every other day for 26 days. Seizure activity was evaluated using the Racine scale, cognitive abilities through modified elevated plus maze and anxiety through forced swimming test. Further, the levels of GABA and oxidative stress biomarkers were also evaluated from the rat’s brain homogenate.ResultsPretreatment with BC significantly reduced (p < .05) the seizure score and increased GABA level in BC treated rats when compared to PTZ alone treated rats. The first transfer latency of PTZ alone treated rats was significantly increased (p < .05) relative to the control rats and rats pretreated with diazepam and BC extract. Pretreatment with BC extract at 250 mg/kg was shown to significantly increase (p < .05) the activities of catalase, reduced glutathione, and superoxide dismutase compared to the PTZ alone treated rats.ConclusionsConclusively, BC was found to prevent seizure, avert neurodegeneration, and enhance cognition in PTZ-treated rats by regulating GABA level and enhancing antioxidant activity. Therefore, BC could be explored further for possible development of antiseizure agents.

Controlled atmosphere storage alleviates the browning of walnut (Juglans regia L.) fruit through enhancing GABA-mediated energy metabolism

Browning is the primary physiological damage that shortens the postharvest life and deteriorates the quality of stored fruits. Controlled atmosphere (CA) storage has been shown to be effective in alleviating the browning of ‘Xifu 1′ in-hull walnut; however, its alleviation mechanism is less understood. To further explore the effect and regulatory mechanism of CA on the browning of fresh in-hull walnut, we stored four varieties of in-hull walnuts under CA-treated (5% O2 + 7.5% CO2) and untreated conditions at 0 ± 0.5 °C with 70–80% relative humidity for 70 d. The indicators related to browning and γ-aminobutyric acid (GABA) metabolism were measured until 56 d of storage. The results showed that the CA significantly increased GABA levels by maintaining higher activities of glutamate decarboxylase (GAD), GABA transaminase (GABAT) and succinate dehydrogenase (SDH). This reduced the changes in the browning index (BI), color values, and respiration rate (RR) of the four walnut fruit varieties compared with controls during storage. Consistent with the active GABA metabolism, higher energy charge (EC) and adenosine triphosphate (ATP), succinic acid (SA), malic acid (MLA), fumaric acid (FA), and citric acid (CTA) contents were also observed in the CA-treated walnut hull compared to the controls. The epicarp degradation of the CA-treated ‘Xifu 1′ walnut fruit occurred later, and their mitochondria and cells maintained better integrity compared to the controls. Among the differentially expressed genes (DEGs) screened via RNA-Sequencing (RNA-Seq), 32 were annotated as part of the citrate cycle (TCA cycle) pathway, and 27 were annotated in the GABA metabolism pathway. Real-time quantitative PCR (RT-qPCR) analysis showed that eight candidate genes were closely related to the effect of CA on the synthesis, transport, and transformation of GABA. In conclusion, CA effectively controlled the browning of different varieties of fresh in-hull walnuts by enhancing GABA metabolism and maintaining energy balance.

Golexanolone reduces glial activation in the striatum and improves non-motor and some motor alterations in a rat model of Parkinson's disease.

Parkinson's disease (PD) affects more than 6 million people worldwide. Along with motor impairments, patients and animal models exhibiting PD symptoms also experience cognitive impairment, fatigue, anxiety, and depression. Currently, there are no drugs available for PD that alter the progression of the disease. A body of evidence suggests that increased GABA levels contribute to the reduced expression of tyrosine hydroxylase (TH) and accompanying behavioral deficits. TH expression may be restored by blocking GABAA receptors. We hypothesized that golexanolone (GR3027), a well-tolerated GABAA receptor-modulating steroid antagonist (GAMSA), may improve Parkinson's symptoms in a rat model of PD. The aims of this study were to assess whether golexanolone can ameliorate motor and non-motor symptoms in a rat model of PD and to identify some underlying mechanisms. We used the unilateral 6-OHDA rat model of PD. The golexanolone treatment started 4 weeks after surgery. Motor symptoms were assessed using Motorater and CatWalk tests. We also analyzed fatigue (using a treadmill test), anhedonia (via the sucrose preference test), anxiety (with an open field test), and short-term memory (using a Y maze). Glial activation and key proteins involved in PD pathogenesis were analyzed using immunohistochemistry and Western blot. Rats with PD showed motor incoordination and impaired locomotor gait, increased fatigue, anxiety, depression, and impaired short-term memory. Golexanolone treatment led to improvements in motor incoordination, certain aspects of locomotor gait, fatigue, anxiety, depression, and short-term memory. Notably, golexanolone reduced the activation of microglia and astrocytes, mitigated TH loss at 5 weeks after surgery, and prevented the increase of α-synuclein levels at 10 weeks. Golexanolone may be useful in improving both motor and non-motor symptoms that adversely affect the quality of life in PD patients, such as anxiety, depression, fatigue, motor coordination, locomotor gait, and certain cognitive alterations.

Lifelong exposure to n-3 PUFA deficiency leads to anxiety-like profile in male and female adolescent rats: Impact on spleen-brain axis

Low consumption of n-3 polyunsaturated fatty acids (PUFA) during the developmental period has been increasingly associated with an increased risk of depressive-like symptoms in both male and female sexes. Therefore, here we performed behavioral and biochemical quantifications in adolescent rats to evaluate possible sex-driven differences in the development of anxiety-like disorders related to life-long n-3 PUFA low intake. Male and female adolescent rats fed for their entire life with n-3 PUFA poor diet showed an anxiety-like profile compared to n6/n-3 PUFA balanced diet. However, such deficiency led to reduced cortical serotonin (5-HT) in females, while increased GABA levels were retrieved in males. Conversely, in amygdala, 5-HT and noradrenaline (NA) were increased in n-3 PUFA poor treated rats. In male rats, n-3 PUFA poor diet induced significant increase in systemic kynurenine levels, while the pro-oxidant metabolite 3-Hydroxy kynurenine was higher in both sexes. In addition, considering the recent involvement of spleen-brain axis on mood disorders and neuroimmune communication, we evaluated biomarkers in the spleen. N-3 PUFA deprivation reduced NA content and increased the indoleamine 2,3-dioxygenase-1 expression in females, while acetylcholine and tumor necrosis factor alpha were higher in males. Taken together, our data indicated that deficiency of n-3 PUFA in diet induced mood disorders in adolescent animals, however this behavioral phenotype is accompanied by a different immune activation in male and female rats.

Anxiolytic activity of Coconut water by GABA Modulation as Evidenced by Pharmacological Experiments and Molecular Docking Studies

Objective: To determine the anxiolytic activity of coconut water by pre-clinical studies. Materials and Methods: The anxiolytic activity of coconut water was screened by neuropharmacology and molecular docking studies. Twenty-four adult female rats of the Wistar strain were divided equally into four groups: Group I: Distilled water [3ml/Kg]; Group II: Coconut water [3ml/Kg]; Group III: Diazepam [5mg/Kg]; Group IV: Coconut water [3ml/Kg] + Diazepam [2.5mg/Kg]. All agents were administered orally for 15 days. Elevated plus maze and light/dark arena apparatus tests were used to assess anxiety in rats. Once the pharmacological screening was done, rats were sacrificed, and brains were removed out to estimate GABA levels. An insilico docking of bio-active components in coconut water was done to probe the possible mechanism of action. Results: This study showed coconut water produced significant anxiolytic activity in rats. Brain biochemical analysis revealed coconut water significantly increased GABA levels. Computational studies revealed that the phytocompound ‘Zeatin’ in coconut water could block gamma-aminobutyric acid transaminase, the enzyme responsible for GABA degradation, thereby increasing GABA levels. Conclusion: Coconut water has anxiolytic-like activity by modulating GABAergic neurotransmission.

A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine

Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action.This article is part of the Special Issue on ‘Ketamine and its Metabolites’.

β-Cyclodextrin-crosslinked synthetic neuropeptide Y-based nanosponges in epilepsy by contributing GABAergic signal

Neuropeptide Y (NPY) is a polypeptide sequence useful in regulating physiological functions like homeostasis, feeding, etc., but its usage is restricted due to its short half-life. β-cyclodextrin-crosslinked nanosponges improve the drug release and stability due to its wide cavity, which is helpful to deliver therapeutics. The present work aimed to formulate synthetic NPY-based nanocarriers as sponges by polymer condensation mechanism using design experiment to improve the peptide release and stability. The validated nanosponges exhibited a particle size of 423.42 ± 5.32 nm, 75.82 ± 7.43 % entrapment efficiency and 83.50 ± 6.54 % NPY release for 24 h. The NPY and β-cyclodextrin interaction was confirmed by X-ray diffraction, Fourier transform infrared and nuclear magnetic resonance spectroscopy. The NPY-loaded nanosponges were found stable for 6 months at two conditions (5 ± 2 °C and 25 ± 2 °C). The cross-linked nanocarriers of synthetic peptide-based nanosponges powder at different doses were administered intranasally using a metered-dose inhaler in the animal model to check its antiepileptic activity. The synthetic NPY-loaded nanosponges at higher doses showed significant antiepileptic effects equivalent to the standard drug (administered orally) in maximal electroshock and chemically-induced seizures with an increase of NPY in the brain directly proportional to GABAergic signalling by increase in GABA levels resulting in convulsions attenuation.

Elevation of GABA levels in the globus pallidus disinhibits the thalamic reticular nucleus and desynchronized cortical beta oscillations

The external globus pallidus (GP) is a GABAergic node involved in motor control regulation and coordinates firing and synchronization in the basal ganglia–thalamic–cortical network through inputs and electrical activity. In Parkinson's disease, high GABA levels alter electrical activity in the GP and contribute to motor symptoms. Under normal conditions, GABA levels are regulated by GABA transporters (GATs). GAT type 1 (GAT-1) is highly expressed in the GP, and pharmacological blockade of GAT-1 increases the duration of currents mediated by GABA A receptors and induces tonic inhibition. The functional contribution of the pathway between the GP and the reticular thalamic nucleus (RTn) is unknown. This pathway is important since the RTn controls the flow of information between the thalamus and cortex, suggesting that it contributes to cortical dynamics. In this work, we investigated the effect of increased GABA levels on electrical activity in the RTn by obtaining single-unit extracellular recordings from anesthetized rats and on the motor cortex (MCx) by corticography. Our results show that high GABA levels increase the spontaneous activity rate of RTn neurons and desynchronize oscillations in the beta frequency band in the MCx. Our findings provide evidence that the GP exerts tonic control over RTn activity through the GP–reticular pathway and functionally contributes to cortical oscillation dynamics.

Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.

Combination of Ocimum sanctum extract and Levetiracetam ameliorates cognitive dysfunction and hippocampal architecture in rat model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease which affects more than 40 million people worldwide with progressive loss of memory and cognitive functions. It is reported, persistent AD is also one of the main causes of epilepsy in elders and comorbidity of both these will contribute to worsening the health status of AD patients. Recently, herbal plants with potent neuroprotective and antioxidant properties were used for increasing the quality of life in neurodegenerative disease patients. The present study was conceptualized to access the protective effect of Ocimum sanctum extract (OSE) and Levetiracetam (LEV) and their combination (OSE+LEV) against AD and epilepsy associated with AD in the rat AD model. AD was induced in aged male Wistar albino rats with Amyloid-β (Aβ) by intracerebroventricular administration. The results reveal, treatment with OSE, LEV and OSE+LEV significantly reversed the memory impairment, increases the BDNF expressions and decreases AChE activity in Aβ induced AD animals. Expression of A-β and p-tau in the hippocampus was significantly reduced in treatment group when compared to the control animals. Treatment with OSE and OSE+LEV also restored the hippocampal architecture by ameliorating the neuronal count in CA1, CA3 and DG regions. It also observed that treatment has decreased the excitoneurotoxicity evidenced by decreased glutamate and increased GABA levels and thus provided protection against epilepsy. Treatment groups also exhibited a potent antioxidant activity when tested endogenous antioxidant enzymes SOD, GSH and LPO in the brain hippocampus. Our findings provide evidence for use of OSE, LEV and OSE+LEV against AD and epilepsy associated with AD in Aβ induced AD animal model. However, further clinical studies are required to prove the use of OSE, LEV and OSE+LEV in the management of AD and AD-associated epilepsy in human volunteers.

Anticonvulsant effects of Cymbopogon giganteus extracts with possible effects on fully kindled seizures and anxiety in experimental rodent model of mesio-temporal epilepsy induced by pilocarpine

Ethnopharmacological relevanceEpilepsy is a neurological disorder of the brain characterized by periodic and unpredictable occurrence of a transient behavior alteration due to the rhythmic, synchronous and disordered firing of brain neuron. Worldwide, approximately 50 million people currently live with epilepsy and close to 80% of people with epilepsy live in poor countries. However, it was noticed in many countries worldwide that people with epilepsy and their families suffer from stigma and discrimination and that situation exposes them to high psychological conditions such as depression and anxiety as well as more physical problems including bruising and fractures from injuries related to seizures. However, several plants-based products used for epilepsy and anxiety treatments in different system of folk medicine have exhibited a significant anti-epileptic and antianxiety activities using animal models with fewer side effects. Aim of the studyThe study aimed at evaluating the antiepileptic, status post-epilepticus and anxiolytic effects of Cymbopogon giganteus decoction in rat model induced by pilocarpine. Materials and methodsA total of 90 rats were partitioned into 7 groups and treated as follow: animals of groups I (normal control) and II (considered the negative control) received distilled water (10 mL/kg); while groups III, IV, V, and VI were treated with the C. giganteus extract at 34, 85, 170 and 340 mg/kg p.o, respectively; and the group VII (considered positive control) received sodium valproate at 300 mg/kg, i.p. After 40 min post-treatment, a single dose of n-methyl-scopolamine (1 mg/kg, i.p) was administered to animals of groups (II, III, IV, V, VI, VII) followed by pilocarpine (360 mg/kg, i.p). Animal of group I (normal group) received distilled water. Rats were further observed for 6 h to evaluate the severity and the duration of the acute seizures of epilepsy according to Racine scale. Anxious behavior status post-epilepticus was also assessed in the same rats used above in the Elevated Plus Maze and number of entries into the open or closed arms and the time spent on either open or closed arms of the platform were recorded. Animals were also evaluated on Open Field Test and the number of rearing, crossing, grooming, defecation and center time were registered. ResultsC. giganteus decoction significantly (P < 0.05) reduced the animal mortality, the number and duration of convulsions and effectively increased the latency of convulsions. The plant extract significantly (P < 0.05) improved GSH level and SOD activity, reduced MDA and CAT activity, increased GABA level and decreased GABA-t activity in hippocampus. The anxiety induced by pilocarpine was also significantly (P < 0.05) inhibited by the extract of the plant. ConclusionsThus, C. giganteus has demonstrated its antiepileptic and anxiolytic activities in rat model and may be used as preventive measure for patients suffering from epilepsy seizures and anxiety.

Jiaotaiwan increased GABA level in brain and serum, improved sleep via increasing NREM sleep and REM sleep, and its component identification

Ethnopharmacological relevanceJiaotaiwan (JTW) is good at communicating the heart and kidney. That meets the main mechanism of insomnia in traditional Chinese medicine. But the mechanism of JTW in promoting sleep is not clear. Aim of the studyTo investigate the mechanism of JTW in promoting sleep and identify the main components. Materials and methodsIn this study, we detected the levels of GABA in serum and brain via LC-MS/MS analysis and investigated the hypnotic effect of JTW and its role in promoting sleep via Sleep monitoring and vigilance state analysis. Further, the identification of the main components was carried out by using LC-MS/MS analysis. ResultsJTW could increase the GABA levels in serum, FC and BS of SDM rats. JTW reduced the amount of wakefulness, increased the time of NREM sleep and REM sleep. A total of 25 compounds were identified. ConclusionsThe current work provides valuable information on the hypnotic effects of JTW and its regulatory mechanisms in promoting sleep.

Honey bee genetics shape the strain-level structure of gut microbiota in social transmission

BackgroundHoney bee gut microbiota transmitted via social interactions are beneficial to the host health. Although the microbial community is relatively stable, individual variations and high strain-level diversity have been detected across honey bees. Although the bee gut microbiota structure is influenced by environmental factors, the heritability of the gut members and the contribution of the host genetics remains elusive. Considering bees within a colony are not readily genetically identical due to the polyandry of the queen, we hypothesize that the microbiota structure can be shaped by host genetics.ResultsWe used shotgun metagenomics to simultaneously profile the microbiota and host genotypes of bees from hives of four different subspecies. Gut composition is more distant between genetically different bees at both phylotype- and “sequence-discrete population” levels. We then performed a successive passaging experiment within colonies of hybrid bees generated by artificial insemination, which revealed that the microbial composition dramatically shifts across batches of bees during the social transmission. Specifically, different strains from the phylotype of Snodgrassella alvi are preferentially selected by genetically varied hosts, and strains from different hosts show a remarkably biased distribution of single-nucleotide polymorphism in the Type IV pili loci. Genome-wide association analysis identified that the relative abundance of a cluster of Bifidobacterium strains is associated with the host glutamate receptor gene specifically expressed in the bee brain. Finally, mono-colonization of Bifidobacterium with a specific polysaccharide utilization locus impacts the alternative splicing of the gluR-B gene, which is associated with an increased GABA level in the brain.ConclusionsOur results indicated that host genetics influence the bee gut composition and suggest a gut-brain connection implicated in the gut bacterial strain preference. Honey bees have been used extensively as a model organism for social behaviors, genetics, and the gut microbiome. Further identification of host genetic function as a shaping force of microbial structure will advance our understanding of the host-microbe interactions.45gpjtUuBYRAxeW78Mk2MGVideo abstract