Processes In Central Nervous System Research Articles

Advances in drug design and therapeutic potential of selective or multitarget 5-HT1A receptor ligands.

5-HT1A receptor (5-HT1A-R) is a serotoninergic G-protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5-HT-R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure-activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5-HT1A-R selective/preferential ligands; (ii) identification of 5-HT1A-R biased agonists, differentiating pre- versus post-synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well-defined poly-pharmacological profiles targeting 5-HT1A-R along with other serotonin receptors, serotonin transporter (SERT), D2-like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5-HT1A-R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017-2023) have been discussed. The development of chemical and pharmacological 5-HT1A-R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5-HT1A-R and the therapeutic potential of ligands targeting this receptor have been considered.

Abstract 4392: Neuropeptide Y system in glioblastoma

Abstract Gliomas constitute the most common primary cerebral tumors of the central nervous system (CNS), with glioblastoma (GBM) representing the most aggressive subtype. Neurotransmitters are important players in maintaining physiological processes in CNS and abnormal levels of their expression is pathogenic, leading to different processes, including neoplasia. Neuropeptide Y (NPY) is one of the neurotransmitters that is found to play a pivotal role in several malignancies. NPY, acting via its cognate receptors Y1, Y2 and Y5 (Y1R, Y2R and Y5R), has been shown to stimulate cancer cell proliferation, migration, invasiveness and dissemination, as well as tumor vascularization in various malignancies including neuroblastoma, Ewing sarcoma, colon, breast, prostate and liver cancers. Thus, the goal of this study was to determine if the NPY system is involved in glioma biology. Our immunohistochemistry staining of NPY, Y1R, Y2R, and Y5R in human GBM tissues revealed positive staining for NPY and Y2R in GBM cells. No expression of Y1R and Y5R was detected in GBM neoplastic population. To further elucidate the association between NPY and its receptors with GBM tumor stage and patients' survival, we used the available clinical data from the Cancer Genome Atlas Program (TCGA) database to analyze the gene expression of the NPY system. Y2R expression was increased in high-grade gliomas, while mRNA levels of NPY, Y1R and Y5R inversely correlated with the degree of glioma malignancy. Moreover, high Y2R expression was associated with worse survival in GBM patients. Importantly, endothelial Y2R is also responsible for angiogenic effects of NPY, suggesting its role in GBM vascularization. Altogether, these data suggest the involvement of NPY/Y2R axis in glioma progression toward more aggressive phenotype. Further functional studies are required to determine the role of the Y2R axis in this process. Citation Format: Nouran Abualsaud, Jason Tilan, Bahauddeen M. Alrfaei, Harrison Glor, Taylor Polk, Ewa Izycka-Swieszewska, Joanna Kitlinska. Neuropeptide Y system in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4392.

Platelet-activating factor receptor (PAFR) regulates neuronal maturation and synaptic transmission during postnatal retinal development.

Platelet-activating factor (PAF), PAF receptor (PAFR), and PAF- synthesis/degradation systems are involved in essential CNS processes such as neuroblast proliferation, differentiation, migration, and synaptic modulation. The retina is an important central nervous system (CNS) tissue for visual information processing. During retinal development, the balance between Retinal Progenitor Cell (RPC) proliferation and differentiation is crucial for proper cell determination and retinogenesis. Despite its importance in retinal development, the effects of PAFR deletion on RPC dynamics are still unknown. We compared PAFR knockout mice (PAFR-/-) retinal postnatal development proliferation and differentiation aspects with control animals. Electrophysiological responses were analyzed by electroretinography (ERG). In this study, we demonstrate that PAFR-/- mice increased proliferation during postnatal retinogenesis and altered the expression of specific differentiation markers. The retinas of postnatal PAFR-/- animals decreased neuronal differentiation and synaptic transmission markers, leading to differential responses to light stimuli measured by ERG. Our findings suggest that PAFR signaling plays a critical role in regulating postnatal RPC cell differentiation dynamics during retinal development, cell organization, and neuronal circuitry formation.

