Regulation Of Neurotransmission Research Articles

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets.

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

The Cognitive-Enhancing Effects of Dendrobium nobile Lindl Extract in Sleep Deprivation-Induced Amnesic Mice.

Chronic sleep deprivation (SD) causes neurological and neurodegenerative dysfunction including learning and memory deficit. The orchid Dendrobium nobile Lindl (DNL), is widely used as a Yin tonic and medicinal food throughout Asia, and has many reported pharmacological effects. This study focused on the cognitive-enhancing effects of DNL in sleep deprivation-induced amnesia in mice and its biochemical mechanisms. Our results showed that the mice displayed significant cognitive deficits after 2-week SD while treatment with the extract of DNL prevented these impairments. In the novel object recognition and object location recognition tasks, a significant increase in the discrimination index was observed in DNL-treated (200 and 400 mg/kg) mice. In the MWM test, DNL (200 and 400 mg/kg) treatment shorten the prolongation of latency and increased the crossing numbers compared with SD mice. The biochemical analysis of brain tissue showed a decrease in NE, dismutase (T-SOD) and catalase (CAT) activity and an increase in 5-HT and malondialdehyde (MDA) concentration after the treatment with DNL in mice. Our findings indicated that DNL exerted a positive effect in preventing and improving cognitive impairment induced by SD, which may be mediated via the regulation of neurotransmitters and alleviation of oxidative stress.

Research Progress on the Pharmacological Mechanism of Sour Date Palm in the Treatment of Insomnia with Anxiety and Depression

Insomnia with anxiety and depression is one of the common psychological disorders, which are closely related and usually appear in the form of co-morbidity. The pathogenesis of this disease is still unclear, but it is mostly related to the function of the hypothalamic-pituitary-adrenal axis (HPA axis), neurotransmitter regulation, and inflammatory response. According to Chinese medicine, this disease belongs to the category of "sleeplessness", "depression" and "dirty restlessness", involving the five internal organs and six internal organs. Modern pharmacological studies have shown that sour date kernel contains flavonoids, saponins, triterpenoids, and phenolic acid compounds. It is also found to act simultaneously through sedative-hypnotic, anti-anxiety, anti-depressant, neurotransmitter regulation, inflammation inhibition, and brain nerve protection. In this paper, the pharmacological effects and mechanisms of the active ingredients of Ziziphus jujube were described by reviewing the pharmacological research literature related to Ziziphus jujube, to illustrate the positive efficacy and medicinal value of Ziziphus jujube in the treatment of insomnia with anxiety and depression.

A role for insulin-like growth factor-1 in hippocampal plasticity following traumatic brain injury.

Traumatic brain injury (TBI) initiates a constellation of secondary injury cascades, leading to neuronal damage and dysfunction that is often beyond the scope of endogenous repair mechanisms. Cognitive deficits are among the most persistent morbidities resulting from TBI, necessitating a greater understanding of mechanisms of posttraumatic hippocampal damage and neuroplasticity and identification of therapies that improve recovery by enhancing repair pathways. Focusing here on hippocampal neuropathology associated with contusion-type TBIs, the impact of brain trauma on synaptic structure and function and the process of adult neurogenesis is discussed, reviewing initial patterns of damage as well as evidence for spontaneous recovery. A case is made that insulin-like growth factor-1 (IGF-1), a growth-promoting peptide synthesized in both the brain and the periphery, is well suited to augment neuroplasticity in the injured brain. Essential during brain development, multiple lines of evidence delineate roles in the adult brain for IGF-1 in the maintenance of synapses, regulation of neurotransmission, and modulation of forms of synaptic plasticity such as long-term potentiation. Further, IGF-1 enhances adult hippocampal neurogenesis though effects on proliferation and neuronal differentiation of neural progenitor cells and on dendritic growth of newly born neurons. Post-injury administration of IGF-1 has been effective in rodent models of TBI in improving learning and memory, attenuating death of mature hippocampal neurons and promoting neurogenesis, providing critical proof-of-concept data. More studies are needed to explore the effects of IGF-1-based therapies on synaptogenesis and synaptic plasticity following TBI and to optimize strategies in order to stimulate only appropriate, functional neuroplasticity.

Insomnia: Therapy and Role of neurotransmitters

Insomnia is one of the most common sleep disorders which affects 30-40 percent of the adult population. The present article provides a combined review on prevalence, categories of insomnia, pathophysiology, role of neurotransmitter on sleep and different types of therapies for insomnia. From this review it was estimated that hormones like melatonin, cortisol, and others produced by the hypothalamic-pituitary-adrenal axis regulate the sleep-wake cycle. Disturbance of this cycle leads to insomnia. Furthermore, Neurotransmitter like GABA-Lglutamic acid, Acetylcholine, Norepinephrine, Dopamine, Serotonin, Steroids, Orexin, and Adenosine plays a major role in sleep regulation. Any alteration or disturbance in the neurotransmitter level affects sleep. It was concluded that Mechanism of action of almost all natural and synthetic derived drugs in regulation of neurotransmitters.

Neurotransmitter regulation rather than cell-intrinsic properties shapes the high-pass filtering properties of olfactory bulb glomeruli.

GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate an intraglomerular 'high-pass' filter through inhibition targeted onto a glomerulus. With this mechanism, weak stimuli (e.g. an odour with a low affinity for an odourant receptor) mainly produce PG cell-driven inhibition but strong stimuli generate enough excitation to overcome inhibition. PG cells may be particularly susceptible to being activated by weak stimuli due to their intrinsically small size and high input resistance. Here, we used dual-cell patch-clamp recordings and imaging methods in bulb slices obtained from wild-type and transgenic rats with labelled GABAergic cells to test a number of predictions of the high-pass filtering model. We first directly compared the responsiveness of PG cells with that of external tufted cells (eTCs), which are a class of excitatory cells that reside in a parallel but opposing position in the glomerular circuitry. PG cells were in fact found to be no more responsive than eTCs at low levels of sensory neuron activity. While PG cells required smaller currents to be excited, this advantage was offset by the fact that a given level of sensory neuron activity produced much smaller synaptic currents. We did, however, identify other factors that shaped the excitation/inhibition balance in a manner that would support a high-pass filter, including glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high-pass filter to enhance the contrast between different olfactory stimuli through mechanisms that are largely independent cell-intrinsic properties. KEY POINTS: GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate a 'high-pass' filter at a single glomerulus that selectively blocks weak stimulus signals. Their efficacy may reflect their intrinsically small size and high input resistance, which allows them to be easily excited. It was found that PG cells were in fact no more likely to be activated by weak stimuli than excitatory neurons. PG cells fired action potentials more readily in response to a fixed current input, but this advantage for excitability was offset by small synaptic currents. Glomeruli nevertheless display an excitation/inhibition balance that can support a high-pass filter, shifting from unfavourable to favourable with increasing stimulus strength. Factors shaping the filter include glial glutamate transporters and presynaptic metabotropic glutamate receptors. It is concluded that a single glomerulus may act as a high-pass filter to enhance stimulus contrast through mechanisms that are largely independent of cell-intrinsic properties.

Valeriana jatamansi Jones ex Roxb. Against Post-Traumatic Stress Disorder, Network Pharmacological Analysis, and In Vivo Evaluation.

Zhi zhu xiang (ZZX) is the root and rhizome of Valeriana jatamansi Jones ex Roxb. Recent studies have shown that ZZX can exert antianxiety, antidepressant, and sedative effects. Because post-traumatic stress disorder (PTSD) is similar to depression and anxiety in terms of its etiology, pathogenesis, and clinical manifestations, it is possible that ZZX may also be useful for the prevention and treatment of PTSD. In this study, a mouse model of PTSD was established and used to study the pharmacological action of a 95% ethanol extract of ZZX on PTSD via a series of classic behavioral tests. We found that a 95% ethanol extract of ZZX was indeed effective for relieving the symptoms of PTSD in mice. Moreover, network pharmacology analysis was used to predict the potential active ingredients, targets, and possible pathways of ZZX in the treatment of PTSD. The neurotransmitter system, the hypothalamic–pituitary–adrenal (HPA) axis, and the endocannabinoid (eCB) system were identified to be the most likely pathways for anti-PTSD action in ZZX. Due to the lack of a falsification mechanism in network pharmacology, in vivo tests were carried out in mice, and the expression levels of neurotransmitters, hormones, and genes of key targets were detected by enzyme-linked immunosorbent assay and real-time PCR to further verify this inference. Analysis showed that the levels of norepinephrine, 5-hydroxytryptamine, and glutamic acid were increased in the hippocampus, prefrontal cortex, and amygdala of PTSD mice, while the levels of dopamine and γ-aminobutyric acid were decreased in these brain regions; furthermore, ZZX could restore the expression of these factors, at least to a certain extent. The levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone were increased in these different brain regions and the serum of PTSD mice; these effects could be reversed by ZZX to a certain extent. The expression levels of cannabinoid receptor 1 and diacylglycerol lipase α mRNA were decreased in PTSD mice, while the levels of fatty acid amide hydrolase and monoacylglycerol lipase mRNA were increased; these effects were restored by ZZX to a certain extent. In conclusion, our findings suggest that ZZX may provide new therapeutic pathways for treating PTSD by the regulation of neurotransmitters, the HPA, and expression levels of eCB-related genes in the brain.

A possible novel mechanism for cognitive resistance to neurodegeneration: modulation of interneuron activity in the hippocampus after exposure to enriched environments

AbstractBackgroundExposure to an enriched environment has been shown in many studies to be beneficial to brain structure and cognition by preserving neuronal integrity and strengthening the functioning and plasticity of neural circuits. These benefits derive from the added spatial, social, and sensory complexities in an enriched environment. It has been well known for a few decades that an enriched environment stimulates neurogenesis and cell proliferation in the dentate gyrus of the hippocampus, leading to an increased number of dentate granule cells (DGCs). However, the changes to other populations of cell types, particularly interneurons, has remained elusive. Interneurons are integral regulators of neurotransmission in the hippocampus. Damage to hippocampal interneurons have serious implications and lead to a decline in cognitive health. Our study sought to elucidate possible changes in interneurons affected by exposure to an enriched environment (EE) and enriched changing (EC) environment.MethodThe topographic distribution of nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPHd) positive neurons was studied in the dentate gyrus of the rat dorsal hippocampus.ResultEnvironmental enrichment increased the number of NADPHd positive neurons found in both enrichment groups. The elevated level of neurons was represented uniformly across almost all six layers of the dentate gyrus and was most significant in the expected granular cell layer (GRCL) and subgranular zone (SGZ).ConclusionThe overall preliminary results suggest that the brain has the ability to adapt to increased amounts of sensory stimulation. These changes highlight a possible new mechanism of physiological homeostasis and physical evidence of a cognitive reserve; with an increased demand for energy from new‐born DGCs and increased sensory input, the brain will regulate its energy expenditure via an increase in either the activity of existing interneurons, or the actual number of interneurons. Further research will involve running a restudy and observing the differences to the ventral hippocampus, CA1, and CA3 regions, and the effects on specific subpopulations of interneurons.

Effects of Berberine on Atherosclerosis.

Atherosclerosis is an epidemic across the globe[A1], and its morbidity and mortality remain high, involving various complications and poor prognoses. In atherosclerosis, endothelial cells (ECs) dysfunction, vascular smooth muscle cells (VSMCs) migration and proliferation, foam cell formation, and inflammatory cell recruitment contribute to disease progression. Vascular stem cells (VSCs) also play a critical role in the cardiovascular system. Important data showed that the simultaneous increase of proliferation and apoptosis of VSMCs is the main cause of graft vein stenosis, suggesting that inhibition of VSMCs proliferation and apoptosis simultaneously is an important strategy for the treatment of atherosclerotic stenosis. Complementary and alternative medicine use among patients with cardiovascular disease (CVD) is growing. Berberine is an extract of Chinese traditional herbs that is known for its antimicrobial and anti-inflammatory effects in the digestive system. Its underlying anti-CVD mechanisms are currently attracting interest, and its pharmacological actions, such as antioxidation, regulation of neurotransmitters and enzymes, and cholesterol-lowering effects, have been substantiated. Recent studying found that berberine could inhibit both the proliferation and apoptosis of VSMCs induced by mechanical stretch stress simultaneously, which suggests that berberine might be an excellent drug to treat atherosclerosis. This review will focus on the recent progress of the effect of berberine on vascular cells, especially VSMCs, to provide important data and a new perspective for the application of berberine in anti-atherosclerosis.

Genome-Wide RNA-Sequencing Reveals Massive Circular RNA Expression Changes of the Neurotransmission Genes in the Rat Brain after Ischemia-Reperfusion.

Ischemic brain stroke is one of the most serious and socially significant diseases. In addition to messenger RNAs (mRNAs), encoding protein, the study of regulatory RNAs in ischemic has exceptional importance for the development of new strategies for neuroprotection. Circular RNAs (circRNAs) have a closed structure, predominantly brain-specific expression, and remain highly promising targets of research. They can interact with microRNAs (miRNAs), diminish their activity and thereby inhibit miRNA-mediated repression of mRNA. Genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra area revealed 395 circRNAs changed their expression significantly at 24 h after transient middle cerebral artery occlusion model (tMCAO) conditions. Furthermore, functional annotation revealed their association with neuroactive signaling pathways. It was found that about a third of the differentially expressed circRNAs (DECs) originate from genes whose mRNA levels also changed at 24 h after tMCAO. The other DECs originate from genes encoding non-regulated mRNAs under tMCAO conditions. In addition, bioinformatic analysis predicted a circRNA–miRNA–mRNA network which was associated with the neurotransmission signaling regulation. Our results show that such circRNAs can persist as potential miRNA sponges for the protection of mRNAs of neurotransmitter genes. The results expanded our views about the neurotransmission regulation in the rat brain after ischemia–reperfusion with circRNA action.

A Case of Pyruvate Carboxylase Deficiency With Longer Survival and Normal Laboratory Findings

Pyruvate carboxylase deficiency (PCD) is a rare autosomal recessive defect in a biotin-containing enzyme, Pyruvate carboxylase, which is considered as an enzyme of TCA-cycle regulation, gluconeogenesis, lipogenesis, and biosynthesis of neurotransmitters. Increased lactate to pyruvate ratio and decreased three hydroxybutyrates to acetoacetate are the main biochemical features of PCD. The elevated level of Citrulline, Proline, and Lysine with a short life span has been reported previously. Patients’ survival in almost all cases is below three months. Here, the authors aimed to report a girl with manifestations of Type B of PCD and longer survival (two-year and four-month-old). This patient did not have any changes in amino acid level, which was a unique case of Type B of PCD.

Catatonia: Clinical Overview of the Diagnosis, Treatment, and Clinical Challenges.

Catatonia is a syndrome that has been associated with several mental illness disorders but that has also presented as a result of other medical conditions. Schizophrenia and other psychiatric disorders such as mania and depression are known to be associated with catatonia; however, several case reports have been published of certain medical conditions inducing catatonia, including hyponatremia, cerebral venous sinus thrombosis, and liver transplantation. Neuroleptic Malignant Syndrome and anti-NMDA receptor encephalitis are also prominent causes of catatonia. Patients taking benzodiazepines or clozapine are also at risk of developing catatonia following the withdrawal of these medications—it is speculated that the prolonged use of these medications increases gamma-aminobutyric acid (GABA) activity and that discontinuation may increase excitatory neurotransmission, leading to catatonia. The treatment of catatonia often involves the use of benzodiazepines, such as lorazepam, that can be used in combination therapy with antipsychotics. Definitive treatment may be found with electroconvulsive therapy (ECT). Aberrant neuronal activity in different motor pathways, defective neurotransmitter regulation, and impaired oligodendrocyte function have all been proposed as the pathophysiology behind catatonia. There are many clinical challenges that come with catatonia and, as early treatment is associated with better outcomes, it becomes imperative to understand these challenges. The purpose of this manuscript is to provide an overview of these challenges and to look at clinical studies regarding the pathophysiology, diagnosis, and treatment of as well as the complications and risk factors associated with catatonia.

S1R agonist modulates rat platelet eicosanoid synthesis and aggregation

Sigma-1 receptor (S1R) is detected in different cell types and can regulate intracellular signaling pathways. S1R plays a role in the pathomechanism of diseases and the regulation of neurotransmitters. Fluvoxamine can bind to S1R and reduce the serotonin uptake of neurons and platelets. We therefore hypothesized that platelets express S1R, which can modify platelet function. The expression of the SIGMAR1 gene in rat platelets was examined with a reverse transcription polymerase chain reaction and a quantitative polymerase chain reaction. The receptor was also visualized by immunostaining and confocal laser scanning microscopy. The effect of S1R agonist PRE-084 on the eicosanoid synthesis of isolated rat platelets and ADP- and AA-induced platelet aggregation was examined. S1R was detected in rat platelets both at gene and protein levels. Pretreatment with PRE-084 of resting platelets induced elevation of eicosanoid synthesis. The rate of elevation in thromboxane B2 and prostaglandin D2 synthesis was similar, but the production of prostaglandin E2 was higher. The concentration-response curve showed a sigmoidal form. The most effective concentration of the agonist was 2 µM. PRE-084 increased the quantity of cyclooxygenase-1 as detected by ELISA. PRE-084 also elevated the ADP- and AA-induced platelet aggregation. S1R of platelets might regulate physiological or pathological functions.

Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain.

Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.

Protein Kinase C-Dependent Effects of Neurosteroids on Synaptic GABAA Receptor Inhibition Require the δ-Subunit.

The dorsal motor nucleus of the vagus (DMV) contains preganglionic motor neurons important for interpreting sensory input from the periphery, integrating that information, and coding the appropriate parasympathetic (vagal) output to target organs. Despite the critical role of hormonal regulation of vagal motor output, few studies examine the role of neurosteroids in the regulation of the DMV. Of the few examinations, no studies have investigated the potential impact of allopregnanolone (Allo), a neuroactive progesterone-derivative, in the regulation of neurotransmission on the DMV. Since DMV neuronal function is tightly regulated by GABAA receptor activity and Allo is an endogenous GABAA receptor ligand, the present study used in vitro whole cell patch clamp to investigate whether Allo alters GABAergic neurotransmission to DMV neurons. Although Allo did not influence GABAergic neurotransmission during initial application (5–20 min), a TTX-insensitive prolongment of decay time and increase in frequency of GABAergic currents was established after Allo was removed from the bath for at least 30 min (LtAllo). Inhibition of protein kinase C (PKC) abolished these effects, suggesting that PKC is largely required to mediate Allo-induced inhibition of the DMV. Using mice that lack the δ-subunit of the GABAA receptor, we further confirmed that PKC-dependent activity of LtAllo required this subunit. Allo also potentiated GABAA receptor activity after a repeated application of δ-subunit agonist, suggesting that the presence of Allo encodes stronger δ-subunit-mediated inhibition over time. Using current clamp recording, we demonstrated that LtAllo-induced inhibition is sufficient to decrease action potential firing and excitability within DMV neurons. We conclude that the effects of LtAllo on GABAergic inhibition are dependent on δ-subunit and PKC activation. Taken together, DMV neurons can undergo long lasting Allo-dependent GABAA receptor plasticity.

The potential role of dexmedetomidine on neuroprotection and its possible mechanisms: Evidence from in vitro and in vivo studies.

Neurological disorders following brain injuries and neurodegeneration are on the rise worldwide and cause disability and suffering in patients. It is crucial to explore novel neuroprotectants. Dexmedetomidine, a selective α2-adrenoceptor agonist, is commonly used for anxiolysis, sedation and analgesia in clinical anaesthesia and critical care. Recent studies have shown that dexmedetomidine exerts protective effects on multiple organs. This review summarized and discussed the current neuroprotective effects of dexmedetomidine, as well as the underlying mechanisms. In preclinical studies, dexmedetomidine reduced neuronal injury and improved functional outcomes in several models, including hypoxia-induced neuronal injury, ischaemic-reperfusion injury, intracerebral haemorrhage, post-traumatic brain injury, anaesthetic-induced neuronal injury, substance-induced neuronal injury, neuroinflammation, epilepsy and neurodegeneration. Several mechanisms are associated with the neuroprotective function of dexmedetomidine, including neurotransmitter regulation, inflammatory response, oxidative stress, apoptotic pathway, autophagy, mitochondrial function and other cell signalling pathways. In summary, dexmedetomidine has the potential to be a novel neuroprotective agent for a wide range of neurological disorders.

In vivo Profiling of the Alk Proximitome in the Developing Drosophila Brain

Anaplastic lymphoma kinase (Alk) is an evolutionary conserved receptor tyrosine kinase belonging to the insulin receptor superfamily. In addition to its well-studied role in cancer, numerous studies have revealed that Alk signaling is associated with a variety of complex traits such as: regulation of growth and metabolism, hibernation, regulation of neurotransmitters, synaptic coupling, axon targeting, decision making, memory formation and learning, alcohol use disorder, as well as steroid hormone metabolism. In this study, we used BioID-based in vivo proximity labeling to identify molecules that interact with Alk in the Drosophila central nervous system (CNS). To do this, we used CRISPR/Cas9 induced homology-directed repair (HDR) to modify the endogenous Alk locus to produce first and next generation Alk::BioID chimeras. This approach allowed identification of Alk proximitomes under physiological conditions and without overexpression. Our results show that the next generation of BioID proteins (TurboID and miniTurbo) outperform the first generation BirA* fusion in terms of labeling speed and efficiency. LC-MS3-based BioID screening of AlkTurboID and AlkminiTurbo larval brains revealed an extensive neuronal Alk proximitome identifying numerous potential components of Alk signaling complexes. Validation of Alk proximitome candidates further revealed co-expression of Stardust (Sdt), Discs large 1 (Dlg1), Syntaxin (Syx) and Rugose (Rg) with Alk in the CNS and identified the protein-tyrosine-phosphatase Corkscrew (Csw) as a modulator of Alk signaling.

Antidepressant effect of acidic polysaccharides from Poria and their regulation of neurotransmitters and NLRP3 pathway

The rats were exposed to chronic unpredictable mild stress(CUMS) and kept in separate cages for inducing depressive disorder, which was judged by behavioral indicators. The number and morphology of neurons in hippocampal CA3 area and prefrontal cortex were observed by hematoxylin-eosin(HE) staining. The levels of brain-derived neurotrophic factor(BDNF), 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), norepinephrine(NE), glutamic acid(GLU), interleukin-1β(IL-1β), interleukin-18(IL-18), and tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay(ELISA). Real-time polymerase chain reaction(RT-PCR) and Western blot were conducted to determine the mRNA and protein expression levels of related molecules in NLRP3 pathway. The results showed that compared with the model group, acidic polysaccharides from Poria at the low-, medium-, and high-doses(0.1, 0.3 and 0.5 g·kg~(-1)·d~(-1)) all improved the depression-like behavior of rats, increased the number of neurons and the levels of BDNF, 5-HT, 5-HIAA, DA, and NE in the hippocampus, and reduced GLU and serum IL-1β, IL-18, and TNF-α levels. The mRNA expression levels of ASC, caspase-1, IL-1β, and IL-18 and the protein expression levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in each medication group were down-regulated, whereas the protein expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18 were up-regulated. All these have indicated that acidic polysaccharides from Poria exerted the antidepressant effect possibly by regulating neurotransmitters and NLRP3 inflammasome signaling pathway.

The combined use of gamma-aminobutyric acid and walnut peptide enhances sleep in mice.

γ-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid in the nervous system and has a wide range of physiological functions in the body. Walnut peptide (WP) contains high levels of arginine, aspartic acid, and glutamate, and has been shown to improve cognitive deficits and memory impairment in mice, while restoring antioxidant enzyme levels and reducing brain inflammatory mediators. This study investigated the effects of GABA and WP, either alone or in combination, on sleep disturbances in mice. The pentobarbital-prolonged sleep test, pentobarbital-threshold sleep test, and barbital-induced sleep test were conducted to assess the effects of GABA and WP on sleep quality by gavage for 30 days as follows: GABA (102.25 mg/kg), WP (102.25 mg/kg), GABA (33.95, 102.25, 306.75 mg/kg)/WP (102.25 mg/kg) mixture. Furthermore, neurotransmitter tests were performed using mice brain tissue to investigate the possible mechanisms of GABA and WP on sleep status. The results showed that the combined use of GABA and WP significantly increased sleep duration compared with single administration of either WP or GABA. Increasing doses of GABA in mice treated with combined GABA and WP elevated the sleep rate to 50.00%, 64.28%, and 64.28%, respectively, compared to mice treated with GABA alone (35.71%) or mice treated with WP alone (28.57%). In mice that received a combination of GABA and WP orally, the latency time was significantly decreased after 30 days compared to control mice (P<0.05). Additionally, in mice treated with GABA, WP, or the combination of GABA and WP, the concentrations of GABA and acetylcholine (Ach) in the brain were significantly elevated and the concentration of serotonin (5-HT) was decreased compared to untreated mice. These results demonstrated that the combined administration of GABA and WP could prolong the sleep duration, increase sleep rate, and shorten the sleep latency more effectively than the administration of either GABA or WP alone. The mechanisms of action may be related to the regulation of neurotransmitters in the brain tissue by the combination of GABA and WP.

Extracellular Vesicles Taken up by Astrocytes.

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes.