Central Nervous System Activity Research Articles

HER2-low breast cancer brain metastases: Incidence and treatment implications.

2035 Background: Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; this is particularly problematic for patients with triple negative disease (TNBC) who have a high likelihood of developing BrM. Given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest. Methods: A retrospective study of two cohorts of patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre between 1999-2013 and 2008-2018 were identified. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2) status were assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathological features were recorded. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). Results: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32-85). 18.6% (n=19) had leptomeningeal disease and 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low and HER2-positive were concordant in 82.3% (n= 42/51) of cases (Cohen’s kappa 0.58, p=0.0719). In 7 cases, the primary breast tissue was HER2-zero whereas the BrM was either HER2-low (n=5) or HER2-positive (n=2). In only one case (2%), expression of HER2 was lower in the BrM (HER2-low) compared to the primary BC (HER2-positive). Median time from primary BC to the development of BrM was 35 months (IQR, 14-69) in the overall cohort; patients with HER2-zero BrM had a numerically longer time to development of BrM (45.8 months), compared to those with HER2-low (35 months) and HER2-positive (35 months) BrM (p=0.948). There was no significant association between HER2-zero, HER2-low and HER2-positive status in BrM and either bsPFS or OS. Conclusions: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.

Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue

Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally adapted. Here, we describe pitfalls and define straightforward orthogonal biochemical approaches essential to measure and understand changes in proteasome composition and activity in the mammalian central nervous system. Through our experimentation in the mammalian brain, we determined an abundance of catalytically active proteasomes exist with and without a 19S cap(s), the regulatory particle essential for ubiquitin-dependent degradation. Moreover, we learned that in-cell measurements using activity-based probes (ABPs) are more sensitive in determining the available activity of the 20S proteasome without the 19S cap and in measuring individual catalytic subunit activities of each β subunit within all neuronal proteasomes. Subsequently, applying these tools to human brain samples, we were surprised to find that post-mortem tissue retained little to no 19S-capped proteasome, regardless of age, sex, or disease state. In comparing brain tissues (parahippocampal gyrus) from patients with Alzheimer's disease (AD) and unaffected individuals, the available 20S proteasome activity was significantly elevated in severe cases of AD, an observation not previously noted. Taken together, our study establishes standardized approaches for the comprehensive investigation of proteasomes in mammalian brain tissue, and we reveal new insight into brain proteasome biology.

Ursolic Acid: Historical Aspects to Promising Pharmacological Actions for the Treatment of Central Nervous System Diseases

Abstract: Ursolic acid (UA) has been utilized to improve memory-related cognitive processes and intellectual functions. This study aims to examine the ethnobotanical uses, phytochemical composition, toxicity, and central nervous system activities of UA. It promotes learning and memory and has biological effects against Alzheimer's disease, Parkinson's disease, and cognitive impairment, according to pharmacological investigations. UA did not cause any death, abnormal body weight, or pathological diseases at any of the test doses. Furthermore, no behavioral, neurotoxin, coagulation, haematological, or clinical chemistry changes were seen as a result of UA treatment. UA is also used as a cosmeceutical product to improve skin functions. This article examines all knowledge that has become available at this time for revealing the chemistry of the current has been extensively investigated based on the data, resulting in UA derivatives with improved potency, bioavailability, and stability being used to treat a number of non-communicable diseases. The pharmacological activity of UA has been exploited to improve learning and memory and treat depression, emotional stress, fatigue, anxiety, insomnia, Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia. The effects of UA on the central nervous system detailed in this review. The majority of UA studies have been preclinical evaluations of cellular mechanisms in the central nervous system, and more translational clinical research is needed to assess the drug's safety and efficacy, as well as its favorable, biodistribution, which could be targeted using different pathways and administration routes. Several in vitro and in vivo studies have investigated the pharmacological properties of UA reporting neuroprotective effects and improvements in cognitive function. These effects are attributed to its antioxidant, antiapoptotic, and anti-inflammatory actions.

The Synergistic Effect of Fluoxetine, Buspirone, and Sumatriptan with Sodium Valproate and Phenobarbitone in Experimental Models of Convulsion

Epilepsy is one of the most common brain disorders, affecting at least 50 million persons worldwide. Antiepileptic’s have several dose-dependent side effects, necessitating a dose reduction or addition of an adjunct therapy. This study investigates the anticonvulsant activity of low dose phenobarbitone and sodium valproate when combined with buspirone, sumatriptan and fluoxetine. Mice were randomly divided into five groups; group I were treated with 0.2 ml of distilled water, group II were administered 20 mg/kg fluoxetine and 150 mg/kg sodium valproate, group III were administered 20 mg/kg sumatriptan and 150 mg/kg sodium valproate, group IV were administered 5 mg/kg buspirone and 150 mg/kg sodium valproate while group V were administered 150mg/kg of sodium valproate. One hour later, 70 mg/kg pentylenetetrazole (PTZ) was intraperitoneally administered to all mice. The onset of central nervous system (CNS) activity and percentage protection were recorded. The above was repeated using phenobarbitone (15 mg/kg). For strychnine (STN)-induced convulsion, the procedure was repeated with 1 mg/kg strychnine used in place of PTZ. For maximal electroshock shock -induced convulsion, mice were subjected to electroshock current of 50 mA for 0.2 seconds after one hour of administering the drugs as done in the other methods. Sumatriptan and sodium valproate combination significantly delayed the onset of CNS activity when compared with the negative control (p<0.05) in PTZ-induced convulsion. Fluoxetine and buspirone in combination with sodium valproate significantly delayed the onset of CNS activity (p<0.0001) against STN-induced convulsion. The different drugs in combination with phenobarbitone protected the mice against MES and PTZ-induced convulsion.

Development of Novel Substituted 1,2,3,4-tetrahydro Cyclohex-1,2,3-trihydro Cyclopenta [B] Indole Derivatives as Potential Therapeutic Agents

Abstract: The current study aims to synthesize, characterize, and evaluate a specific class of heterocyclic compounds called fused polycyclic indoles, in combination with carbazoles, carbolines, and their partially saturated counterparts. These compounds have been known to have potent biological activity. The study's procedures involve synthesizing these compounds and evaluating them for central nervous system activity. Results showed that all the compounds had CNS-depressing effects in mice. Some compounds, such as YA1 and YA5, were found to have a stronger CNS-depressing activity than others. All compounds tested, YA1 to YA7, caused more than 50% change in locomotor activity when compared to a standard drug. YA3 and YA5 were found to have the highest activity at 86.2% and 83.9% respectively after 120 minutes of administration at a dose of 100 mg/kg. In addition, the acute oral toxicity studies showed that YA3 was non-toxic and YA5 was found to be toxic. The findings of the study provide evidence that these title compounds have good CNS activity.

Efficiency of Nanoparticles (Micromage-B) in the Complex Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is a serious neurological problem because of its high prevalence, chronic course, frequent disability, and propensity to affect young people. The immunopathogenesis hypothesis underlies the origin of MS. Selective sorption activity of biocompatible magnetite nanoparticles against surface proteins of cell membranes, circulating immune complexes, lymphocytotoxic antibodies, complement system, the effect of increasing phagocytic activity and leukocyte phagocytosis completion index allows the effective use of these nanodevices for immunocorrection. The main goal of the study is to slow down the progression of MS, improve the neurological status and general condition of the patient, and reduce the dynamics of the spread of demyelinating foci in the brain. Materials and methods: a patient diagnosed with multiple sclerosis, secondary progressive type of course, cerebro-spinal form, clinical aggravation stage; EDSS neurological status and disability assessment scales; contrast-enhanced MRI of the brain. An oral form of the nanodevice Micromage-B was used as an immunosorbent and immunomodulator. The choice of the regimen and dosage of Micromage-B was personalized. Assessment of the general condition and neurological status was performed every 7 days for 6 months. Contrast-enhanced MRI of the brain was performed at the 5th month of the study. As a result of using Micromage-B in MS treatment, objective improvement of neurological status, reduction of stiffness and rapid fatigability of the lower extremities were observed. Gait and coordination improved, hand tremors decreased, depression and signs of concentration disorders disappeared, appetite restored, and speech improved. During the entire period of Micromage-B application, positive dynamics in the normalization of the neurological status was observed. After 6 months of treatment, the total score dropped by 165 to 35. It was found that the maximum positive effect was observed in the evaluation of the pyramidal system and coordination. The EDSS Disability Scale score decreased from 6.0 to 5.0. Contrast-enhanced MRI brain examination for the first time showed a decrease in the number of new foci of demyelination in the brain by the 4th month of Micromage-B administration. The positive dynamics of normalization of the neurological status correlated with the results of brain MRI. The process of recovery of central nervous system activity in MS is not only due to the immunosuppressive properties of magnetite nanoparticles, but is probably caused by the activation of remyelination mechanisms and oligodendrocyte differentiation through enzymatic methylation. Considering the above, the use of biocompatible nanodevices in the complex treatment of MS is a promising direction. The scheme and method of using biocompatible magnetite nanoparticles to improve the effectiveness of MS treatment require further improvement and study.

Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours

Antibody-drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood-brain or blood-tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.

The introduction and current status of the multidimensional model of pain neurobiology.

Conceptual models are useful because they guide our practical actions related to whatever is represented by the model; this includes research that reveals the limitations of these actions and the potential for their improvement. These statements apply to many aspects of daily life and especially to pain as a challenge for both clinical practice specifically and neurobiology generally. In the first half of the 20th century, our conceptual model of pain, to the extent that it existed at all, was based on evidence supporting the proposition that pain emerged from activity within a very spatially limited set of central nervous system (CNS) structures located within the cerebral cortex and it's oligosynaptic connections with the thalamus. This CNS activity was strongly associated with the activation of physiologically distinct and specialized somatovisceral afferent fibers. All, or nearly all, aspects of the pain experience were thought to arise from, and be modified by, changes in that localized CNS activity. There was no compelling and widely accepted reason to consider an alternative model. However, neurophysiological, neuroanatomical, behavioral, and clinical evidence emerging in the late mid-20th century prompted a reconsideration of the prevailing model of pain neurobiology. Based on this new evidence and the perceived limitations of the prevailing model, pain could then be reasonably conceived as a multidimensional experience arising from the conjoint activation of physiologically and anatomically distinct but interacting CNS structures each separately mediating sensory discriminative, affective, and cognitive aspects of pain. This brief historical review describes the intellectual climate at the time this multidimensional model was proposed, the dispositions for resisting or accepting it, and concludes with a comment on the current status of the model as a fusion of distributed activations that create a unified perception of pain.

The First-Night Effect on the Instability of Stage N2: Evidence from the Activity of the Central and Autonomic Nervous Systems

A series of studies have suggested that stage N2 is vulnerable and strongly affected by the first-night effect (FNE). However, the neurophysiological mechanism underlying the vulnerability of stage N2 of the FNE has not been well examined. A total of 17 healthy adults (11 women and 6 men, mean age: 21.59 ± 2.12) underwent two nights of polysomnogram recordings in the sleep laboratory. We analyzed sleep structure and central and autonomic nervous system activity during stage N2 and applied the electroencephalographic (EEG) activation index (beta/delta power ratio) and heart rate variability to reflect changes in central and autonomic nervous system activity caused by the FNE. Correlation analyses were performed between EEG activation and heart rate variability. The results showed that EEG activation and high-frequency heart rate variability increased on the adaptation night (Night 1). Importantly, EEG activation was significantly associated with the percentage of stage N1, and the correlation between EEG activation and high-frequency heart rate variability decreased due to the FNE. These findings indicate that the FNE affects the instability of stage N2 by increasing central nervous system activity and uncoupling the activity between the central and autonomic nervous systems.

Small Molecule Decoys of Aggregation for Elimination of Aβ-Peptide Toxicity.

Several lines of evidence suggest that a characteristic of the neuropathology of Alzheimer's disease (AD) is the aggregation of the amyloid beta peptides (Aβ), fragments of the human amyloid precursor protein (hAPP). The dominating species are the Aβ40 and Aβ42 fragments with 40 and 42 amino acids, respectively. Aβ initially forms soluble oligomers that continue to expand to protofibrils, suggestively the neurotoxic intermediates, and thereafter turn into insoluble fibrils that are markers of the disease. Using the powerful tool of pharmacophore simulation, we selected small molecules not known to possess central nervous system (CNS) activity but that might interact with Aβ aggregation, from the NCI Chemotherapeutic Agents Repository, Bethesda, MD. We assessed the activity of these compounds on Aβ aggregation using the thioflavin T fluorescence correlation spectroscopy (ThT-FCS) assay. Förster resonance energy transfer-based fluorescence correlation spectroscopy (FRET-FCS) was used to characterize the dose-dependent activity of selected compounds at an early stage of Aβ aggregation. Transmission electron microscopy (TEM) confirmed that the interfering substances block fibril formation and identified the macrostructures of Aβ aggregates formed in their presence. We first found three compounds generating protofibrils with branching and budding never observed in the control. One compound generated a two-dimensional sheet structure and another generated a double-stranded filament. Importantly, these compounds generating protofibrils with altered macrostructure protected against Aβ-induced toxicity in a cell model while showing no toxicity in a model of cognition in normal mice. The data suggest that the active compounds act as decoys turning the aggregation into nontoxic trajectories and pointing toward novel approaches to therapy.

Central androgen action reverses hypothalamic astrogliosis and atherogenic risk factors induced by orchiectomy and high-fat diet feeding in male mice.

Hypogonadism in males confers elevated cardiovascular disease (CVD) risk by unknown mechanisms. Recent radiological evidence suggests that low testosterone (T) is associated with mediobasal hypothalamic (MBH) gliosis, a central nervous system (CNS) cellular response linked to metabolic dysfunction. To address mechanisms linking CNS androgen action to CVD risk, we generated a hypogonadal, hyperlipidemic mouse model with orchiectomy (ORX) combined with hepatic PCSK9 overexpression. After 4 wk of high-fat, high-sucrose diet (HFHS) consumption, despite equal body weights and glucose tolerance, androgen-deficient ORX mice had a more atherogenic lipid profile and increased liver and leukocyte inflammatory signaling compared with sham-operated control mice. Along with these early CVD risk indicators, ORX markedly amplified HFHS-induced astrogliosis in the MBH. Transcriptomic analysis further revealed that ORX and high-fat diet feeding induced upregulation of inflammatory pathways and downregulation of metabolic pathways in hypothalamic astrocytes. To interrogate the role of sex steroid signaling in the CNS in cardiometabolic risk and MBH inflammation, central infusion of T and dihydrotestosterone (DHT) was performed on ORX mice. Central DHT prevented MBH astrogliosis and reduced the liver inflammatory signaling and monocytosis induced by HFHS and ORX; T had a partial protective effect. Finally, a cross-sectional study in 41 adult men demonstrated a positive correlation between radiological evidence of MBH gliosis and plasma lipids. These findings demonstrate that T deficiency in combination with a Western-style diet promotes hypothalamic gliosis concomitant with increased atherogenic risk factors and provide supportive evidence for regulation of lipid metabolism and cardiometabolic risk determinants by the CNS action of sex steroids.NEW & NOTEWORTHY This study provides evidence that hypothalamic gliosis is a key early event through which androgen deficiency in combination with a Western-style diet might lead to cardiometabolic dysregulation in males. Furthermore, this work provides the first evidence in humans of a positive association between hypothalamic gliosis and LDL-cholesterol, advancing our knowledge of CNS influences on CVD risk progression.

Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway

BackgroundAlzheimer's disease (AD) represents the common neurodegenerative disease featured by the manifestations of cognitive impairment and memory loss. AD could be alleviated with medication and improving quality of life. Clinical treatment of AD is mainly aimed at improving the cognitive function of patients. Donepezil, memantine and galantamine are commonly used drug. But they could only relieve AD, not cure it. Therefore, new treatment strategies focusing on AD pathogenesis are of great significance and value. Myricetin (Myr) is a natural flavonoid extracted from Myrica rubra. And it shows different bioactivities, such as anti-inflammation, antioxidation as well as central nervous system (CNS) activities. Nonetheless, its associated mechanism in treating AD remains unknown. PurposeHere we focused on investigating Myr's effect on treating AD and exploring if its protection on the nervous system activity was associated with specifically inhibiting P38 MAPK signaling pathway while regulating mitochondria-NLRP3 inflammasome-microglia. Study design and methodsThis work utilized triple transgenic mice (3 × Tg-AD) as AD models and Aβ25–35 was used to induce BV2 cells to build an in vitro AD model. Behavioristics, pathology and related inflammatory factors were examined. Molecular mechanisms are investigated by western-blot, immunofluorescence staining, CETSA, molecular docking, network pharmacology. ResultsAccording to our findings, Myr could remarkably improve memory loss, spatial learning ability, Aβ plaque deposition, neuronal and synaptic damage in 3 × Tg-AD mice through specifically inhibiting P38 MAPK pathway activation while restraining microglial hyperactivation. Furthermore, Myr promoted the transformation of microglial phenotype, restored the mitochondrial fission-fusion balance, facilitated mitochondrial biogenesis, and restrained NLRP3 inflammasome activation and neuroinflammation. For the in-vitro experiments, P38 agonist dehydrocorydaline (DHC) was utilized to confirm the key regulatory role of P38 MAPK signaling pathway on the mitochondria-NLRP3 inflammasome-microglia channel. ConclusionsOur results revealed the therapeutic efficacy of Myr in experimental AD, and implied that the associated mechanism is possibly associated with inhibiting tmitochondrial dysfunction, activating NLRP3 inflammasome, and neuroinflammation which was mediated by P38 MAPK pathway. Myr is the drug candidate in AD therapy via targeting P38 MAPK pathway.

Brain not exempt from social determinants of health.

Before combination antiretroviral therapy (ART), HIV-associated neurological complications were widespread and sometimes profound. Even with viral suppression on ART, however, neurobiological abnormalities persist in people living with HIV. Typically, these abnormalities are attributed to viral reservoir in the central nervous system and attendant microglial activation.1 However, an exclusive focus on biological factors probably obscures key contributors to brain differences observed in people living with HIV: social and structural determinants of health.

In-silico Validation of Pyrazolone Derivatives as the Potent Scaff old for Modulating Protein Abnormalities Associated with Parkinson’s Disease

Aim: We explored pyrazolone derivatives for anti-Parkinson’s activity using in-silico tools to identify novel lead hits against Parkinson’s disease. Background: Parkinson’s disease is the most predominant neuronal degenerative disorder, caused by protein aggregation and dopamine imbalance. The available therapeutic agents on prolonged exposure lead to severe adverse eff ects and provide only symptomatic relief. Therefore, it is a need for novel drug molecules that would modulate the disease condition. Objectives: To identify novel hit molecule for a sequence of molecules designed using pyrazolone as a parent moiety by computer-aided drug design techniques. Materials and Methods: Derivatives are generated by various substituted functional groups and further, pharmacokinetic profi le, the biological spectrum, adverse drug eff ect, molecular docking, molecular dynamic, and MMPBSA evaluation was performed. Results: Thirty-four compounds follow a pharmacokinetic profi le. 15 compounds were predicted to possess a positive central nervous system activity score. The compounds C13, C12, C14, A1, C9, and C7 possessed the highest binding affi nity of -7.81, -3.15, -8.49, -3.43, -6.09, and -2.77 kcal/mol with various targets involved in Parkinson’s disease. Compound C13 exhibit ed highest binding score of -9.78 kcal/mol formono amino oxidase-B. Conclusion: From our investigations, we hope that novel substituted pyrazolone derivatives can act as an assuring virtual hit molecule for developing anti-Parkinson’s agents. These predictions obtained via in-silico techniques could aid the development of pharmacological inhibitors for Parkinson’s disease.

Sugar, salt, immunity and the cause of primary hypertension.

Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension.

Regular short-duration breaks do not prevent mental fatigue and decline in cognitive efficiency in healthy young men during an office-like simulated mental working day: An EEG study

Employees in Europe work on average 7.2 h per day. Prolonged periods of uninterrupted cognitive activity during the working day can cause changes in motivation, mental fatigue, and deterioration in cognitive function. In this exploratory study, we aimed to determine the effectiveness of taking 10-min breaks for light exercise every 50 min in preventing these negative effects during a simulated 7-h office-like computer work. Eighteen healthy young adult men (aged 26 ± 3 years) who did not work in an office participated. The effects of 7 h of office-like work with 10-min breaks every 50 min on central nervous system activity, cognitive function, mood, and motivation were investigated and compared with those measured on a control day without work. Our study found that engaging in 7 h of mental work similar to that found in an office environment, with 10-min breaks every 50 min, can negatively impact cognitive efficiency, suppress brain neural network activity, and cause mental fatigue. These effects do not fully recover after a 4.5-h rest. Additionally, taking short breaks during the workday does not prevent mental exhaustion or impairments in cognitive function. These findings should be considered when discussing strategies to prevent mental exhaustion caused by mental work.

Brain-Computer Interface Technologies for Neurological Diseases

A Brain-Computer Interface (BCI) is a device that monitors central nervous system (CNS) activity and transforms it into artificial output that can be used to replace, improve, supplement, or restore the natural CNS output. Brain-Computer Interface (BCI) technologies for neurological diseases are vital for the well-being of related patients. This paper presents 4 forms of BCI technologies used for neurological diseases: EEG-based BCI for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), Neural Cursor and BCI Spellers for ALS patients, Seizure Prediction BCI for those with epilepsy, and Motor Imagery BCI (MI-BCI) for the treatment of upper-limb strokes. The development and applications of the aforementioned BCI technologies are covered in detail. This literature review's objective is to examine the key characteristics of BCI technologies used to make the life quality of neurological disease sufferers better. The author aims to assist concerned researchers and individuals with the gathered information and help future researchers to learn better from previous studies.

Ethical Challenges Posed by Brain-Computer Interface in a Medical Context

Brain-Computer Interface (BCI) is a group of relatively recent technologies that connects Central Nervous System (CNS) activity with an external device. The resulting interconnected pathway may possess a variety of functions, from extracting and showing electrical activity in the brain to modifying entire cognitive functions. Owing to its revolutionary capability of accessing individuals’ neural systems and modifying their mental states, BCI accounts for major breakthroughs in medical neuroscience, but are also ethically problematic. Under closer scrutiny, BCI notably gives rise to concerns relevant to privacy, autonomy, and identity, three basic rights of the individual. By focusing on ethical definitions, ethical scenarios, and two specific cases concerning vulnerable social groups, this essay examines the ethical repercussions of Brain-Computer Interface in the context of medical research and treatment.

2D-QSAR, molecular docking and MD simulation based virtual screening of the herbal molecules against Alzheimer’s disorder: an approach to predict CNS activity

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer’s Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of −11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD. Communicated by Ramaswamy H. Sarma

EFFECTS OF THE ESSENTIAL OIL OF DRIED FRUITS OF PIPER GUINEENSE (PIPERACEAE) ON NEUROLOGICAL SYNDROMES ASSOCIATED WITH CEREBRAL MALARIA IN MICE

Background: Cerebral Malaria (CM), is associated with neurological syndromes characterized by cognitive and neurobehavioral abnormalities. Piper guineense Schum and Thonnis known to possess anti-oxidant and central nervous system activities. In this study, effects of essential oil of P. guineense (EOPG) dried fruitson selected behavioral and functional indices in mice with cerebral malaria was evaluated. Method: Mice with confirmed CM, following intraperitoneal inoculation with 1x107 Plasmodium berghei ANKA parasitized blood in 0.2 ml of normal saline, were randomly allocated into 14 groups (n=12), namely, parasitized control, quinine control, EOPG graded doses (6.25, 12.5, 25, 50, 100 and 150mg/kg), and combination of quinine and EOPG graded doses. Quinine was administered at a dose of 20 mg/kg stat, then 10 mg/kg twice daily for next two days, while EOPG was administered once daily for 3 days, beginning from day 5 post inoculation. Non-parasitized (n=12) and parasitized controls were treated with the vehicle (5% Tween 80 in distilled water). Parasitemia, weight, survival and behavioral assessment using SHIRPA protocol were taken daily. Results: EOPG showed anti-plasmodial activity in a dose dependent manner, significantly mitigated mortality rate at higher doses (100 and 150mg/kg), and exhibit dose dependent central nervous system protective effects. Also, except for quinine/6.25 mg/kg EOPG, 100% mortality was observed with combination groups, suggesting a potential to precipitate toxicity. Conclusion: The study concluded that EOPG possesses antimalarial and central nervous system protective effects and may therefore serves to mitigate neurological syndrome in cerebral malaria. Peer Review History: Received: 20 December 2022; Revised: 27 January 2023; Accepted: 28 February, Available online: 15 March 2023 Academic Editor: Dr. Jennifer Audu-Peter, University of Jos, Nigeria, drambia44@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Dr. Rima Benatoui,Laboratory of Applied Neuroendocrinology, Department of Biology, Faculty of Science, Badji Mokhtar University Annaba, Algeria. benattouiryma@gmail.com Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr