Modulation Of Neurotransmission Research Articles

Pharmacological manipulation of neurotransmitter activity induces disparate effects on cerebral blood flow and resting-state fluctuations

Abstract Functional MRI methods can assess aspects of drug-induced brain response. Resting blood oxygenation level dependent (BOLD) fMRI and arterial spin labeling (ASL) perfusion MRI indirectly measure brain function through the coupling of activity to cerebral blood flow (CBF) and oxygenation but their relative sensitivity has not been directly compared. We assessed changes in resting measures of BOLD and ASL MRI in response to two neurotransmitter modulators: citalopram, a selective serotonin reuptake inhibitor, and alprazolam, a positive allosteric modulator of GABA type A receptor. Thirty healthy subjects were imaged in a placebo-controlled study, with N=20 subjects receiving each treatment as part of an incomplete block design. Time-averaged CBF images from ASL and measures of resting-state fluctuations of BOLD and ASL images were assessed for significant effects. Following acute citalopram administration, analysis of the ASL data showed a reduction in time-averaged regional CBF in regions associated with high levels of 5-HT1A receptor density. In contrast, following alprazolam administration, BOLD amplitude of low frequency fluctuations showed a highly significant and cortically widespread increase, consistent with the distribution of GABA-A receptors. Only a marginal decrease in ASL CBF was detected after alprazolam intake. BOLD and ASL are each sensitive to drugs targeting neurotransmitter systems, but appear to reflect different aspects of neural metabolism and the balance between excitatory and inhibitory activity. Accordingly, their combination may best capture the effects of neurotransmitter modulations, and thus be advantageous for pharmacological MRI studies.

The Potential Role of Herbal Plants in the Management of Depression: Pre-Clinical and Clinical Evidence

Depression, a debilitating mental health disorder affecting millions worldwide, con-tinues to challenge the medical community. While several pharmacological interventions ex-ist, their efficacy and side effects often warrant the exploration of alternative treatments. Natu-ral products derived from plants have gained attention for their potential antidepressant prop-erties in preclinical studies. This comprehensive review examines the antidepressant activity of various plant-based extracts through preclinical investigations and explores the underlying mechanisms of action. Our review systematically analyzes the literature, encompassing a wide range of plants. We present evidence from pre-clinical and clinical studies, highlighting the behavioural and neurochemical changes induced by these plant-derived compounds. Further-more, we delve into the potential mechanisms of action, encompassing modulation of neuro-transmitters, anti-inflammatory effects, neurogenesis promotion, and antioxidant properties. The reviewed studies suggest that numerous plants possess promising antidepressant proper-ties, potentially offering novel therapeutic avenues. However, the variability in methodologies and the need for further clinical validation underscore the complexity of translating preclinical findings into effective treatments. This review serves as a valuable resource for researchers and clinicians alike, shedding light on the current state of knowledge regarding plants with an-tidepressant potential and their underlying mechanisms of action, paving the way for future investigations and therapeutic developments in the field of depression management.

Effects of Environmental Noise Stress on Mouse Metabolism

Environmental noise is associated with various health outcomes. However, the mechanisms through which these outcomes influence behavior and metabolism remain unclear. This study investigated how environmental noise affects the liver, adipose tissue, and brain metabolic functions, leading to behavioral and body weight changes. Mice were divided into a noise group exposed to construction noise and an unexposed (control) group. Behavior and body weight changes were monitored over 50 days. Early changes in response to noise exposure were assessed by measuring plasma cortisol and glial fibrillary acidic protein expression in brain tissues on days 1, 15, and 30. Chronic responses, including changes in lipoprotein and fat metabolism and neurotransmitters, were investigated by analyzing serum lipoprotein levels and body fat mass and evaluating liver, fat, and brain tissue after 50 days. The noise group showed higher locomotor activity and reduced anxiety in the open-field and Y-maze tests. Noise exposure caused an initial weight loss; however, chronic noise increased fat mass and induced adipocyte hypertrophy. Our findings underscore the role of environmental noise-induced stress in augmenting locomotor activity and reducing anxiety in mice through neurotransmitter modulation while increasing the risk of obesity by decreasing HDL cholesterol levels and promoting adipocyte hypertrophy.

Neuronutritional Approach to Fibromyalgia Management: A Narrative Review.

Fibromyalgia (FM) is a complex and common syndrome characterized by chronic widespread pain, fatigue, sleep disturbances, and various functional symptoms without clear structural or pathological causes. Affecting approximately 1-5% of the global population, with a higher prevalence in women, FM significantly impacts patients' quality of life, often leading to considerable healthcare costs and loss of productivity. Despite its prevalence, the etiology of FM remains elusive, with genetic, environmental, and psychological factors, including nutrition, being implicated. Currently, no universally accepted treatment guidelines exist, and management strategies are often symptomatic. This narrative review explores the potential of a neuronutritional approach to FM management. It synthesizes existing research on the relationship between FM and nutrition, suggesting that dietary interventions could be a promising complementary treatment strategy. Various nutritional interventions, including vitamin D, magnesium, iron, and probiotics supplementation, have shown potential in reducing FM symptoms, such as chronic pain, anxiety, depression, cognitive dysfunction, sleep disturbances, and gastrointestinal issues. Additionally, weight loss has been associated with reduced inflammation and improved quality of life in FM patients. The review highlights the anti-inflammatory benefits of plant-based diets and the low-FODMAPs diet, which have shown promise in managing FM symptoms and related gastrointestinal disorders. Supplements such as vitamin D, magnesium, vitamin B12, coenzyme Q10, probiotics, omega-3 fatty acids, melatonin, S-adenosylmethionine, and acetyl-L-carnitine are discussed for their potential benefits in FM management through various mechanisms, including anti-inflammatory effects, modulation of neurotransmitters, and improvement of mitochondrial function. In conclusion, this review underscores the importance of considering neuronutrition as a holistic approach to FM treatment, advocating for further research and clinical trials to establish comprehensive dietary guidelines and to optimize management strategies for FM patients.

Peripheral Nerve Stimulation for Neuropathic Pain Management: A Narrative Review.

This narrative review examines the therapeutic efficacy of peripheral nerve stimulation (PNS) in the treatment of neuropathic pain (NP), a type of pain arising from lesions or diseases of the somatosensory system with a global prevalence ranging from 6.90% to 10.00%. Traditional pharmacological interventions often fall short for many persons, highlighting the need for alternative treatments such as PNS, which has demonstrated significant promise with minimal side effects. The review summarizes the effectiveness of PNS in various NP conditions, including trigeminal neuralgia and postherpetic neuralgia, and underscores the need for further research to refine treatment approaches. The mechanism of PNS is discussed, involving the activation of non-nociceptive Aβ fibers and modulation of neurotransmitters, and offering pain relief through both peripheral and central pathways. Despite the proven efficacy of PNS, challenges remain, including the need for randomized controlled trials and the optimization of stimulation parameters. The review concludes that PNS is a promising treatment modality for NP, warranting additional high-quality trials to solidify its role in clinical practice.

Buprenorphine for the Treatment of Military-related PTSD With Treatment-resistant Depression and Unexpected Benefit for Chronic Pain: Case Report.

The prevalence of treatment-resistant depression within global and military populations highlights the need for novel treatment approaches beyond monoamine neurotransmitter modulators. Buprenorphine (BUP), a semi-synthetic partial opioid agonist, is approved for the treatment of opioid use disorder and has shown promise in treating both depression and chronic pain. This case report discusses the use of transdermal BUP in treating a 36 year-old man with treatment-resistant depression with prominent anhedonia, military-related posttraumatic stress disorder, and chronic pain because of barosinusitis. Significant reductions in anxious and depressive symptoms, including in anhedonia, were observed with lasting effects. An unexpected finding was the discontinuation of prescribed hydromorphone for pain, suggesting the potential unique benefit of BUP in treating chronic pain and treatment resistant depression comorbidities. These findings implicate the diverse beneficial potential of BUP in psychiatric treatments for military populations.

Modulation of Neurotransmission by Acid-Sensing Ion Channels.

Interstitial pH fluctuations occur normally in the brain and significantly modulate neuronal functions. Acid-sensing ion channels (ASICs), which serve as neuronal acid chemosensors, play important roles in synaptic plasticity, learning, and memory. However, the specific mechanisms by which ASICs influence neurotransmission remain elusive. Here, we report that ASICs modulate transmitter release and axonal excitability at a glutamatergic synapse in the rat and mouse hippocampus. Blocking ASIC1a channels with the tarantula peptide psalmotoxin 1 down-regulates basal transmission and alters short-term plasticity. Notably, the effect of psalmotoxin 1 on ASIC-mediated modulation is age-dependent, occurring only during a limited postnatal period (postnatal weeks 2-6). This finding suggests that protons, through the activation of ASICs, may act as modulators in synapse formation and maturation during early development.

Multi-omics analysis of gut-brain axis reveals novel microbial and neurotransmitter signatures in patients with arteriosclerotic cerebral small vessel disease

Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as Faecalibacterium prausnitzli and Roseburia intestinalis, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target.

Neuroprotective role of chlorogenic acid against hippocampal neuroinflammation, oxidative stress, and apoptosis following acute seizures induced by pentylenetetrazole.

This study investigated the neuroprotective effect of chlorogenic acid (CGA) on pentylenetetrazole (PTZ)-induced acute epileptic seizures in mice. Epileptic animals received CGA (200mg/kg) or sodium valproate (standard antiepileptic agent, 200mg/kg) for four weeks. Results revealed that pre-administration of CGA significantly reversed the behavioral changes following pentylenetetrazole (PTZ) injection. Further, CGA pre-treatment caused significant increases in acetylcholinesterase (AChE) activity and brain-derived neurotrophic factor (BDNF) levels, along with marked increases in dopamine, norepinephrine, and serotonin levels. Additionally, the increased antioxidant enzymes activities, along with higher glutathione (GSH) contents and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression, were indicative of a notable improvement in the cellular antioxidant defense in mice treated with CGA. These results were associated with lowered malondialdehyde (MDA) and nitric oxide (NO) levels. Moreover, epileptic mice that received CGA showed significant declines in the content of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and nuclear factor kappa-B (NF-κB), besides downregulating inducible nitric oxide synthase (iNOS) expression. Remarkably, CGA counteracted hippocampal apoptosis by lessening the levels of pro-apoptotic biomarkers [Bcl-2-associated X protein (Bax) and caspase-3] and increasing the anti-apoptogenic marker level of B-cell lymphoma 2 (Bcl-2). The hippocampal histopathological findings corroborated the abovementioned changes. In sum, these findings suggest that CGA could mediate the neuroprotective effect against PTZ-induced epilepsy via modulation of neurotransmitters, oxidative damage, neuroinflammation, and apoptosis. CGA, therefore, could be considered a valuable antiepileptic therapeutic supplement.

Effects of acupuncture on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats

To observe the effects of acupuncture at "antihypertensive acupoint prescription" on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats, and explore the vascular regulation and central regulation mechanisms of acupuncture for anti-hypertension. Thirty SPF grade male spontaneous hypertension rats were randomly divided into a model group (15 rats) and an acupuncture group (15 rats). Besides, 15 Wistar Kyoto rats were collected as a blank control group (normal group). In the acupuncture group, acupuncture was delivered at the "antihypertensive acupoint prescription" (bilateral "Renying" [ST 9], "Quchi" [LI 11], "Zusanli" [ST 36], "Taichong" [LR 3] and "Neiguan" [PC 6]), with needles retained for 30 min, once daily. The duration of intervention was 28 days. Every week, using the the irritation scale, the sign of sympathetic irritation was evaluated dynamically. The arterial blood pressure of the rats tail was determined, using non-invasive blood pressure measurement system. ELISA was adopted to detect the levels of calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1 (ET-1), neuropeptide Y (NPY) in the serum. DAB chromogenic in situ hybridization (CISH) was provided to detect the mRNA expression of endothelial nitric oxide synthase (eNOS) in the internal carotid artery and the arcuate nucleus (ARC), and that of CGRP in the paraventricular nucleus posterior (PVP) and the ventrolateral medulla (VLM). Liquid chromatography-mass spectrometry (LC-MS) was used to detect the levels of epinephrine (E) and norepinephrine (NE) in the paraventricular nucleus anterior (PVA). Compared with the normal group, the irritation scores, systolic blood pressure and diastolic blood pressure were increased at each time point in the model group (P<0.05). When compared with the model group, the irritation scores after the intervention for 3 and 4 weeks, and systolic and diastolic blood pressure after intervention for 2, 3 and 4 weeks were reduced in the acupuncture group (P<0.05). In comparison with the normal group, the serum CGRP and NO levels of the rats were decreased (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels in PVA were increased (P<0.05) in the model group. The levels of serum CGRP and NO were elevated (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels of PVA were reduced (P<0.05) in the acupuncture group when compared with those of the model group. In the model group, the media of internal carotid artery exhibited thickening and remodeling, while the neuron volume in ARC was small. In the acupuncture group, every layer of internal carotid artery was acceptably arranged, and the parvicellular neuron of ARC was moderate in volume. For the in situ hybridization of eNOS mRNA for the rats of each group, the smooth muscle cells were predominantly expressed in each layer of the internal carotid artery, whereas the expression of parvicellular neurons was dominated in ARC. In the model group, the large and small neurosecretory cells were distributed sparsely in the nerves of PVP; in the acupuncture group, the cells of these two species were distributed regularly; and there were few species of glial cell in the VLM of either the model group or the acupuncture group. In each group, for the in situ hybridization of CGRP mRNA, the small neurosecretory cells were expressed predominately in the PVP, while, the expression of glial cell nuclei and the cell cytoplasm was dominated in the VLM. Compared with the normal group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP mRNA in the PVP and VLM was decreased in the model group (P<0.05). In the acupuncture group, when compared with the model group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP in the PVP and VLM was increased in the acupuncture group (P<0.05). Acupuncture at "antihypertensive acupoint prescription" can upregulate the level of vascular relaxing factors, downregulate the level of contracting factors, enhance the response of relaxing factors in targeting blood vessels and regulating the center. The mechanism may be related to the modulation of the sympathetic-adrenergic autonomic neurotransmitters in the paraventricular nucleus in spontaneous hypertension rats.

Preclinical efficacy profiles of the sigma-1 modulator E1R and of fenfluramine in two chronic mouse epilepsy models.

Given its key homeostatic role affecting mitochondria, ionotropic and metabotropic receptors, and voltage-gated ion channels, sigma-1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. Although modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance. To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE-100. Whereas E1R exerted pronounced dose-dependent antiseizure effects at well-tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine, without a clear dose dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE-100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre-exposure to NE-100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine's antiseizure effects. In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad-spectrum potential of fenfluramine.

Dairy and Headaches: What is the Connection?

Headaches represent a prevalent and burdensome health condition, affecting individuals of all ages worldwide. While dietary factors have been implicated in headache pathophysiology, the association between dairy consumption and headaches remains controversial and inadequately understood. This comprehensive review systematically examines the existing literature to elucidate the relationship between dairy intake and headaches, addressing methodological challenges, potential biases, and gaps in the current knowledge. A thorough search of electronic databases identified relevant observational studies, clinical trials, and mechanistic investigations exploring the impact of dairy consumption on headache incidence, frequency, severity, and duration. Methodological considerations, including study design, measurement of exposure and outcome variables, confounding factors, and sources of bias, were critically evaluated to assess the strength of evidence and validity of findings. Despite heterogeneity across studies, emerging evidence suggests a complex and multifaceted relationship between dairy intake and headaches, influenced by individual characteristics, dietary patterns, headache subtype, and study context. While some studies report a positive association between dairy consumption and headaches, others indicate no significant effect or potential therapeutic benefits of dairy restriction. Mechanistic insights suggest plausible biological mechanisms, including neuroinflammatory pathways, neurotransmitter modulation, vascular effects, and gut-brain interactions, which may mediate the observed associations. Future research directions encompass longitudinal studies, mechanistic investigations, stratified analyses, randomized controlled trials, and exploration of the gut microbiota to further elucidate the underlying mechanisms and inform evidence-based dietary recommendations for headache management. This integrative review underscores the importance of interdisciplinary collaboration and personalized approaches to address the complex interplay between diet, headaches, and overall health.

Neuroprotective Efficacy and Complementary Treatment with Medicinal Herbs: A Comprehensive Review of Recent Therapeutic Approaches in Epilepsy Management.

Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment. Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices. Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures. In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.

The Impact of Antidepressants on Gut Microbiome and Depression Management

Depression is a widespread psychiatric disorder that significantly impacts an individual’s quality of life. It affects mental and emotional well-being and has far-reaching consequences on their physical health, relationships, and overall ability to function in daily life. Recent advances in psychiatric research have revealed a connection between the gut-brain axis, a bidirectional communication system linking the brain's emotional and cognitive centers with intestinal functions. Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), are commonly prescribed to alleviate symptoms of depression. However, their influence extends beyond neurotransmitter modulation in the brain to significant effects on gastrointestinal physiology. Antidepressants can alter gut motility, secretion, and microbiota composition, which in turn can influence mood and mental health. This review aims to provide insights into the impact of antidepressants on gut health and their implications for depression treatment. Additionally, it explores the potential of probiotics as an adjunct treatment to enhance the efficacy of antidepressants and mitigate gastrointestinal side effects. Restoring healthy gut microbiota can improve gastrointestinal and mental health outcomes, suggesting a promising avenue for integrated therapeutic approaches.

Histamine in the neocortex: Towards integrating multiscale effectors.

Histamine is a modulatory neurotransmitter, which has received relatively less attention in the central nervous system than other neurotransmitters. The functional role of histamine in the neocortex, the brain region that controls higher-order cognitive functions such as attention, learning and memory, remains largely unknown. This article focuses on the emerging roles and mechanisms of histamine release in the neocortex. We describe gaps in current knowledge and propose the application of interdisciplinary tools to dissect the detailed multiscale functional logic of histaminergic action in the neocortex ranging from sub-cellular, cellular, dendritic and synaptic levels to microcircuits and mesoscale effects.

Auranofin-loaded PLGA nanoparticles alleviate cognitive deficit induced by streptozotocin in rats model: modulation of oxidative stress, neuroinflammatory markers, and neurotransmitters.

Alzheimer's disease remains an unsolved neurological puzzle with no cure. Current therapies offer only symptomatic relief, hindered by limited uptake through the blood-brain barrier. Auranofin, an FDA-approved compound, exhibits potent antioxidative and anti-inflammatory properties targeting brain disorders. Yet, its oral bioavailability challenge prompts the exploration of nanoformulation-based solutions enhancing blood-brain barrier penetrability. The study aimed to investigate the neuroprotective potential of auranofin nanoparticles in streptozotocin-induced AD rats. Auranofin-containing polylactic-co-glycolic acid nanoparticles were formulated by the multiple emulsion solvent evaporation method. Characterization was done by determining entrapment efficiency, particle size distribution, surface charge, and morphology. An in vivo study was performed by administering streptozotocin (3mg/kg/i.c.v., days 1 and 3), auranofin (5 and 10mg/kg), auranofin nanoparticles (2.5 and 5mg/kg), and donepezil (2mg/kg) for 14days orally. Behavioral deficits were evaluated using the open field test, Morris water maze, objective recognition test, change in oxidative stress levels, and AD markers in the brain. Following the decapitation of the rats, the brains were excised to isolate the hippocampus. Subsequent analyses included the quantification of biochemical and neuroinflammatory markers, as well as the assessment of neurotransmitter levels. The characterization of auranofin nanoparticles showed an entrapment efficiency of 98%, an average particle size of 101.5 ± 10.3nm, a surface charge of 27.5 ± 5.10mV, and a polydispersity index of 0.438 ± 0.12. In vivo, administration of auranofin and auranofin nanoparticles significantly reversed streptozotocin-induced cognitive deficits, biochemical alteration, neuroinflammatory markers, and neurotransmitter levels. The present finding suggests that auranofin nanoparticles have more significant neuroprotective potential than auranofin alone. The therapeutic efficacy may be attributed to its antioxidant and anti-inflammatory properties, as well as its positive neuromodulatory effects. Therefore, our findings suggest that it could be a promising candidate for Alzheimer's disease therapy.

Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor.

The intricate signaling network within the central nervous system (CNS) involving N-methyl-d-aspartate receptors (NMDARs) has been recognized as a key player in severe neurodegenerative diseases. The indirect modulation of NMDAR-mediated neurotransmission through inhibition of serine racemase (SR)-the enzyme responsible for the synthesis of the NMDAR coagonist d-serine-has been suggested as a therapeutic strategy to treat these conditions. Despite the inherent challenges posed by SR conformational flexibility, a ligand-based drug design strategy has successfully produced a series of potent covalent inhibitors structurally related to amino acid analogues. Among these inhibitors, O-(2-([1,1'-biphenyl]-4-yl)-1-carboxyethyl)hydroxylammonium chloride (28) has emerged as a valuable candidate with a K d of about 5 μM, which makes it one of the most potent hSR inhibitors reported to date. This molecule is expected to inspire the identification of selective hSR inhibitors that might find applications as tools in the study and treatment of several CNS pathologies.

Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity.

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.

Intellectual Deepening Influences the Development and Expression of Introversion

This scholarly investigation delves into the neurological interplay between enhanced intellectual engagement and social interaction preferences, focusing on the critical role of specific brain regions and neurotransmitter modulation. Activation patterns in the hippocampus and the prefrontal cortex, particularly influenced by neurotransmitters such as dopamine and serotonin, are explored in relation to their impact on memory enhancement and social motivation. Elevated activity in these brain areas can enhance retention of intellectually stimulating stimuli, potentially fostering social isolation. This research elucidates the neurochemical variations that influence social engagement capacities and clarifies the underlying biological mechanisms predisposing highly intellectual individuals to favor isolation over less stimulating social interactions. This study aims to deepen the understanding of how neuroanatomical and neurochemical dynamics shape introverted behaviors and preference for solitary activities, thereby influencing social integration processes.

Efficacy and Safety of Intravenous Magnesium Sulfate in Spinal Surgery: A Systematic Review and Meta-Analysis.

Optimizing pain management in spinal surgery is crucial for preventing adverse events due to delayed mobilization. Magnesium sulfate has potential benefits in spinal surgery because of its analgesic properties and modulation of neurotransmitters and autonomic nervous system. Existing evidence regarding the use of magnesium sulfate is partial and controversial, necessitating a comprehensive meta-analysis to evaluate its efficacy and safety. The aim of this study was to conduct a comprehensive meta-analysis to evaluate the efficacy and safety of magnesium sulfate in spinal surgery compared to other available options. This meta-analysis adhered to the PRISMA guidelines. Patients undergoing spinal surgery were included, with the intervention group receiving intravenous magnesium sulfate (MS) at various doses or combinations, whereas the comparison group received other alternatives or a placebo. The efficacy and safety outcomes were assessed. Data were collected from multiple databases and analyzed using Review Manager version 5.4. Heterogeneity was assessed and fixed- or random-effects models were applied. The meta-analysis included eight studies (n = 541). Magnesium sulfate demonstrated significant reductions in pain at 24 h (MD -0.20, 95% CI: -0.39 to -0.02) and opioid consumption (SMD -0.66, 95% CI: -0.95 to -0.38) compared to placebo. Additionally, a decrease in the use of muscle relaxants (SMD -0.91, 95% CI: -1.65 to -0.17) and remifentanil (SMD -1.52, 95% CI: -1.98 to -1.05) was observed. In contrast, an increase in extubation time (MD 2.42, 95% CI: 1.14 to 3.71) and verbal response (MD 1.85, 95% CI: 1.13 to 2.58) was observed compared to dexmedetomidine. In conclusion, magnesium sulfate administration in spinal surgery reduced pain and opioid consumption, and prolonged orientation and verbal response. No significant differences in blood pressure or heart rate were observed between the groups.