Unveiling the potential of A. fabrum and γ-aminobutyric acid for mitigation of nickel toxicity in fenugreek.

Nickel (Ni) is a heavy metal that adversely affects the growth of different crops by inducing oxidative stress and nutrient imbalance. The role of rhizobacteria (RB) is vital to resolve this issue. They can promote root growth and facilitate the uptake of water and nutrients, resulting in better crop growth. On the other hand, γ-aminobutyric acid (GABA) can maintain the osmotic balance and scavenge the reactive oxygen species under stress conditions. However, the combined effect of GABA and RB has not been thoroughly explored to alleviate Ni toxicity, especially in fenugreek plants. Therefore, in the current pot study, four treatments, i.e., control, A. fabrum (RB), 0.40 mM GABA, and 0.40 mM GABA + RB, were applied under 0Ni and 80 mg Ni/kg soil (80Ni) stress. Results showed that RB + 0.40 mM GABA caused significant improvements in shoot length (~ 13%), shoot fresh weight (~ 47%), shoot dry weight (~ 47%), root length (~ 13%), root fresh weight (~ 60%), and root dry weight (~ 15%) over control under 80 Ni toxicity. A significant enhancement in total chlorophyll (~ 14%), photosynthetic rate (~ 17%), stomatal CO2 concentration (~ 19%), leaves and roots N (~ 10 and ~ 37%), P (~ 18 and ~ 7%) and K (~ 11 and ~ 30%) concentrations, while a decrease in Ni (~ 83 and ~ 49%) concentration also confirmed the effectiveness of RB + 0.40 mM GABA than control under 80Ni. In conclusion, fabrum + 0.40 mM GABA can potentially alleviate the Ni toxicity in fenugreek plants. The implications of these findings extend to agricultural practices, environmental remediation efforts, nutritional security, and ecological impact. Further research is recommended to elucidate the underlying mechanisms, assess long-term effects, and determine the practical feasibility of using A. fabrum + 0.40GABA to improve growth in different crops under Ni toxicity.

Parvalbumin Regulates GAD Expression through Calcium Ion Concentration to Affect the Balance of Glu-GABA and Improve KA-Induced Status Epilepticus in PV-Cre Transgenic Mice.

Aims: the study aimed to (i) use adeno-associated virus technology to modulate parvalbumin (PV) gene expression, both through overexpression and silencing, within the hippocampus of male mice and (ii) assess the impact of PV on the metabolic pathway of glutamate and γ-aminobutyric acid (GABA). Methods: a status epilepticus (SE) mouse model was established by injecting kainic acid into the hippocampus of transgenic mice. When the seizures of mice reached SE, the mice were killed at that time point and 30 min after the onset of SE. Hippocampal tissues were extracted and the mRNA and protein levels of PV and the 65 kDa (GAD65) and 67 kDa (GAD67) isoforms of glutamate decarboxylase were assessed using real-time quantitative polymerase chain reaction and Western blot, respectively. The concentrations of glutamate and GABA were detected with high-performance liquid chromatography (HPLC), and the intracellular calcium concentration was detected using flow cytometry. Results: we demonstrate that the expression of PV is associated with GAD65 and GAD67 and that PV regulates the levels of GAD65 and GAD67. PV was correlated with calcium concentration and GAD expression. Interestingly, PV overexpression resulted in a reduction in calcium ion concentration, upregulation of GAD65 and GAD67, elevation of GABA concentration, reduction in glutamate concentration, and an extension of seizure latency. Conversely, PV silencing induced the opposite effects. Conclusion: parvalbumin may affect the expression of GAD65 and GAD67 by regulating calcium ion concentration, thereby affecting the metabolic pathways associated with glutamate and GABA. In turn, this contributes to the regulation of seizure activity.

Gamma-aminobutyric acid (GABA) improves salinity stress tolerance in soybean seedlings by modulating their mineral nutrition, osmolyte contents, and ascorbate-glutathione cycle.

BACKGROUND: In plants, GABA plays a critical role in regulating salinity stress tolerance. However, the response of soybean seedlings (Glycine max L.) to exogenous gamma-aminobutyric acid (GABA) under saline stress conditions has not been fully elucidated. RESULTS: This study investigated the effects of exogenous GABA (2 mM) on plant biomass and the physiological mechanism through which soybean plants are affected by saline stress conditions (0, 40, and 80 mM of NaCl and Na2SO4 at a 1:1 molar ratio). We noticed that increased salinity stress negatively impacted the growth and metabolism of soybean seedlings, compared to control. The root-stem-leaf biomass (27- and 33%, 20- and 58%, and 25- and 59% under 40- and 80 mM stress, respectively]) and the concentration of chlorophyll a and chlorophyll b significantly decreased. Moreover, the carotenoid content increased significantly (by 35%) following treatment with 40 mM stress. The results exhibited significant increase in the concentration of hydrogen peroxide (H2O2), malondialdehyde (MDA), dehydroascorbic acid (DHA) oxidized glutathione (GSSG), Na+, and Cl- under 40- and 80 mM stress levels, respectively. However, the concentration of mineral nutrients, soluble proteins, and soluble sugars reduced significantly under both salinity stress levels. In contrast, the proline and glycine betaine concentrations increased compared with those in the control group. Moreover, the enzymatic activities of ascorbate peroxidase, monodehydroascorbate reductase, glutathione reductase, and glutathione peroxidase decreased significantly, while those of superoxide dismutase, catalase, peroxidase, and dehydroascorbate reductase increased following saline stress, indicating the overall sensitivity of the ascorbate-glutathione cycle (AsA-GSH). However, exogenous GABA decreased Na+, Cl-, H2O2, and MDA concentration but enhanced photosynthetic pigments, mineral nutrients (K+, K+/Na+ ratio, Zn2+, Fe2+, Mg2+, and Ca2+); osmolytes (proline, glycine betaine, soluble sugar, and soluble protein); enzymatic antioxidant activities; and AsA-GSH pools, thus reducing salinity-associated stress damage and resulting in improved growth and biomass. The positive impact of exogenously applied GABA on soybean plants could be attributed to its ability to improve their physiological stress response mechanisms and reduce harmful substances. CONCLUSION: Applying GABA to soybean plants could be an effective strategy for mitigating salinity stress. In the future, molecular studies may contribute to a better understanding of the mechanisms by which GABA regulates salt tolerance in soybeans.

Litchi pulp-derived gamma-aminobutyric acid (GABA) extract counteracts liver inflammation induced by litchi thaumatin-like protein.

Gamma-aminobutyric acid (GABA) is the predominant amino acid in litchi pulp, known for its neuroregulatory effects and anti-inflammatory properties. Although previous research has highlighted the pro-inflammatory characteristics of litchi thaumatin-like protein (LcTLP), interplay between GABA and LcTLP in relation to inflammation remains unclear. This study aims to explore the hepatoprotective effects of the litchi pulp-derived GABA extract (LGE) against LcTLP-induced liver inflammation in mice and LO2 cells. In vivo experiments demonstrated that LGE significantly reduced the levels of aspartate transaminase and alanine transaminase, and protected the liver against infiltration of CD4+ and CD8+ T cells and histological injury induced by LcTLP. Pro-inflammatory cytokines including interleukin-6, interleukin-1ß, and tumor necrosis factor-α were also diminished by LGE. The LGE appeared to modulate the mitogen-activated protein kinase (MAPK) signaling pathway to exert its anti-inflammatory effects, as evidenced by a reduction of 47%, 35%, and 31% in phosphorylated p38, JNK, and ERK expressions, respectively, in the liver of the high-dose LGE group. Additionally, LGE effectively improved the translocation of gut microbiota by modulating its microbiological composition and abundance. In vitro studies have shown that LGE effectively counteracts the increase in reactive oxygen species, calcium ions, and pro-inflammatory cytokines induced by LcTLP. These findings may offer new perspectives on the health benefits and safety of litchi consumption.

Structure, Self-Assembly, and Phase Behavior of Neuroactive N-Acyl GABAs: Doxorubicin Encapsulation in NPGABA/DPPC Liposomes and Release Studies.

N-Acylated amino acids and neurotransmitters in mammals exert significant biological effects on the nervous system, immune responses, and vasculature. N-Acyl derivatives of γ-aminobutyric acid (N-acyl GABA), which belong to both classes mentioned above, are prominent among them. In this work, a homologous series of N-acyl GABAs bearing saturated N-acyl chains (C8-C18) have been synthesized and characterized with respect to self-assembly, thermotropic phase behavior, and supramolecular organization. Differential scanning calorimetric studies revealed that the transition enthalpies and entropies of N-acyl GABAs are linearly dependent on the acyl chain length. The crystal structure of N-tridecanoyl GABA showed that the molecules are packed in bilayers with the acyl chains aligned parallel to the bilayer normal and that the carboxyl groups from opposite layers associate to form dimeric structures involving strong O-H···O hydrogen bonds. In addition, N-H···O and C-H···O hydrogen bonds between amide moieties of adjacent molecules within each layer stabilize the molecular packing. Powder X-ray diffraction studies showed odd-even alternation in the d spacings, suggesting that the odd chain and even chain compounds pack differently. Equimolar mixtures of N-palmitoyl GABA and dipalmitoylphosphatidylcholine (DPPC) were found to form stable unilamellar vesicles with diameters of ∼300-340 nm, which could encapsulate doxorubicin, an anticancer drug, with higher efficiency and better release characteristics than DPPC liposomes at physiologically relevant pH. These liposomes exhibit faster release of doxorubicin at acidic pH (<7.0), indicating their potential utility as drug carriers in cancer chemotherapy.

Effect of terahertz waves on the aggregation behavior of neurotransmitters.

Understanding the dynamics of neurotransmitters is crucial for unraveling synaptic transmission mechanisms in neuroscience. In this study, we investigated the impact of terahertz (THz) waves on the aggregation of four common neurotransmitters through all-atom molecular dynamics (MD) simulations. The simulations revealed enhanced nicotine (NCT) aggregation under 11.05 and 21.44 THz, with a minimal effect at 42.55 THz. Structural analysis further indicated strengthened intermolecular interactions and weakened hydration effects under specific THz stimulation. In addition, enhanced aggregation was observed at stronger field strengths, particularly at 21.44 THz. Furthermore, similar investigations on epinephrine (EPI), 5-hydroxytryptamine (5-HT), and γ-aminobutyric acid (GABA) corroborated these findings. Notably, EPI showed increased aggregation at 19.05 THz, emphasizing the influence of vibrational modes on aggregation. However, 5-HT and GABA, with charged or hydrophilic functional groups, exhibited minimal aggregation under THz stimulation. The present study sheds some light on neurotransmitter responses to THz waves, offering implications for neuroscience and interdisciplinary applications.

Prophylactic Supplementation with Lactobacillus Reuteri or Its Metabolite GABA Protects Against Acute Ischemic Cardiac Injury.

The gut microbiome has emerged as a potential target for the treatment of cardiovascular disease. Ischemia/reperfusion (I/R) after myocardial infarction is a serious complication and whether certain gut bacteria can serve as a treatment option remains unclear. Lactobacillus reuteri (L. reuteri) is a well-studied probiotic that can colonize mammals including humans with known cholesterol-lowering properties and anti-inflammatory effects. Here, the prophylactic cardioprotective effects of L. reuteri or its metabolite γ-aminobutyric acid (GABA) against acute ischemic cardiac injury caused by I/R surgery are demonstrated. The prophylactic gavage of L. reuteri or GABA confers cardioprotection mainly by suppressing cardiac inflammation upon I/R. Mechanistically, GABA gavage results in a decreased number of proinflammatory macrophages in I/R hearts and GABA gavage no longer confers any cardioprotection in I/R hearts upon the clearance of macrophages. In vitro studies with LPS-stimulated bone marrow-derived macrophages (BMDM) further reveal that GABA inhibits the polarization of macrophages toward the proinflammatory M1 phenotype by inhibiting lysosomal leakage and NLRP3 inflammasome activation. Together, this study demonstrates that the prophylactic oral administration of L. reuteri or its metabolite GABA attenuates macrophage-mediated cardiac inflammation and therefore alleviates cardiac dysfunction after I/R, thus providing a new prophylactic strategy to mitigate acute ischemic cardiac injury.

Specific transcription factors Ascl1 and Lhx6 attenuate diabetic neuropathic pain by modulating spinal neuroinflammation and microglial activation in mice.

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1ß, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.

Sucrose, cell wall, and polyamine metabolisms involve in preserving postharvest quality of 'Zaosu' pear fruit by L-glutamate treatment.

'Zaosu' pear fruit is prone to yellowing of the surface and softening of the flesh after harvest. This work was performed to assess the influences of L-glutamate treatment on the quality of 'Zaosu' pears and elucidate the underlying mechanisms involved. Results demonstrated that L-glutamate immersion reduced ethylene release, respiratory intensity, weight loss, brightness (L*), redness (a*), yellowness (b*), and total coloration difference (ΔE); enhanced ascorbic acid, soluble solids, and soluble sugar contents; maintained chlorophyll content and flesh firmness of pears. L-glutamate also restrained the activities of neutral invertase and acid invertase, while enhancing sucrose phosphate synthetase and sucrose synthase activities to facilitate sucrose accumulation. The transcriptions of PbSGR1, PbSGR2, PbCHL, PbPPH, PbRCCR, and PbNYC were suppressed by L-glutamate, resulting in a deceleration of chlorophyll degradation. L-glutamate concurrently suppressed the transcription levels and enzymatic activities of polygalacturonases, pectin methylesterases, cellulase, and ß-glucosidase. It restrained polygalacturonic acid trans-eliminase and pectin methyl-trans-eliminase activities as well as inhibited the transcription levels of PbPL and Pbß-gal. Moreover, the gene transcriptions and enzymatic activities of arginine decarboxylase, ornithine decarboxylase, S-adenosine methionine decarboxylase, glutamate decarboxylase, γ-aminobutyric acid transaminase, glutamine synthetase along with the PbSPDS transcription was promoted by L-glutamate. L-glutamate also resulted in the down-regulation of PbPAO, PbDAO, PbSSADH, PbGDH, and PbGOGAT transcription levels, while enhancing γ-aminobutyric acid, glutamate, and pyruvate acid contents in pears. These findings suggest that L-glutamate immersion can effectively maintain the storage quality of 'Zaosu' pears via modulating key enzyme activities and gene transcriptions involved in sucrose, chlorophyll, cell wall, and polyamine metabolism.

Autoimmune and paraneoplastic seizures.

Seizures are a common feature of autoimmune encephalitis and are especially prevalent in patients with the commonest autoantibodies, against LGI1, CASPR2 and the NMDA, GABAB, and GABAA receptors. In this chapter, we discuss the classification, clinical, investigation, and treatment aspects of patients with these, and other autoantibody-mediated and -associated, illnesses. We highlight distinctive and common seizure semiologies which, often alongside other features we outline, can help the clinical diagnosis of an autoantibody-associated syndrome. Next, we classify these syndromes by either focusing on whether they represent underlying causative autoantibodies or T-cell-mediated syndromes and on the distinction between acute symptomatic seizures and a more enduring tendency to autoimmune-associated epilepsy, a practical and valuable distinction for both patients and clinicians which relates to the pathogenesis. We emphasize the more effective immunotherapy response in patients with causative autoantibodies, and discuss the emerging evidence for various first-, second-, and third-line immunotherapies. Finally, we highlight available clinical rating scales which can guide autoantibody testing and immunotherapy in patients with seizures of unknown etiology. Throughout, we relate the clinical and therapeutic observations to the immunobiology and neuroscience which drive these seizures.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

Linalool, a Fragrance Compound in Plants, Protects Dopaminergic Neurons and Improves Motor Function and Skeletal Muscle Strength in Experimental Models of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in reduced dopamine levels in the striatum and eventual onset of motor symptoms. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a monoterpene in aromatic plants exhibiting antioxidant, antidepressant, and anti-anxiety properties. The objective of this study is to evaluate the neuroprotective impacts of linalool on dopaminergic SH-SY5Y cells, primary mesencephalic and cortical neurons treated with 1-methyl-4-phenylpyridinium ion (MPP+), as well as in PD-like mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell viability, α-tubulin staining, western blotting, immunohistochemistry and behavioral experiments were performed. In MPP+-treated SH-SY5Y cells, linalool increased cell viability, reduced neurite retraction, enhanced antioxidant defense by downregulation of apoptosis signaling (B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 and poly ADP-ribose polymerase (PARP)) and phagocyte NADPH oxidase (gp91phox), as well as upregulation of neurotrophic signaling (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) and nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In MPP+-treated primary mesencephalic neurons, linalool enhanced the expressions of tyrosine hydroxylase (TH), Sirtuin 1 (SirT1), and parkin. In MPP+-treated primary cortical neurons, linalool upregulated protein expression of SirT1, γ-Aminobutyric acid type A-α1 (GABAA-α1), and γ-Aminobutyric acid type B (GABAB). In PD-like mice, linalool attenuated the loss of dopamine neurons in SNpc. Linalool improved the motor and nonmotor behavioral deficits and muscle strength of PD-like mice. These findings suggest that linalool potentially protects dopaminergic neurons and improves the impairment symptoms of PD.

Increased GABA signaling in liver macrophage promotes HBV replication in HBV-carrier mice.

Gamma-aminobutyric acid (GABA) signals in various non-neuronal cells including hepatocytes and some immune cells. Studies, including ours, show that type A GABA receptors (GABAARs)-mediated signaling occurs in macrophages regulating tissue-specific functions. Our recent study reveals that activation of GABAARs in liver macrophages promotes their M2-like polarization and increases HBV replication in mice. This short article briefly summarizes the GABA signaling system in macrophages and discusses potential mechanisms by which GABA signaling promotes HBV replication.

Cholinergic Control of GnRH Neuron Physiology and Luteinizing Hormone Secretion in Male Mice: Involvement of ACh/GABA Cotransmission.

Gonadotropin-releasing hormone (GnRH)-synthesizing neurons orchestrate reproduction centrally. Early studies have proposed the contribution of acetylcholine (ACh) to hypothalamic control of reproduction, although the causal mechanisms have not been clarified. Here, we report that in vivo pharmacogenetic activation of the cholinergic system increased the secretion of luteinizing hormone (LH) in orchidectomized mice. 3DISCO immunocytochemistry and electron microscopy revealed the innervation of GnRH neurons by cholinergic axons. Retrograde viral labeling initiated from GnRH-Cre neurons identified the medial septum and the diagonal band of Broca as exclusive sites of origin for cholinergic afferents of GnRH neurons. In acute brain slices, ACh and carbachol evoked a biphasic effect on the firing rate in GnRH neurons, first increasing and then diminishing it. In the presence of tetrodotoxin, carbachol induced an inward current, followed by a decline in the frequency of miniature postsynaptic currents (mPSCs), indicating a direct influence on GnRH cells. RT-PCR and whole-cell patch-clamp studies revealed that GnRH neurons expressed both nicotinic (α4ß2, α3ß4, and α7) and muscarinic (M1-M5) AChRs. The nicotinic AChRs contributed to the nicotine-elicited inward current and the rise in firing rate. Muscarine via M1 and M3 receptors increased, while via M2 and M4 reduced the frequency of both mPSCs and firing. Optogenetic activation of channelrhodopsin-2-tagged cholinergic axons modified GnRH neuronal activity and evoked cotransmission of ACh and GABA from a subpopulation of boutons. These findings confirm that the central cholinergic system regulates GnRH neurons and activates the pituitary-gonadal axis via ACh and ACh/GABA neurotransmissions in male mice.

Change of physiochemical characteristics, nutritional quality, and volatile compounds of Chenopodium quinoa Willd. during germination.

The impacts of varying germination periods (0-72 h) on morphological properties, proximate composition, amino acid profile, GABA levels, antioxidant attributes, polyphenol content (both free and bound), and volatile compounds of quinoa were evaluated. Germination significantly increased the content of fiber, amino acids, GABA, polyphenols, and in-vitro antioxidant activities in quinoa. The optimal nutritional quality and antioxidant capacity of quinoa were observed during the 36-72 h germination period. We examined the dynamics of 47 phenolic compounds in quinoa during germination and noted a substantial rise in free phenolic acids and bound flavonoids post-germination. A total of 53 and 84 volatile compounds were respectively identified in ungerminated quinoa and germinated quinoa. It was found that the germination period of 24-48 h contributed to reducing the presence of undesirable flavors. TEM analysis revealed significant structural damage to the ultrastructure and relaxation of the cell wall in germinated quinoa grains.

Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial. METHODS: Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated. RESULTS: APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice. CONCLUSION: Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model.

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.

Glutamate application maintains quality and antioxidant capacity of fresh-cut carrots by modulating GABA shunt, phenylpropanoid and ROS metabolism.

The effects of exogenous glutamate treatment on the quality attributes, γ-aminobutyric acid (GABA) shunt, phenylpropanoid pathway, and antioxidant capacity of fresh-cut carrots were investigated. Results showed that glutamate treatment suppressed the increases in lightness and whiteness values, inhibited the degradation of total carotenoids and maintained better flavor and taste in fresh-cut carrots. Moreover, glutamate treatment rapidly promoted the activities of glutamate decarboxylase and GABA transaminase, thus improving the GABA content. It also significantly enhanced the activities of phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, and 4-coumarate coenzyme A ligase and promoted the accumulation of total phenolics as well as the main individual phenolic compounds, including chlorogenic and caffeic acid. In addition, glutamate application activated the reactive oxygen system-related enzyme including peroxidase, superoxide dismutase, ascorbate peroxidase, and catalase activities to maintain higher antioxidant capacity in fresh-cut carrots. These results demonstrated that exogenous glutamate treatment maintained better nutritional quality and alleviated color deterioration by accelerating the accumulation of GABA and phenolics and enhancing the antioxidant capacity in fresh-cut carrots.

nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus.

Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

Guhan Yangsheng Jing mitigates hippocampal neuronal pyroptotic injury and manifies learning and memory capabilities in sleep deprived mice via the NLRP3/Caspase1/GSDMD signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Guhan Yangsheng Jing (GHYSJ) is a traditional Chinese patent medicine, that has the function of nourishing the kidney and replenishing the essence, invigorating the brain and calming the mind. It is often used to treat dizziness, memory loss, sleep disorders, fatigue, and weakness, etc. However, its mechanism for improving sleep has not yet been determined. AIM OF THE STUDY: This study aims to explore the effects of GHYSJ on Sleep Deprivation (SD)-induced hippocampal neuronal pyroptotic injury, learning and cognitive abilities, and sleep quality in mice. METHODS: In this study, a PCPA-induced SD mouse model was established. We assessed the influence of GHYSJ on sleep quality and mood by using the pentobarbital-induced sleep test (PIST) and sucrose preference test (SPT). The pharmacological effects of GHYSJ on learning and memory impairment were evaluated by the Morris Water Maze (MWM) and Open Field Test (OFT). Pathological changes in the hippocampal tissue of the SD rats were observed via HE staining and Nissl staining. The severity of neuronal damage was evaluated by detecting the expression of the neuronal marker Microtubule-associated protein 2 (MAP2), via immunohistochemistry and immunofluorescence. Furthermore, the levels of neurotransmitter 5-hydroxytryptophan (5-HTP), 5-hydroxy tryptamine (5-HT), γ-aminobutyric acid (GABA), and Glutamic acid (Glu) in hippocampal tissues, as well as the expression of inflammatory factors Interleukin-1ß (IL-1ß) and Interleukin-18 (IL-18) in serum, were determined by ELISA. The expressions of mRNA and protein NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Gasdermin D (GSDMD), Cysteinyl aspartate specific proteinase1 (Caspase1), High mobility group box-1 protein (HMGB1) and Apoptosis-associated speck-like protein containing CARD (ASC) related to the cellular ferroptosis pathway were tested and analyzed by RT-PCR and WB respectively. RESULTS: PCPA significantly diminishes the sleep span of experimental animals by expediting the expenditure of 5-HT, consequently establishing an essentially direct SD model. The intervention of GHYSJ displays remarkable efficacy in mitigating insomnia symptoms, encompassing difficulties in initiating sleep and insufficient sleep duration. Likewise, it ameliorates memory function impairments induced by sleep deprivation, along with symptoms such as fatigue and depletion of vitality. GHYSJ exerts a protective influence on hippocampal neurons facilitated by inhibiting the down regulation of MAP2 and maintaining the equilibrium of neurotransmitters (5-HTP, 5-HT, GABA, and Glu). It diminishes the expression of intracellular pyroptosis-associated inflammatory factors (IL-1ß and IL-18) and curbs the activation of the NLRP3/Caspase1/GSDMD pyroptosis-related signaling pathways, thereby alleviating the damage caused by hippocampal neuronal pyroptosis.