Nervous System Research Articles

Exploring the Neuroprotective Behaviour and Hepatoprotective Effects of Plumbagin in MPTP-Induced Parkinson's Disease

Aims: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms like tremors and bradykinesia, as well as non-motor symptoms such as sleep disturbances and autonomic dysfunction. Recent research suggests a link between PD and liver dysfunction, including altered metabolism and elevated liver enzymes. Plumbagin, recognized for its antioxidant and neuroprotective properties, may offer therapeutic benefits. This study explores its effects on both motor and non-motor symptoms in MPTP-treated mice, as well as its impact on liver function through serum enzyme analysis. The aim is to assess the neuroprotective and hepatoprotective potential of plumbagin in countering MPTP-induced neurodegeneration and liver dysfunction. Methodology: Thirty mice (22-30g, 8-12 weeks old) were randomly assigned to five groups of six each. The experiment spanned 28 days, with the mice housed under controlled conditions and provided standard feed and water. Behavioral tests, including the Marble Burying and Tail Suspension tests, were conducted to assess anxiety and depressive-like behavior. Serum biochemistry, including ALT, AST, and BUN, was measured using standard ERBA kits to evaluate liver function health. Results: In the marble burying and tail suspension tests, MPTP-induced mice (DC group) exhibited significantly higher anxiety and depressive-like behaviors compared to the sham and plumbagin groups. Plumbagin treatment (PD) and levodopa (LS) significantly reduced these behavioral symptoms. Liver function markers (ALT, AST, ALP) and BUN levels were elevated in DC mice, indicating liver and kidney damage, while plumbagin treatment mitigated these effects, showing values comparable to the standard treatment (LS). Conclusion: This study demonstrates that MPTP exposure affects both the central nervous system and liver function, leading to anxiety, depression, and liver damage, as evidenced by elevated liver enzymes. Plumbagin showed protective effects, reducing these behavioral and biochemical changes through its antioxidant properties, suggesting its potential as a therapeutic agent against MPTP-induced neurotoxicity and hepatotoxicity. These findings suggest that future research should investigate plumbagin's clinical potential for treating Parkinson's disease and liver dysfunction, offering promise for its use in developing neuroprotective therapies.

Growth Factor Gene Therapy for Alzheimer's Disease.

Nervous system growth factors are natural proteins of the brain that influence neuronal survival and function throughout life, from embryonic development to old age. In animal models of Alzheimer's disease (AD), the growth factor brain derived neurotrophic factor (BDNF) prevents neuronal death, activates neuronal function, builds new synapses and improves learning and memory. Accordingly, we are determining whether gene delivery of BDNF in patients with AD will slow disease progression and improve memory. In a previous clinical trial of nerve growth factor (NGF) gene therapy in AD patients (NCT00017940, June 2001), we learned that growth factors can unequivocally elicit classic trophic responses from degenerating neurons in AD. Experience gained from the earlier NGF gene therapy trial is guiding our effort to optimize gene delivery of BDNF in our present clinical program (NCT05040217, June 2021).

Alzheimer's Disease Protein Targets: Comprehensive Review and Future Directions.

Alzheimer's disease (AD) is a gradual degenerative ailment of the nervous system that is marked by the buildup of amyloid-β plaques and neurofibrillary tangles. This accumulation causes problems with the connections between nerve cells and the loss of these cells. This review paper explores the complex pathophysiology of AD, analyzing the neuronal loss reported in key brain regions like the entorhinal cortex, amygdala, hippocampus, and cortical association areas. The text also examines subcortical nuclei participation, such as the noradrenergic locus coeruleus, serotonergic dorsal raphe, and cholinergic basal nucleus. Also, this review discusses the importance of tau protein hyperphosphorylation, oxidative stress, and metal ion dysregulation in the evolution of AD. Moreover, it explores the cholinergic theory and the influence of the APOE (apolipoprotein E) genotype on the effectiveness of therapy. This article thoroughly summarizes the current knowledge on AD, including its clinical symptoms and possible treatment approaches, by combining several theories and new targets. The study highlights the connection between the degree of tangle development and the severity of dementia, underlining the need for creative methods to tackle the complex difficulties of discovering drugs for AD.

Antibody-Drug Conjugates for the Treatment of Non-Small Cell Lung Cancer with Central Nervous System Metastases.

Antibody-drug conjugates (ADCs) represent an emerging class of targeted anticancer agents that have demonstrated impressive efficacy in numerous cancer types. In non-small cell lung cancer (NSCLC), ADCs have become a component of the treatment armamentarium for a subset of patients with metastatic disease. Emerging data suggest that some ADCs exhibit impressive activity even in central nervous system (CNS) metastases, a disease site that is difficult to treat and associated with poor prognosis. Herein, we describe and summarize the existing evidence surrounding ADCs in NSCLC with a focus on CNS activity.

Ghrelin in Depression: A Promising Therapeutic Target.

Depression is a widespread disease affecting over 300 million individuals of various ethnicities and socioeconomic backgrounds globally. It frequently strikes early in life and becomes a chronic or recurring lifelong illness. Out of the various hypotheses for the pathophysiology of depression, the gut-brain axis and stress hypothesis are the ones that need to be researched, as psychological stress impairs one or more pathways of the brain-gut axis and is likely to cause brain-gut axis dysfunction and depression. A dysfunctional reciprocal gut-brain relationship may contribute to many diseases, including inflammatory disorders, abnormal stress responses, impaired behavior, and metabolic changes. The hormone ghrelin is a topic of interest concerning the gut-brain axis as it interacts with the gut-brain axis indirectly via the central nervous system or via crossing the blood-brain barrier. Ghrelin release is also affected by the gut microbes, which has also been discussed in the review. This review elaborates on Ghrelin's role in depression and its effect on various aspects like neurogenesis, HPA axis, and neuroinflammation. Furthermore, this review focuses on ghrelin as a potential target for alleviation of depressive symptoms.

A DISEASE-BASED PERSPECTIVE OF THE RELATIONSHIP BETWEEN NEUROINFLAMMATION AND IMPAIRED GLUCOSE METABOLISM

Neuroinflammation is a significant contributor to the pathogenesis of several central nervous system disorders including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, and amyotrophic lateral sclerosis. Neuroinflammation is the immune response of the central nervous system against central or peripheral abnormalities disturbed by foreign agents, molecules, metabolic activities, or various diseases. Astrocytes and microglia activation are the main activators of neuroinflammation. The polarization changes of these defender cells have some key roles in bodily metabolism as much as neuronal behavior. The blood-brain barrier is known as the first defender of brain parenchyma. Neuroinflammation disrupts blood-brain barrier integrity and may cause blood-brain barrier breakdown. Glucose is the main energy source of brain and glucose uptake is achieved through the blood-brain barrier. Altered glucose metabolism may have detrimental effects on brain functions and may cause brain disorders. Also, it has been suggested that neuroinflammation may have crucial roles in glucose metabolism. The distribution of the blood-brain barrier in vascular endothelial cells of neurons, astrocytes, and microglia contributes to the transport of glucose to the cells of brain. Microglia and astrocyte polarization are suggested as the two main underlying mechanisms in neuroinflammation. It’s obviously determined that neuroinflammation-caused neurodegenerative diseases are tightly linked with the brain insulin resistance and disrupted cerebral and peripheral glucose metabolism. However, there is lacking knowledge about glucose metabolism deficiencies and microglia/astrocyte polarization. Herein this review, we summarized the neuroinflammation and glucose metabolism with the most common neurological diseases and the possible effects of microglia/astrocyte polarization on glucose metabolism.

Primary central nervous system diffuse large B-cell lymphoma with MYC and BCL2 rearrangements associated with deep brain stimulation device.

Primary central nervous system diffuse large B-cell lymphoma with MYC and BCL2 rearrangements associated with deep brain stimulation device.

Main etiological factors and comorbid pathology in severe cerebral palsy

Introduction The largest number of factors contributing to the development of cerebral palsy (CP) relate to the pre- and intranatal periods. Premature birth and low birth weight are the most important predictors of cerebral palsy and are associated with persistent brain and motor disorders. Purpose To evaluate the main etiological factors of severe cerebral palsy and comorbid pathology in children with severe motor disorders.Material and methods A retrospective observational study included 170 patients with severe forms of cerebral palsy, divided into two groups (85 subjects each) depending on motor disorders: GMFCS IV, GMFCS V. Perinatal risk factors for severe cerebral palsy were assessed, correlations between perinatal risk factors for expressed movement disorders and height/weight indicators, comorbid pathology in children at the time of admission to the trauma and orthopaedic hospital.Results Prenatal risk factors were responsible for the development of cerebral palsy in children in 71 % of cases. In the GMFCS IV group, gestational age had an inverse correlation with preterm birth (R = –0.53; R2 = 28 %). In the GMFCS V group, disorders caused by a shorter gestational age were interrelated with the duration of the antenatal period (R = –0.79; R2 = 62 %), and also directly correlated with delivery by cesarean section (R = 0.58; R2 = 34 %). Among the comorbid pathologies, eye diseases and psychological development disorders were most often detected.Discussion Low height/weight parameters of patients were due to comorbid pathology, rather than phenotypic constitutional features. Inverse correlation between the disorders caused by the gestational age, low birth weight and duration of pregnancy, risk of developing respiratory disorders, and a direct correlation with cesarean section seem logical. Severe conmobid diseases were more frequently diagnosed in patients with GMFCS V, indicating more extensive perinatal catastrophes in the central nervous system and the relationship between the developed pathology and severe motor disorders.Conclusions The main risk factors for the development of cerebral palsy in patients with severe GMFCS IV–V motor impairments are associated with the pre- and intranatal periods. Comorbid pathology of patients with severe forms of cerebral palsy is caused by severe brain damage and movement disorders that have developed against this background.

MAPbrain: a multi-omics atlas of the primate brain.

The brain is the central hub of the entire nervous system. Its development is a lifelong process guided by a genetic blueprint. Understanding how genes influence brain development is critical for deciphering the formation of human cognitive functions and the underlying mechanisms of neurological disorders. Recent advances in multi-omics techniques have now made it possible to explore these aspects comprehensively. However, integrating and analyzing extensive multi-omics data presents significant challenges. Here, we introduced MAPbrain (http://bigdata.ibp.ac.cn/mapBRAIN/), a multi-omics atlas of the primate brain. This repository integrates and normalizes both our own lab's published data and publicly available multi-omics data, encompassing 21 million brain cells from 38 key brain regions and 436 sub-regions across embryonic and adult stages, with 164 time points in humans and non-human primates. MAPbrain offers a unique, robust, and interactive platform that includes transcriptomics, epigenomics, and spatial transcriptomics data, facilitating a comprehensive exploration of brain development. The platform enables the exploration of cell type- and time point-specific markers, gene expression comparison between brain regions and species, joint analyses across transcriptome and epigenome, and navigation of cell types across species, brain regions, and development stages. Additionally, MAPbrain provides an online integration module for users to navigate and analyze their own data within the platform.

Non-invasive respiratory support in children and young adults with complex medical conditions in pediatric palliative care

ObjectiveDyspnoea and sleep-disordered breathing (SDB) are common in children with life-limiting conditions but studies on treatment with non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) are scarce. The aim...

Demyelination detection in CSF based on electrochemical monitoring of myelin basic protein in comparison between Apta vs. Immuno sensing strategies

Multiple sclerosis (MS) is a recurrent inflammatory, demyelinating disease of the white matter in central nervous system (CNS). The number of MS patients is increasing, but the diagnostic process is still quite difficult, costly and requires combination of several methods. Myelin basic protein (MBP) makes up to 30 % of the myelin in CNS. It is known that MBP is released into the cerebrospinal fluid (CSF) as MS bioindicator. Herein, myelin specific DNA aptamer earlier developed for possible therapeutic purposes and anti-MBP antibody were applied as bioreceptors for MBP recognition on the same nanomodified sensor surfaces and their performances were compared. Biosensors were developed by using graphene oxide (GO) nanoparticles integrated onto pencil graphite electrodes (PGE) and bioreceptor molecules immobilized to create a bioactive layer for MBP binding. The measurements were run with electrochemical impedance spectroscopy (EIS). Selectivity of the biosensors was evaluated using human serum albumin (HSA). After optimization of binding parameters, biosensors were validated in artificial CSF. It was shown that LJM-5708 based aptasensor had LOD 0.65 ng/mL that was comparable to immunosensor LOD (0.36 ng/mL) in artificial CSF and showed its applicability in the clinical concentration range between 1 and 128 ng/mL.

Tractography analysis results of the trigeminus nerve, which contains fibers responsible for proprioception sensation and motor control in Adolescent Idiopathic Scoliosis.

Cross-sectional Study. It is not yet clear whether the loss of proprioceptive sensation and muscle weakness seen in adolescent idiopathic scoliosis (AIS) is the result of central nervous system dysfunction or secondary to spinal deformity. In our study, in order to find an answer to this question, we examined the microarchitecture of the nervus trigeminus, which is least affected by spinal deformity and contains both proprioceptive sensory and motor fibers. In this single-center, cross-sectional cohort study, 40 Lenke Type 3 (27 female, 13 male) AIS patients and 40 (25 female, 15 male) healthy individuals between the ages of 10-18 years. Tractography of the nervus trigenimus was performed using the "DSI Studio" program. The volumes of the targeted musculus pterygoideus lateralis and musculus pterygoideus medialis were measured using the Insight Segmentation and Registration Tool Kit (ITK -SNAP) program. The data were evaluated using the Statistical Package for the Social Sciences 22.0 program for Windows. There was no significant difference between the two groups in terms of baseline characteristics (p˃0.05). Left nervus trigeminus fiber number and fiber ratio were significantly higher in the control group compared to the scoliosis group p < 0.05. Right and left lateral pterygoid muscle showed lower volume and volume percentage in the scoliosis group compared to the control group (p < 0.05). According to the study data, proprioceptive sensory and motor control dysfunction in AIS is predicted to develop independently of spinal deformity.

МЕЗО-ФОРТЕ ТЕРАПИЯ В НЕЙРОРЕАБИЛИТАЦИИ ДЕТЕЙ С МИОПИЕЙ — ПИЛОТНОЕ ИССЛЕДОВАНИЕ

This article presents the results of a pilot clinical and experimental study of the prospects for neurorehabilitation of children with myopia using Meso-Forte Therapy (MFT), an innovative hardware method of restorative treatment using digital music therapy programs. For the first time, data from complex psycho physiological and ophthalmological studies is published, revealing the mechanisms of corrective regulation of the psycho emotional status, the autonomic nervous system, and the tone of the accommodating muscles of the eye using the main algorithms of musical and acoustic effects.

Gut bacteria-derived succinate induces enteric nervous system regeneration.

Enteric neurons control gut physiology by regulating peristalsis, nutrient absorption, and secretion 1 . Disruptions in microbial communities caused by antibiotics or enteric infections result in the loss of enteric neurons and long-term motility disorders 2-5 . However, the signals and underlying mechanisms of this microbiota-neuron communication are unknown. We studied the effects of microbiota on the recovery of the enteric nervous system after microbial dysbiosis caused by antibiotics. We found that both enteric neurons and glia are lost after antibiotic exposure, but recover when the pre-treatment microbiota is restored. Using murine gnotobiotic models and fecal metabolomics, we identified neurogenic bacterial species and their derived metabolite succinate as sufficient to rescue enteric neurons and glia. Unbiased single-nuclei RNA-seq analysis uncovered a novel neural precursor-like population marked by the expression of the neuronal gene Nav2. Genetic fate-mapping showed that Plp1+ enteric glia differentiate into neurons following antibiotic exposure. In contrast, Nav2+ neurons expand upon succinate treatment and indicate an alternative mode of neuronal regeneration under recovery conditions. Our findings highlight specific microbial species, metabolites, and the underlying cellular mechanisms involved in neuronal regeneration, with potential therapeutic implications for peripheral neuropathies.

The Emerging Role of Immunoglobulins and Complement in the Stimulation of Neuronal Activity and Repair: Not as Simple as We Thought

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to treat these disorders. Recent data suggest that autoreactive naturally occurring immunoglobulins produced by subsets of B cells, called B1 B cells, combined with complement, are actively involved in the processes of restoration of neuronal functions during pathological conditions and remyelination. The focus of this review is to discuss the possibility of creating specific therapeutic antibodies that can activate and fix complement to enhance neuronal survival and promote central nervous system repair after injuries associated with many types of neurodegenerative diseases.

Overcoming Barriers: Diagnosis of High-Grade Melanoma: Perspective from a Clinical Case

We present the case of a 30-year-old male patient with loss of visual acuity in the left eye. The imaging study detected a lesion of high suspicion of tumor in the left eye. Enucleation of the left eye was performed, confirming the diagnosis of choroidal melanoma by histopathological study. Subsequently, the disease progressed with neoplastic activity in the lungs, liver, lymph nodes and central nervous system. A case description is provided along with a bibliographic review, focusing on the approach and prognostic factors in patients with metastatic disease.

Acute Quetiapine Intoxication: Relationship Between Ingested Dose, Serum Concentration and Clinical Presentation-Structured Literature Review and Analysis.

Over the past decade, quetiapine has become one of the most commonly used psychotropic drugs in acute intoxication events worldwide. A structured literature review and analysis were conducted to assess the relationship between the kinetic and dynamic profiles in acute quetiapine intoxication. The correlation between dose and peak serum concentration (cmax) was determined using Pearson's correlation coefficient. Binary logistic regression was used to evaluate dose and cmax as predictors of the most common clinical events, signs and symptoms. One hundred and thirty-four cases of acute quetiapine ingestion were included in the analysis, with a median ingested dose of 10 g and a median cmax of 4 mg/L. The typical half-life was estimated to be 16.5 h, significantly longer than at therapeutic doses. For the immediate-release formulation, a biphasic disposition could not be excluded. Dose and cmax demonstrated a weak but significant correlation (r = 0.256; N = 63; p = 0.043). Central nervous system depression and tachycardia were the most common clinical signs. Higher doses and concentrations increased the risk of severe intoxication and were good predictors of intubation, tachycardia, hypotension, QTc prolongation and seizures, but not QRS prolongation, arrhythmia, heart block, hypokalaemia or acidosis. The thresholds for dose and cmax that increased the risk for individual signs and symptoms varied widely. However, doses > 3 g or cmax > 2 mg/L can be considered as alert levels that represent a high risk for severe clinical course of acute quetiapine intoxication.

Glutamate signaling and neuroligin/neurexin adhesion play opposing roles that are mediated by major histocompatibility complex I molecules in cortical synapse formation.

Although neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation (Verhage et al., 2000; Sando et al., 2017; Sigler et al., 2017; Held et al., 2020), yet glutamate clearly regulates glutamate receptor trafficking (Roche et al., 2001; Nong et al., 2004) and induces spine formation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999; Toni et al., 1999; Kwon and Sabatini, 2011; Oh et al., 2016). Using rat and murine culture systems to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing N-methyl-D-aspartate receptor (NMDAR) transport and surface expression as well as co-transport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels in both sexes. Thus, like acetylcholine at the neuromuscular junction (NMJ), glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.Significance Statement The role for neurotransmitter release in synaptogenesis in the central nervous system (CNS) remains unclear. Here, we reconcile conflicting results in the field by showing that glutamate plays an important role in synapse formation by acting as a dispersal signal for NMDARs that is counteracted by trans-synaptic adhesion in intact tissue, similar to the role for neurotransmitter at the NMJ. We also describe a novel form of homeostatic plasticity in young neurons that allows them to respond to changes in activity through surprisingly rapid changes in synapse density. Finally, we show that this plasticity is modulated by immune proteins-MHCI molecules-through negative regulation of NL1 levels, connecting two important synaptic signaling pathways for the first time.

Three cases of autoinflammatory disease with novel NLRC4 mutations, and the first mutation reported in the CARD domain of NLRC4 associated with autoinflammatory infantile enterocolitis (AIFEC)

BackgroundGain of function (GOF) mutations in NOD-like receptor family CARD-containing 4 protein (NLRC4) gene induce a wide spectrum of autoinflammatory phenotypes. Currently, we categorize them into four groups: familial cold autoinflammatory syndrome (FCAS)4, autoinflammatory infantile enterocolitis (AIFEC), NLRC4-macrophage associated syndrome (MAS), and neonatal-onset multisystem inflammatory disease (NOMID). The rarity and complexity of the disease necessitate the description of new cases and a reexamination of our understanding of the condition.Case presentationsWe present three patients with NLRC4-GOF mutations and AIFEC phenotypes. The first patient is an infant girl with periodic fever, seizure, high inflammatory markers, and an episode of macrophage associated syndrome (MAS). History of recurrent fever episodes since childhood was reported in mother and maternal grandmother. A heterozygous mutation was found in CARD domain of NLRC4: c.A91C: p.Asn31His. The second patient is an adolescent boy with periodic fever, diarrhea, aphthous stomatitis, seizure, and central nervous system (CNS) vasculitis. A heterozygous mutation was found in NLRC4 gene: c.1202T > C. p. Val401Ala. The third patient is a child with chronic diarrhea and elevated inflammatory markers. We found a heterozygous mutation in NLRC4 gene: c.390delG: p.S132Afs*21. All mutations have been reported for the first time as NLRC4 mutations associated with autoinflammation. We introduced novel mutations in the CARD domain and between CARD and NBD domain in the first and third cases, respectively. All three children are under remission following treatment.ConclusionsNLRC4-GOF mutations can be associated with autoinflammation with diverse symptoms. Given the rarity of the disease and the possibility of new mutations being identified, the existence of a phenotype/genotype correlation has yet to be thoroughly investigated. The variety in manifestations and severity spectrum mandates a variety of treatments. Adalimumab has shown favorable outcomes in our AIFEC cases.

Myelin oligodendrocyte glycoprotein antibody–associated disease with histopathologic features of primary CNS angiitis without demyelination: Case report and literature review

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disease that affects both small- and medium-sized vessels of the CNS, while myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) is a novel antibody-mediated inflammatory demyelinating disorder that causes damage to the myelin in CNS. We report a case diagnosed as MOGAD due to a history of recurrent myelitis, brain lesions, and positive anti-MOG, but the brain biopsy showed vasculitis without demyelination.