Clinical observations in acute neurology: A historical explanation of the present.

The history of the development of acute neurologic disease as a biologic mechanism is of interest. Equally important is how it translated to the bedside and how the clinical examination differentiated itself. This paper reviews primary sources pertaining to acute neurologic conditions described mostly in the 19th and 20th century. A review of monographs, treatises, textbooks, and peer-reviewed articles was conducted. The evolution of clinical signs and syndromes associated with dynamic intracranial pathologies was predicated on the idea that animal studies informed clinicians, who then linked clinical signs to these observations. A dominant theme is that innovative technologies could trace acute processes through all their various stages, affording a complete picture of the disease process. Just as clinical descriptors of central nervous system processes evolved, the presentation of acute neuromuscular respiratory failure became better defined. Once practices incorporated these acute clinical signs, textbooks cemented their "gold standard" status with relative impunity. The practise of acute neurology and neurocritical care must find out what, historically, others were seeking but could not find. Patterns of clinical presentation in acute neurology are sufficiently recognizable to guide practise decisions. Although, the currently well-documented clinical syndromes of acute neurologic conditions (at presentation and during deterioration) have been taught for generations, practitioners have noted that they lack consistency and predictability. History also taught us that part of this improved knowledge came with designated units-a clear example of how protean systems (not always innovative neurologists or neuroscientists or technologies) shaped the history of neurology.

Isolation and monoculture of functional primary astrocytes from the adult mouse spinal cord.

Astrocytes are a widely heterogenic cell population that play major roles in central nervous system (CNS) homeostasis and neurotransmission, as well as in various neuropathologies, including spinal cord injury (SCI), traumatic brain injury, and neurodegenerative diseases, such as amyotrophic lateral sclerosis. Spinal cord astrocytes have distinct differences from those in the brain and accurate modeling of disease states is necessary for understanding disease progression and developing therapeutic interventions. Several limitations to modeling spinal cord astrocytes in vitro exist, including lack of commercially available adult-derived cells, lack of purchasable astrocytes with different genotypes, as well as time-consuming and costly in-house primary cell isolations that often result in low yield due to small tissue volume. To address these issues, we developed an efficient adult mouse spinal cord astrocyte isolation method that utilizes enzymatic digestion, debris filtration, and multiple ACSA-2 magnetic microbead purification cycles to achieve an astrocyte monoculture purity of ≅93-98%, based on all markers assessed. Importantly, the isolated cells contain active mitochondria and express key astrocyte markers including ACSA-1, ACSA-2, EAAT2, and GFAP. Furthermore, this isolation method can be applied to the spinal cord of male and female mice, mice subjected to SCI, and genetically modified mice. We present a primary adult mouse spinal cord astrocyte isolation protocol focused on purity, viability, and length of isolation that can be applied to a multitude of models and aid in targeted research on spinal-cord related CNS processes and pathologies.

The oral-brain axis: can periodontal pathogens trigger the onset and progression of Alzheimer's disease?

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a progressive cognitive decline. Sporadic AD, accounting for more than 95% of cases, may arise due to the influence of environmental factors. It was reported that periodontitis, a common oral ailment, shares several risk factors with AD, including advanced age, smoking, diabetes, and hypertension, among others. Periodontitis is an inflammatory disease triggered by dysbiosis of oral microorganisms, whereas Alzheimer's disease is characterized by neuroinflammation. Many studies have indicated that chronic inflammation can instigate brain AD-related pathologies, including amyloid-β plaques, Tau protein hyperphosphorylation, neuroinflammation, and neurodegeneration. The potential involvement of periodontal pathogens and/or their virulence factors in the onset and progression of AD by the oral-brain axis has garnered significant attention among researchers with ongoing investigations. This review has updated the periodontal pathogens potentially associated with AD, elucidating their impact on the central nervous system, immune response, and related pathological processes in the brain to provide valuable insights for future research on the oral-brain axis.

Research progress on the pathogenesis of chest tightness variant asthma characterized by chest tightness.

Chest tightness variant asthma (CTVA) is an atypical form of asthma with chest tightness as the sole or predominant symptom. The underlying receptors for chest tightness are bronchial C-fibers or rapidly adapting receptors. The nerve impulses are transmitted via the vagus nerve and processed in different regions of the cerebral cortex. Chest tightness is associated with sensory perception, and CTVA patients may have heightened ability to detect subtle changes in lung function, but such sensory perception is unrelated to respiratory muscle activity, lung hyperinflation, or mechanical loading of the respiratory system. Airway inflammation, pulmonary ventilation dysfunction (especially involving small airways), and airway hyperresponsiveness may underlie the sensation of chest tightness. CTVA patients are prone to comorbid anxiety and depression, which share similar central nervous system processing pathways with dyspnea, suggesting a possible neurological basis for the development of CTVA. This article examines the recognition and mechanisms of chest tightness, and explores the pathogenesis of CTVA, focusing on its association with airway inflammation, ventilation dysfunction, airway hyperresponsiveness, and psychosocial factors.

Transforming growth factor-β1 protects against white matter injury and reactive astrogliosis via the p38 MAPK pathway in rodent demyelinating model.

In central nervous system (CNS), demyelination is a pathological process featured with a loss of myelin sheaths around axons, which is responsible for the diseases of multiple sclerosis, neuromyelitis optica, and so on. Transforming growth factor-beta1 (TGF-β1) is a multifunctional cytokine participating in abundant physiological and pathological processes in CNS. However, the effects of TGF-β1 on CNS demyelinating disease and its underlying mechanisms are controversial and not well understood. Herein, we evaluated the protective potential of TGF-β1 in a rodent demyelinating model established by lysophosphatidylcholine (LPC) injection. It was identified that supplement of TGF-β1 evidently rescued the cognitive deficit and motor dysfunction in LPC modeling mice assessed by novel object recognition and balance beam behavioral tests. Besides, quantified by luxol fast blue staining, immunofluorescence, and western blot, administration of TGF-β1 was found to significantly ameliorate the demyelinating lesion and reactive astrogliosis by suppressing p38 MAPK pathway. Mechanistically, the results of invitro experiments indicated that treatment of TGF-β1 could directly promote the differentiation and migration of cultured oligodendrocytes. Our study revealed that modulating TGF-β1 activity might serve as a promising and innovative therapeutic strategy in CNS demyelinating diseases.

PROFILE OF NITRIC OXIDE METABOLISM INDICATORS IN PRETERM INFANTS WITH PERINATAL CENTRAL NERVOUS SYSTEM INJURIES

Introduction. Premature infants often experience a heightened risk of brain damage, potentially leading to various disorders affecting motor, cognitive, behavioral, social, and sensory functions. The underlying pathological processes of hypoxic-ischemic central nervous system (CNS) injury predominantly stem from compromised cerebral blood flow and oxygen transport. Timely diagnosis and treatment options for prematurely born children with perinatal CNS damage remain limited. Nitric oxide, a universal regulator of physiological functions, plays a crucial role. Endothelial dysfunction, marked by the loss of the neurovascular protective functions of nitric oxide, could significantly contribute to the development of cognitive impairment in hypoxic-ischemic CNS damage. Objectives. The study aims to evaluate the specificities of nitrate metabolism indicators in premature infants with hypoxic-ischemic CNS lesions in the early neonatal period. This involves examining and comparing clinical indicators characterizing hemodynamics, as well as the levels of nitrites, nitrates, and nitrosothiols in urine among patients in the studied groups. Subjects and Methods. The study comprised 14 premature infants with hypoxic-ischemic CNS injury (main group), with a separate selection of 4 infants who did not survive during the neonatal period. The comparison group included 20 relatively healthy prematurely born children. Stratification was based on the results of a genetic study, specifically the determination of the rs61722009 polymorphism of the eNOS gene. The patients underwent routine clinical examinations, including blood pressure measurements, and assessments of nitrates, nitrites, and nitrosothiols in urine. Subgroups were identified as follows: 1st subgroup - 4bb (n=10), and 2nd subgroup - 4aa/4ab (n=10). Results. It was observed that newborns who did not survive had significantly lower systolic and diastolic blood pressure readings on the first day of life, in comparison to relatively healthy children in the two control subgroups (day 1 - p=0.018; p=0.027; p=0.036; p=0.053). Additionally, they exhibited lower heart rate indicators on the first day (p=0.001; p=0.002). However, overall, hemodynamic indicators in newborns with hypoxic-ischemic central nervous system damage did not show statistically significant differences from the corresponding indicators in relatively healthy children. The results indicate a significantly lower level of diuresis in children who died as a result of severe with hypoxic-ischemic central nervous system damage, probably due to the development of multiple organ failure immediately after birth. As a result, it was found that the levels of nitrites (p<0.001; p<0.0001) and nitrates (p<0.01; p<0.0001) were reduced in children with with hypoxic-ischemic central nervous system damage, compared to children in the control groups, regardless of genotype variant. While the level of nitrosothiols did not differ significantly, it was even much higher in children who did not survive, 3.55±0.39 vs 2.23±0.22; p=0.008. The differences found may indicate a disruption of the regulatory effect of nitric oxyde on vascular tone and the condition of neuroglia, particularly in children with hypoxic-ischemic central nervous system damage, as a result of its insufficient production, as well as insufficient mobilization from the depot due to nitrite and nitrate reductases. Conclusions. Hemodynamic patterns in children from the examined groups, except for those who did not survive, did not exhibit significant differences. The notably lower urine output in deceased children indicates the development of multiple organ failure due to severe hypoxia. In children with hypoxic-ischemic central nervous system damage, there is a reduction in the levels of nitrites and nitrates in urine compared to relatively healthy premature infants, while the level of nitrosothiols did not show significant differences and was even notably higher in children who did not survive. The outcome of studying the levels of nitrates, nitrites, and nitrosothiols in urine in a larger patient sample may lead to the development of an algorithm for early diagnosis and management, contingent on the severity of metabolic disorders resulting from hypoxia, considering the potential influence of nitric oxide on energy deficit and mitochondrial dysfunction.

Astrocytes and microglia in the coordination of CNS development and homeostasis.

Glia have emerged as important architects of central nervous system (CNS) development and maintenance. While traditionally glial contributions to CNS development and maintenance have been studied independently, there is growing evidence that either suggests or documents that glia may act in coordinated manners to effect developmental patterning and homeostatic functions in the CNS. In this review, we focus on astrocytes, the most abundant glia in the CNS, and microglia, the earliest glia to colonize the CNS highlighting research that documents either suggestive or established coordinated actions by these glial cells in various CNS processes including cell and/or debris clearance, neuronal survival and morphogenesis, synaptic maturation, and circuit function, angio-/vasculogenesis, myelination, and neurotransmission. Some molecular mechanisms underlying these processes that have been identified are also described. Throughout, we categorize the available evidence as either suggestive or established interactions between microglia and astrocytes in the regulation of the respective process and raise possible avenues for further research. We conclude indicating that a better understanding of coordinated astrocyte-microglial interactions in the developing and mature brain holds promise for developing effective therapies for brain pathologies where these processes are perturbed.

Sirtuins as Potential Targets for Neuroprotection: Mechanisms of Early Brain Injury Induced by Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a prevalent cerebrovascular disease with significant global mortality and morbidity rates. Despite advancements in pharmacological and surgical approaches, the quality of life for SAH survivors has not shown substantial improvement. Traditionally, vasospasm has been considered a primary contributor to death and disability following SAH, but anti-vasospastic therapies have not demonstrated significant benefits for SAH patients' prognosis. Emerging studies suggest that early brain injury (EBI) may play a crucial role in influencing SAH prognosis. Sirtuins (SIRTs), a group of NAD + -dependent deacylases comprising seven mammalian family members (SIRT1 to SIRT7), have been found to be involved in neural tissue development, plasticity, and aging. They also exhibit vital functions in various central nervous system (CNS) processes, including cognition, pain perception, mood, behavior, sleep, and circadian rhythms. Extensive research has uncovered the multifaceted roles of SIRTs in CNS disorders, offering insights into potential markers for pathological processes and promising therapeutic targets (such as SIRT1 activators and SIRT2 inhibitors). In this article, we provide an overview of recent research progress on the application of SIRTs in subarachnoid hemorrhage and explore their underlying mechanisms of action.

Non-invasive central nervous system assessment of a porcine model of neuropathic pain demonstrates increased latency of somatosensory-evoked potentials

BackgroundThe study of chronic pain and its treatments requires a robust animal model with objective and quantifiable metrics. Porcine neuropathic pain models have been assessed with peripheral pain recordings and behavioral responses, but thus far central nervous system electrophysiology has not been investigated. This work aimed to record non-invasive, somatosensory-evoked potentials (SEPs) via electroencephalography in order to quantitatively assess chronic neuropathic pain induced in a porcine model.New method: Peripheral neuritis trauma (PNT) was induced unilaterally in the common peroneal nerve of domestic farm pigs, with the contralateral leg serving as the control for each animal. SEPs were generated by stimulation of the peripheral nerves distal to the PNT and were recorded non-invasively using transcranial electroencephalography (EEG). The P30 wave of the SEP was analyzed for latency changes. ResultsP30 SEPs were successfully recorded with non-invasive EEG. PNT resulted in significantly longer P30 SEP latencies (p < 0.01 [n = 8]) with a median latency increase of 14.3 [IQR 5.0 – 17.5] ms. Histological results confirmed perineural inflammatory response and nerve damage around the PNT nerves.Comparison with existing method(s): Control P30 SEPs were similar in latency and amplitude to those previously recorded invasively in healthy pigs. Non-invasive recordings have numerous advantages over invasive measures. ConclusionsP30 SEP latency can serve as a quantifiable neurological measure that reflects central nervous system processing in a porcine model of chronic pain. Advancing the development of a porcine chronic pain model will facilitate the translation of experimental therapies into human clinical trials.

Alzheimer’s Disease Diagnosis Using Machine Learning: A Survey

Alzheimer’s is a neurodegenerative disorder affecting the central nervous system and cognitive processes, explicitly impairing detailed mental analysis. Throughout this condition, the affected individual’s cognitive abilities to process and analyze information gradually deteriorate, resulting in mental decline. In recent years, there has been a notable increase in endeavors aimed at identifying Alzheimer’s disease and addressing its progression. Research studies have demonstrated the significant involvement of genetic factors, stress, and nutrition in developing this condition. The utilization of computer-aided analysis models based on machine learning and artificial intelligence has the potential to significantly enhance the exploration of various neuroimaging methods and non-image biomarkers. This study conducts a comparative assessment of more than 80 publications that have been published since 2017. Alzheimer’s disease detection is facilitated by utilizing fundamental machine learning architectures such as support vector machines, decision trees, and ensemble models. Furthermore, around 50 papers that utilized a specific architectural or design approach concerning Alzheimer’s disease were examined. The body of literature under consideration has been categorized and elucidated through the utilization of data-related, methodology-related, and medical-fostering components to illustrate the underlying challenges. The conclusion section of our study encompasses a discussion of prospective avenues for further investigation and furnishes recommendations for future research activities on the diagnosis of Alzheimer’s disease.

Cultured Vagal Afferent Neurons as Sensors for Intestinal Effector Molecules.

The gut-brain axis embodies the bi-directional communication between the gastrointestinal tract and the central nervous system (CNS), where vagal afferent neurons (VANs) serve as sensors for a variety of gut-derived signals. The gut is colonized by a large and diverse population of microorganisms that communicate via small (effector) molecules, which also act on the VAN terminals situated in the gut viscera and consequently influence many CNS processes. However, the convoluted in vivo environment makes it difficult to study the causative impact of the effector molecules on VAN activation or desensitization. Here, we report on a VAN culture and its proof-of-principle demonstration as a cell-based sensor to monitor the influence of gastrointestinal effector molecules on neuronal behavior. We initially compared the effect of surface coatings (poly-L-lysine vs. Matrigel) and culture media composition (serum vs. growth factor supplement) on neurite growth as a surrogate of VAN regeneration following tissue harvesting, where the Matrigel coating, but not the media composition, played a significant role in the increased neurite growth. We then used both live-cell calcium imaging and extracellular electrophysiological recordings to show that the VANs responded to classical effector molecules of endogenous and exogenous origin (cholecystokinin serotonin and capsaicin) in a complex fashion. We expect this study to enable platforms for screening various effector molecules and their influence on VAN activity, assessed by their information-rich electrophysiological fingerprints.

Cough Sensitivity to Several External Triggers is Associated with Multiple Non-respiratory Symptoms

PurposeEnhanced responsiveness to external triggers is thought to reflect hypersensitivity of the cough reflex. It may involve an enhanced sensitivity of the afferent nerves in the airways and/or an abnormal processing of the afferent information by the central nervous system (CNS). The CNS processing of cough has been shown to involve the same regions as those in symptom amplification, a phenomenon that often manifests as multiple symptoms. The main purpose of the present study was to define whether the presence of several cough triggers is associated with multiple symptoms.Methods2131 subjects with current cough responding to two email surveys filled in a comprehensive questionnaire about social background, lifestyle, general health, doctors’ diagnoses and visits, symptoms, and medication. Multiple symptoms was defined as three or more non-respiratory, non-mental symptoms.ResultsA carefully controlled multiple regression analysis revealed that the number of cough triggers was the only cough characteristic associating with multiple non-respiratory, non-mental symptoms [aOR 1.15 (1.12–1.19) per one trigger, p < 0.001]. Among the 268 subjects with current cough both in the first survey and in the follow-up survey 12 months later, the repeatability of the trigger sum was good with an intraclass correlation coefficient of 0.80 (0.75–0.84).ConclusionThe association between the number of the cough triggers and multiple symptoms suggests that the CNS component of cough hypersensitivity may be a manifestation of non-specific alteration in the CNS interpretation of various body sensations. The number of cough triggers is a repeatable measure of cough sensitivity.

Purinergic approach to effective glioma treatment with temozolomide reveals enhanced anti-cancer effects mediated by P2X7 receptor

The purinergic signaling pathway is the oldest evolutionary transmitter system that regulates a wide array of physiological and pathophysiological processes in central nervous system. However, the question of how the purinergic compounds interact with administrated drugs is rarely addressed. We aimed to clarify the interplay between purinergic signaling and chemotherapeutic drug temozolomide (TMZ) in human glioma cell line.We applied an initial retinoic acid-induced differentiation of A172 glioma cells and tested the P2X7 receptor expression in undifferentiated and differentiated gliomas. We compared the P2X7 receptor agonists/antagonists influence and their co-action with TMZ in both cell types through assessment of cell proliferation, viability and migrative properties. Molecular docking allowed to indicate the potential binding site for TMZ in the structure of hP2X7 receptor. Differentiated cells turned out to be more susceptible to ATP and TMZ alone but also to the concerted action of TMZ and ATP. Enhanced effects triggered by ATP and TMZ treatment include the decreased by 70% viability, and reduced migration ability of differentiated A172 glioma cells. Noteworthy, these results can be achieved already at low non-toxic ATP concentration and at reduced to 125 μM effective concentration of TMZ.Therefore, ATP molecules must be present and maintained at appropriate concentration in glioma cells microenvironment to achieve their co-action with TMZ and enhanced anti-cancer activity. All that, in turn, could shorten the therapy, increase its efficacy and limit the side effects for the patient. Our purinergic approach creates a promising perspective for developing novel combined oncological therapies.

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

PIEZO1-Related Physiological and Pathological Processes in CNS: Focus on the Gliomas.

PIEZO1 is ubiquitously expressed in cells in different kinds of tissues throughout the body, which can sense physical or mechanical stimuli and translate them into intracellular electrochemical signals to regulate organism functions. In particular, PIEZO1 appears in complex interactive regulatory networks as a central node, governing normal and pathological functions in the body. However, the effect and mechanism of the activation or expression of PIEZO1 in diseases of the central nervous system (CNS) remain unclear. On one hand, in CNS diseases, pathophysiological processes in neurons and glial are often accompanied by variations in the mechanical properties of the cellular and extracellular matrix stiffness. The expression of PIEZO1 can therefore be upregulated, in responding to mechanical stimulation, to drive the biological process in cells, which in turns indirectly affects the cellular microenvironment, resulting in alterations of the cellular status. On the other hand, it may have contradictory effects with the change of active patterns and/or subcellular location. This review highlights the biological processes involved with PIEZO1 in CNS cells, with special emphasis on its multiple roles in glioma-associated phenotypes. In conclusion, PIEZO1 can be used as an indicator to assess the malignancy and prognosis of patients with gliomas, as well as a therapeutic target for clinical application following fully exploring the potential mechanism of PIEZO1 in CNS diseases.

Protective roles of adropin in neurological disease.

Adropin is a highly conserved secreted peptide encoded by the Energy Homeostasis Associated gene (Enho). It is expressed in many tissues throughout the body, including the liver and brain, and plays a crucial role in maintaining lipid homeostasis and regulating insulin sensitivity. Adropin also participates in several other pathophysiological processes of multiple central nervous system (CNS) diseases. There is strong evidence of the protective effects of adropin in stroke, heart disease, aging, and other diseases. The peptide has been shown to reduce the risk of disease, attenuate histological alterations, and reduce cognitive decline associated with neurological disorders. Recent findings support its critical role in regulating endothelial cells and maintaining blood-brain barrier integrity through an endothelial nitric oxide synthase (eNOS)-dependent mechanism. Here we discuss current evidence of the protective effects of adropin in CNS diseases specifically involving the cerebrovasculature and highlight potential mechanisms through which the peptide exhibits these effects.

Neuroinflammation of traumatic brain injury: Roles of extracellular vesicles.

Traumatic brain injury (TBI) is a major cause of neurological disorder or death, with a heavy burden on individuals and families. While sustained primary insult leads to damage, subsequent secondary events are considered key pathophysiological characteristics post-TBI, and the inflammatory response is a prominent contributor to the secondary cascade. Neuroinflammation is a multifaceted physiological response and exerts both positive and negative effects on TBI. Extracellular vesicles (EVs), as messengers for intercellular communication, are involved in biological and pathological processes in central nervous system (CNS) diseases and injuries. The number and characteristics of EVs and their cargo in the CNS and peripheral circulation undergo tremendous changes in response to TBI, and these EVs regulate neuroinflammatory reactions by activating prominent receptors on receptor cells or delivering pro- or anti-inflammatory cargo to receptor cells. The purpose of this review is to discuss the possible neuroinflammatory mechanisms of EVs and loading in the context of TBI. Furthermore, we summarize the potential role of diverse types of cell-derived EVs in inflammation following TBI.