Central Nervous System Activity Research Articles

Neurophysiological Parameters Influencing Sleep-Wake Discrepancy in Insomnia Disorder: A Preliminary Analysis on Alpha Rhythm during Sleep Onset.

Sleep state misperception (SSM) is a common issue in insomnia disorder (ID), causing a discrepancy between objective and subjective sleep/wake time estimation and increased daytime impairments. In this context, the hyperarousal theory assumes that sustained central nervous system activation contributes to the SSM. This study investigates factors influencing SSM during sleep latency (SL) and total sleep time (TST). Objective polysomnographic sleep variables (the alpha density index, latency-to-sleep stages and the first K-complex, and Rapid Eye Movement (REM) arousal density) and subjective sleep indices, taken from sleep diaries, were analyzed in 16 ID patients. Correlation analyses revealed a positive association between the degree of SL misperception (SLm) and the percentage of epochs that contained a visually scored stereotyped alpha rhythm during objective SL. A regression analysis showed that the REM arousal density and alpha density index significantly predicted TST misperception (TSTm). Furthermore, the degree of SLm was associated with an increased probability of transitioning from stage 1 of non-REM sleep to wakefulness during subjective SL. These findings support the role of hyperarousal in SSM and highlight the importance of alpha activity in unravelling the heterogeneous underpinnings of SSM.

Peripheral 5-HT/HTR6 axis is responsible for obesity-associated hypertension

Hypertension is one of the major life-threatening complications of obesity. Recently adipose multipotent mesenchymal stromal cells (MSCs) were implicated to the pathogenesis of obesity-associated hypertension. These cells amplify noradrenaline-induced vascular cell contraction via cAMP-mediated signaling pathway. In this study we tested the ability of several cAMP-mediated hormones to affect the adrenergic sensitivity of MSCs and their associated contractility. Despite that adipose MSCs express a plethora of receptors capable of cAMP signaling activation, only 5-HT was able to elevate α1A-adrenoceptor-induced Ca2+ signaling in MSCs. Furthermore, 5-HT markedly enhanced noradrenaline-induced MSCs contractility. Using HTR isoform-specific antagonists followed by CRISPRi-mediated knockdown, we identified that the observed 5-HT effect on MSCs was mediated by the HTR6 isoform. This receptor was previously associated exclusively with 5-HT central nervous system activity. Discovered effect of HTR6 on MSCs contractility points to it as a potential therapeutic target for the prevention and treatment of obesity-associated hypertension.

Morus alba; A Ray of Hope for Psychiatric Illnesses

Purpose: Over the years, plants have been used in treatment of various health ailments. Morus alba also known as White Mulberry is a deciduous tree which belongs to family Moraceae. Mulberry is rich in antioxidants such as hydrophobic flavonoids, polyphenols, carotenoids, vitamin A, C and E.
 Materials and Methods: This study analyses the central nervous system activities including memory enhancement, learning abilities, changes in behavior, cognition, anxiety and depression. These effects will be studied on experimental mice, which will be distributed in control and test groups. Aqueous fruit extract prepared by Maceration extraction will be given to test group in three different doses per oral over a time period of 30 days, whereas control will be given water for injection for same duration.
 Findings: Afterwards, changes in aforementioned effects will be observed to determine the pharmacological effects of taken fruit. The obtained results suggest an antidepressant like effect of mulberry in the initial two weeks of dosing. Afterwards it shows anxiolytic effect at higher doses.
 Implications to Theory, Practice and Policy: All these tests can be repeated weekly while dosing the animals daily for 90 days for chronic toxicity analysis. Furthermore, we can add a brain biopsy/histopathology to evaluate the changes in chemical neurotransmitters.

Abstract C151: BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets

Abstract Introduction: Uncommon EGFR mutations in non-small cell lung cancer (NSCLC), including exon 20 insertion and atypical mutations, are generally associated with poorer clinical outcomes than common EGFR mutations. Patients (pts) with these mutations have limited effective therapeutic options. Afatinib is the only approved agent for uncommon mutations but is associated with high rates of toxicity and limited central nervous system (CNS) penetration. Amivantamab and mobocertinib are approved for patients with relapsed EGFR exon 20 insertion NSCLC but are associated with limitations in efficacy and CNS activity. BLU-451 is an investigational, CNS-penetrant, EGFR-wild-type (WT)–sparing, selective inhibitor against exon 20 insertion and uncommon EGFR mutations that is currently being evaluated in the phase 1/2 CONCERTO study (NCT05241873). Here, we report on the prevalence of uncommon EGFR mutations from a single center, real-world data set (MD Anderson Cancer Center [MDACC]), and report preclinical activity of BLU-451 on a broad spectrum of uncommon EGFR mutations by structure classification. Methods: BLU-451 cellular activity was evaluated in engineered BaF3 cell lines expressing 62 EGFR kinase domain mutations as well as in cell lines dependent on WT EGFR, using the CellTiter-Glo® Luminescent Cell Viability Assay and a phosphorylation-specific EGFR AlphaLISA® assay. The MDACC Moon Shot™ Genomic Marker-Guided Therapy Initiative (GEMINI) database was searched for pts with NSCLC whose tumors harbored EGFR kinase domain mutations. Results: In the MDACC GEMINI database, a total of 1495 unique patients with NSCLC harboring EGFR mutations were identified, including 1025 with classical mutations (exon 19 deletion and L858R) with or without T790M, 223 with exon 20 insertion mutations, and 247 with only atypical mutations. In BaF3 cells, BLU-451 demonstrated nanomolar potency in multiple atypical and exon 20 insertion mutation cell lines with selectivity against WT EGFR. Conclusion: Atypical EGFR mutations represent a sizable NSCLC pt population, of similar magnitude to that of EGFR exon 20 insertion mutations. BLU-451 preclinical data in EGFR atypical and exon 20 insertion mutations showed broad, potent, and selective activity, supporting continued evaluation of BLU-451 in the phase 1/2 CONCERTO study in pts with advanced or metastatic NSCLC harboring uncommon EGFR mutations. Citation Format: Xiuning Le, Yves Millet, Monique Nilsson, Aditya Dhande, Jeffrey Keats, Holly Ponichtera, Joseph Kim, Junqin He, Yasir Y. Elamin, John V. Heymach, Chiara Conti, Stephanie Lee. BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C151.

Abstract C036: A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer

Abstract Background: Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver, intrinsic driver, and acquired resistance mutations. BDTX-1535 is an orally available, highly potent, brain penetrant, selective, irreversible small molecule tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Methods: BDTX-1535-101 (NCT05256290) is a Phase 1, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics (PK), central nervous system (CNS) activity, and preliminary antitumor activity of BDTX-1535 in locally advanced or metastatic NSCLC with or without CNS disease or recurrent GBM (rGBM). The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, PK, pharmacodynamic, and preliminary antitumor activity. The monotherapy dose escalation portion evaluates BDTX-1535 in patients with locally advanced/metastatic NSCLC harboring intrinsic driver EGFR mutations following standard of care or with acquired resistance EGFR mutations following a 3rd generation EGFR inhibitor in the 1st line setting, in addition to patients with rGBM expressing EGFR alterations who previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). A capsule-to-tablet bridging cohort and a food effect cohort will also be assessed. Following the establishment of a preliminary recommended Phase 2 dose (RP2D), the disease-specific expansion portion of the study will further evaluate the safety, tolerability, and preliminary antitumor effect of BDTX-1535. Cohorts include the following:1) advanced/metastatic NSCLC with intrinsic resistance EGFR mutations following up to 2 lines of therapy, one of which must be an EGFR inhibitor treatment, 2) advanced/metastatic NSCLC with acquired resistance EGFR mutation following a 3rd generation EGFR inhibitor in the first line setting, 3) rGBM with confirmed EGFR alterations with or without amplifications. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with newly diagnosed GBM harboring EGFR alterations. Enrollment was initiated in 2022 and dose escalation is almost complete. Initiation of the dose expansion cohorts of NSCLC patients with EGFR acquired resistance and intrinsic driver mutations after progression on prior EGFR inhibitor is planned for the second half of 2023. For additional information, please contact ClinicalTrials@bdtx.com. Citation Format: Helena Yu, Melissa Johnson, Jason T Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C036.

Acute toxicity (LD50 values) and neuropharmacological profile of n-hexane fraction of Petiveria alliacea L. (Phytolaccaceae) in mice

Background: Petiveria alliacea L. (Phytolaccaceae) ethnomedically is known for its sedative property and beneficial treatment of other central nervous system (CNS) disorders. However, the neuropharmacological properties of the n-hexane extract of this aromatic plant leaf have not been reported, hence this study. Objective: To determine the acute toxicity profile (LD50) and some CNS activities of the n-hexane extract of fresh leaf of P. alliacea (NHEPA) in mice. Method: The fresh leaf of Petiveria alliacea was collected and the n-hexane extract obtained using appropriate technique. The LD50 was determined for both the oral and intraperitoneal (i.p.) route. All treatments were administered via i.p. route. Behavioural activity was evaluated using the novelty-induced behaviour (NIB) to assess rearing, grooming and locomotion; sedative activity was tested on ketamine-induced hypnosis while the anticonvulsant potential was assessed using chemo-convulsants. The mechanism of action was determined using amphetamine as agonist and flumazenil as an antagonist. Results: The LD50 values obtained for the extract was 2450 and 346 mg/kg for oral and intraperitoneal routes respectively. The extract displayed significant CNS depressant activity on all NIB parameters. NHEPA significantly prolonged sleep latency and total sleeping time at 100 and 150 mg/kg. i.p. The extract also offered some mild protection against convulsion across the model used. The probable mechanism of action may include inhibition of monoamine pathways and augmentation of the GABAA- benzodiazepine complex pathway. Conclusion: NHEPA showed CNS depressant activity, exhibited significant sedative activity and mild anticonvulsant activity.

Efficacy and Safety of Selinexor-Based Combination Therapy in CNS Lymphoma: A Retrospective Experience

Introduction ： Primary central nervous system lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma (DLBCL) with distinct clinical and biological features, characterized by an aggressive course and poor prognosis. Patients with relapsed/refractory (R/R) disease have an unmet medical need due to a median overall survival (OS) of only 6.8 months. Novel therapies are urgently required for patients with R/R CNSL. In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with R/R DLBCL. Selinexor has demonstrated central nervous system (CNS) penetration and activity in secondary CNS lymphoma (SCNSL) patients. Thus, we conducted a retrospective review of PCNSL/SCNSL cases treated with a selinexor-based regimen to preliminarily evaluate its effectiveness and safety. Methods: We retrospectively analyzed the medical records of 13 patients with CNSL who received selinexor-based combination therapy between June 2021 and June 2023 at three research centers in China. Among these cases, 2 were previously untreated, and 11 were relapsed or refractory patients. All patients had histopathologically confirmed DLBCL at the time of initial diagnosis. Data collection included baseline characteristics, treatment efficacy and safety evaluation. Results: A total of 13 patients (10 PCNSL and 3 SCNSL) were included in the study, with a median age of 62 years (range, 28-73), including three male patients. The median international extranodal lymphoma study group (IELSG) score for PCNSL cases was 3 (range, 1-3). The median International Prognosis Index (IPI) score for the three systemic DLBCL cases was 5 (range, 3-5), and three cases were at Ann Arbor stage IV. Among the patients, 11 had relapsed or refractory disease with a median of 2 prior treatments (range, 1-4), and 10 of them were refractory to previous treatments. The main patient characteristics, responses, and toxicities of the selinexor-based combination regimen are summarized in Table 1. Figure 1 presents the response of all evaluable patients. The overall response rate (ORR) of the patients was 84.6% (11 /13), with a complete response (CR) rate of 76.9% (10/13). Both treatment-naïve patients achieved CR after four and six cycles of the selinexor-containing first-line regimen, respectively. They are currently experiencing sustained remission, with the longest duration reaching 13 months. For relapsed/refractory CNSL, the ORR and CR rate were 81.8% (9/11) and 72.7% (8/11), respectively. Two patients had stable disease (SD). Among the 9 patients who achieved remission, 4 patients are still in remission, with the longest duration reaching 20 months, 2 patients received CART bridging therapy, one received radiation therapy, and 2 patients experienced disease progression after 5 months, but all are currently still alive. These patients are currently under continuous observation. Due to the heterogeneity of the selinexor-based regimens, the categories and severity of adverse events (AEs) varied greatly among the different regimens. The median treatment cycle number was six (range, 2-22). One patient died due to pneumonia infection, one patient was lost to follow-up, three patients successfully bridged to CART/RT, and eight patients completed the treatment as planned. The common AEs included thrombocytopenia, infection, nausea, vomiting, and gastrointestinal bleeding(Table 1). Conclusion: This report provides encouraging evidence of the efficacy and tolerable safety of the selinexor-based regimen in the treatment of CNSL. However, further prospective studies with a larger sample size are needed to provide more comprehensive evidence regarding the efficacy of selinexor in central nervous system lymphoma and to determine the appropriate dosage and optimal combination strategies.v

Abstract 14283: Brain-Mediated Cardioprotective Actions of Leptin: Potential Role of Brown Adipose Tissue and Its Release of Extracellular Vesicles

Background: We recently demonstrated that leptin has powerful central nervous system (CNS) actions that dramatically improve cardiac function following ischemia/reperfusion (IR) injury. How the brain communicates with the heart during CNS leptin infusion to improve cardiac function is unknown. One potential mechanism is activation of brown adipose tissue (BAT) which may be an important source of extracellular vesicles (EVs) carrying cardioprotective microRNAs (miR), including miR-125b-5p. Hypothesis: We investigated whether BAT contributes to the cardioprotective effect of CNS leptin infusion and the potential role of EVs carrying the miR-125b-5p in this protection. Methods: Male Sprague-Dawley rats were submitted to interscapular BAT ablation (iBATx) and instrumented with an intracerebroventricular (ICV) cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO), myocardial IR was induced by temporary ligation of the left anterior descending coronary artery. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/hr) was infused ICV chronically for 28 days using osmotic pumps. Cardiac function was assessed weekly by ECHO. Another set of animals with intact iBAT was treated with ICV leptin or vehicle for 4 weeks and had their iBAT collected for EVs isolation and quantification. Expression of the miR-125b-5p was measured in the heart of leptin treated rats with intact iBAT or iBATx. Results: Compared to vehicle-treated animals, ICV leptin infusion increased iBAT-derived EVs and removal of iBAT prevented leptin’s CNS-mediated cardioprotective effects after IR injury as indicated by a lack of improvement in ejection fraction (26±6 vs 41±3%) and stroke volume (162±31 vs 275±19μL) at week 4 post-IR. Expression of the mature miR-125b-5p was increased in the heart of ICV leptin treated rats and iBATx abolished this effect. Conclusion: These results indicate that the BAT plays an important role in mediating the cardioprotective effect of CNS leptin administration after IR injury and suggest that iBAT-derived EVs may be involved in delivering the miR-125b-5p to the heart during central leptin infusion. AHA 835218, 1R01HL163076, P20GM104357, and P20GM104320-07

A preclinical study of Elettaria cardamomum for its antianxiety activity in Wistar albino rats

Background: Elettaria cardamomum, commonly known as cardamom, is one of the most widely used spices worldwide and is conventionally well known for its effects on the central nervous system (CNS) as a food additive. Aims and Objectives: This study was carried out to assess the ethanolic extract of E. cardamomum (EEEC) for its CNS activity in rats. The purpose of this study was to validate the traditional use of E. cardamomum as an antianxiety agent. Materials and Methods: The elevated plus maze and light–dark arena models were used to evaluate its anxiolytic activity. The open field test and actophotometer were used for assessing its effect on locomotor activity. The experiments were performed in Wistar albino rats of either sex after grouping the animals into three different groups. Twelve animals per group were used. Distilled water (10 mL/kg) was used as Control and Diazepam (1 mg/kg) were used as standard drugs for the respective tests. Results: EEEC (at a dose of 100 mg/kg) has shown anxiolytic and reduced locomotor activity. Conclusion: The results of this study indicate that EEEC has anxiolytic and sedative effects, similar to benzodiazepine and possibly similar mechanisms.

Serum neurofilament and glial fibrillary acidic protein in idiopathic and seropositive transverse myelitis.

Serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) reflect the disease activity and disability in central nervous system (CNS) demyelinating diseases. However, the clinical significance of NfL and GFAP in idiopathic transverse myelitis (iTM), an inflammatory spinal cord disease with unknown underlying causes, remains unclear. This study aimed to investigate NfL and GFAP levels in iTM and their association with the clinical parameters compared with those in TM with disease-specific antibodies such as anti-aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies (sTM). We collected serum and clinical data of 365 patients with CNS inflammatory diseases from 12 hospitals. The serum NfL and GFAP levels were measured in patients with iTM (n=37) and sTM (n=39) using ultrasensitive single-molecule array assays. Regression analysis was performed to investigate the associations between serum levels of NfL and GFAP and the clinical parameters such as higher EDSS scores (EDSS ≥ 4.0). Mean NfL levels were not significantly different between iTM (50.29pg/ml) and sTM (63.18pg/ml) (p=0.824). GFAP levels were significantly lower in iTM (112.34pg/ml) than in sTM (3814.20pg/ml) (p=0.006). NfL levels correlated with expanded disability status scale (EDSS) scores in sTM (p=0.001) but not in iTM (p=0.824). Disease duration also correlated with higher EDSS scores in sTM (p=0.017). NfL levels and disease duration correlated with EDSS scores in sTM, and GFAP levels could be a promising biomarker to differentiate iTM from sTM.

Low Glycolysis Is Neuroprotective during Anoxic Spreading Depolarization (SD) and Reoxygenation in Locusts.

Migratory locusts enter a reversible hypometabolic coma to survive environmental anoxia, wherein the cessation of CNS activity is driven by spreading depolarization (SD). While glycolysis is recognized as a crucial anaerobic energy source contributing to animal anoxia tolerance, its influence on the anoxic SD trajectory and recovery outcomes remains poorly understood. We investigated the effects of varying glycolytic capacity on adult female locust anoxic SD parameters, using glucose or the glycolytic inhibitors 2-deoxy-d-glucose (2DG) or monosodium iodoacetate (MIA). Surprisingly, 2DG treatment shared similarities with glucose yet had opposite effects compared with MIA. Specifically, although SD onset was not affected, both glucose and 2DG expedited the recovery of CNS electrical activity during reoxygenation, whereas MIA delayed it. Additionally, glucose and MIA, but not 2DG, increased tissue damage and neural cell death following anoxia-reoxygenation. Notably, glucose-induced injuries were associated with heightened CO2 output during the early phase of reoxygenation. Conversely, 2DG resulted in a bimodal response, initially dampening CO2 output and gradually increasing it throughout the recovery period. Given the discrepancies between effects of 2DG and MIA, the current results require cautious interpretations. Nonetheless, our findings present evidence that glycolysis is not a critical metabolic component in either anoxic SD onset or recovery and that heightened glycolysis during reoxygenation may exacerbate CNS injuries. Furthermore, we suggest that locust anoxic recovery is not solely dependent on energy availability, and the regulation of metabolic flux during early reoxygenation may constitute a strategy to mitigate damage.

Impact of seasonality on certain parameters of behavioral testing in rats

Introduction. Effects of the daytime period (circadian photoperiod) and seasonality on behavioral reactions and physiology of humans and animals remains one of the important issues of modern science.
 Material and methods. We have summarized our own data on control animals collected in experimental studies conducted in all seasons of the year. The hole-board test and summation threshold index were chosen to assess the behavior of rats. The data analysis was performed in Microsoft Excel 2016 using Student’s t-test, p<0.05. In addition, we estimated a percent deviation of the indicators under study from their annual averages.
 Results. We established that, as assessed by the number of head dips in the hole-board test, male rats kept at natural lighting demonstrated the most active exploratory behavior in spring and autumn while in summer, on the opposite, their exploration was statistically reduced. Values of the summation threshold index were the highest in winter and summer but lower in spring and especially in autumn. In springtime, the summation threshold index in male rats was statistically different from that observed in autumn and winter. In female rats, the index of the the hole-board test in spring was statistically significantly increased compared to data for all seasons of the year.
 Limitations of the study. An analysis was carried out of the data obtained at the experimental animal clinic of the Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers for 7 years (2015–2022).
 Conclusion. Our findings show that duration of the daytime period and seasonality can affect the results of some behavioral tests measuring lability of the central nervous system and exploratory activity of animals. They can contribute to the methodological basis for planning toxicity testing with account for seasonal fluctuations in physiological parameters of laboratory rodents.

In-silico Studies of Quinazolinone Analogues to Distinguish their Hypothetical Binding Mode using the X-ray crystal Structure Human carbon Anhydrase II (HCAII) Enzyme Complex with Sugar Sulfamate for Anticonvulsant Activity

The quinazolinone moiety is a significant pharmacophore that depicts various types of pharmacological activities as shown in recent exhaustive ligatures. Quinazolinone exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory and anticonvulsant. To develop these views and application profiles, attempt have been made to report a drug/ligand or receptor/protein interactions by identifying the suitable active site against X-ray crystal structure of Human Carbonic Anhydrase II (HCA II) enzyme for anticonvulsant activity using Vlife MDS version 4.6 Software because the protein-ligand interaction plays a significant role in structural based drug designing. The interaction was evaluated based on the score comparison between quinazolinone derivatives with sugar sulfamate. The quinazolinone ring forms hydrophobic and hydrogen bond contacts amino acid residues. The ligands 4t and 4s were shown to possess minimum dock score i.e. minimum binding energy in Kcal/mole i.e. these molecules has more affinity for the active site of the receptor. Molecules with low dock score and binding energy show more affinity towards the receptor. The data reported in this article may be helpful for the medicinal chemists who are working in this area.

The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production.

Schizophrenia, a severe mental illness affecting about 1% of the population, manifests during young adulthood, leading to abnormal mental function and behavior. Its multifactorial etiology involves genetic factors, experiences of adversity, infection, and gene-environment interactions. Emerging research indicates that maternal infection or stress during pregnancy may also increase schizophrenia risk in offspring. Recent research on the gut-brain axis highlights the gut microbiome's potential influence on central nervous system (CNS) function and mental health, including schizophrenia. The gut microbiota, located in the digestive system, has a significant role to play in human physiology, affecting immune system development, vitamin synthesis, and protection against pathogenic bacteria. Disruptions to the gut microbiota, caused by diet, medication use, environmental pollutants, and stress, may lead to imbalances with far-reaching effects on CNS function and mental health. Of interest are short-chain fatty acids (SCFAs), metabolic byproducts produced by gut microbes during fermentation. SCFAs can cross the blood-brain barrier, influencing CNS activity, including microglia and cytokine modulation. The dysregulation of neurotransmitters produced by gut microbes may contribute to CNS disorders, including schizophrenia. This review explores the potential relationship between SCFAs, the gut microbiome, and schizophrenia. Our aim is to deepen the understanding of the gut-brain axis in schizophrenia and to elucidate its implications for future research and therapeutic approaches.

Linking Migraine to Gut Dysbiosis and Chronic Non-Communicable Diseases.

In the world, migraine is one of the most common causes of disability in adults. To date, there is no a single cause for this disorder, but rather a set of physio-pathogenic triggers in combination with a genetic predisposition. Among the factors related to migraine onset, a crucial role seems to be played by gut dysbiosis. In fact, it has been demonstrated how the intestine is able to modulate the central nervous system activities, through the gut-brain axis, and how gut dysbiosis can influence neurological pathologies, including migraine attacks. In this context, in addition to conventional pharmacological treatments for migraine, attention has been paid to an adjuvant therapeutic strategy based on different nutritional approaches and lifestyle changes able to positively modulate the gut microbiota composition. In fact, the restoration of the balance between the different gut bacterial species, the reconstruction of the gut barrier integrity, and the control of the release of gut-derived inflammatory neuropeptides, obtained through specific nutritional patterns and lifestyle changes, represent a possible beneficial additive therapy for many migraine subtypes. Herein, this review explores the bi-directional correlation between migraine and the main chronic non-communicable diseases, such as diabetes mellitus, arterial hypertension, obesity, cancer, and chronic kidney diseases, whose link is represented by gut dysbiosis.

How far neuroscience is from understanding brains.

The cellular biology of brains is relatively well-understood, but neuroscientists have not yet generated a theory explaining how brains work. Explanations of how neurons collectively operate to produce what brains can do are tentative and incomplete. Without prior assumptions about the brain mechanisms, I attempt here to identify major obstacles to progress in neuroscientific understanding of brains and central nervous systems. Most of the obstacles to our understanding are conceptual. Neuroscience lacks concepts and models rooted in experimental results explaining how neurons interact at all scales. The cerebral cortex is thought to control awake activities, which contrasts with recent experimental results. There is ambiguity distinguishing task-related brain activities from spontaneous activities and organized intrinsic activities. Brains are regarded as driven by external and internal stimuli in contrast to their considerable autonomy. Experimental results are explained by sensory inputs, behavior, and psychological concepts. Time and space are regarded as mutually independent variables for spiking, post-synaptic events, and other measured variables, in contrast to experimental results. Dynamical systems theory and models describing evolution of variables with time as the independent variable are insufficient to account for central nervous system activities. Spatial dynamics may be a practical solution. The general hypothesis that measurements of changes in fundamental brain variables, action potentials, transmitter releases, post-synaptic transmembrane currents, etc., propagating in central nervous systems reveal how they work, carries no additional assumptions. Combinations of current techniques could reveal many aspects of spatial dynamics of spiking, post-synaptic processing, and plasticity in insects and rodents to start with. But problems defining baseline and reference conditions hinder interpretations of the results. Furthermore, the facts that pooling and averaging of data destroy their underlying dynamics imply that single-trial designs and statistics are necessary.

Signal processing and machine learning algorithm to classify anaesthesia depth

BackgroundPoor assessment of anaesthetic depth (AD) has led to overdosing or underdosing of the anaesthetic agent, which requires continuous monitoring to avoid complications. The evaluation of the central nervous system...

Discovery of MAO-A Inhibitors as Antidepressant Based on Virtual Screening

Aim: Major depression and anxiety have increased significantly worldwide since the 2019 outbreak of COVID-19. The development of highly effective antidepressants with low side effects is attracting researchers. Methods: Monoamine oxidase A (MAO-A) is a key enzyme that catalyzes the metabolism of norepinephrine (NE), dopamine (DA), and serotonin (5-HT), etc. Elevated level of MAO-A would lead to increased metabolism of its substrates, thereby causing a decrease in the levels of these neurotransmitter monoamines in the brain leading to depression. Consequently, inhibition of MAO-A was thought to be an effective strategy, as this would treat the root cause of depression. Results and Discussion: Based on the crystal structure of MAO-A, 4 star-hits, as potential MAO-A inhibitors was screened from the compound libraries with central nervous system (CNS) activity by using various computational techniques. Molecular dynamics simulation was used to verify the stability of the ligand- receptor complexes. Conclusion: Furthermore, the ADMET (absorption, distribution, metabolism, excretion and toxicity properties) of the virtual hits were predicted in order to evaluate their lead-like properties and safety. This work provides ideas for the drugs discovery of antidepressant.

Central Nervous System Relapse in T and NK cell Lymphomas.

T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment. Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs.

CLRM-11 ALK TYROSINE KINASE INHIBITOR THERAPY AND BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: IMPACT ON TUMOR SIZE AND DISTRIBUTION

Abstract Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) is known to have a high propensity to form brain metastases (BrM), with over 50% of ALK+ lung cancer patients developing BrM despite effective ALK tyrosine kinase inhibitor (TKI) therapy with central nervous system (CNS) activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs have suggested that there may be differences in drug concentration between white and gray matter in the brain, which may play a role in BrM formation patterns and response. In this study, we aimed to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort. Brain MRI data from patients with ALK+ NSCLC were retrospectively reviewed, and each tumor was marked in a standard space brain model using 3D Slicer-4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. We found that TKI-exposed patients had significantly smaller BrM diameters than TKI-naïve patients (6.1±3.8 vs. 10.2±5.5mm, p=0.02) and were more likely to have white matter-exclusive (3.5±4.4 vs. 1.4±2.0, p=0.05) and deep white matter metastases (3.2±4.3 vs. 1.3±2.0, p=0.06). The metastatic burden was similar between the groups, while the mean number of BrM per patient was numerically higher in the TKI-exposed group (10.6±11.9 vs. 6.2±9.5; p=0.22). These findings suggest that TKI therapy may result in smaller individual lesions that are more likely to be exclusive to the white matter, where drug concentrations may be significantly lower. This suboptimal CNS distribution of TKIs in the white matter may contribute to the progression of brain metastases in ALK+ patients despite TKI therapy. Further analyses are ongoing to evaluate ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions.