Disease Of Central Nervous System Research Articles

Emergence of a New Pathogen: A Retrospective Study of HPeV-5 Central Nervous System Disease in Alberta, Canada

Human parechoviruses (HPeVs) are known to cause meningo-encephalitis among neonates and infants. We aimed to describe the epidemiology of HPeVs causing central nervous system infections in Alberta from 2014 to 2019 with comparison of known HPeV-3 and emerging HPeV-5. Genomic analysis was completed on a subset of HPeV-5 strains to understand genetic relatedness to other known strains. All cerebrospinal fluid (CSF) samples in Alberta with detection of HPeVs were identified and a case review of medical records was conducted, retrospectively, to gather demographic and clinical details. Descriptive and analytic statistics were used to describe and compare the characteristics of cases affected by HPeV-3 with HPeV-5. Genome amplification was completed on six HPeV-5 samples. During the study period, 18,882 CSF samples were tested; 56 were positive for HPeV-3 or HPeV-5, and 52 patients were included in this study (40 HPeV-3 cases and 12 HPeV-5). A total of 40% of cases occurred in 2016, and 64% of infections occurred in the months of August to October. The mean age of cases was 18 days for HPeV-5 compared with 26 days for HPeV-3 (p = 0.045). Phylogenetic comparison showed similarity to a recombinant strain reported in Australia. HPeV meningo-encephalitis affected neonates/infants, mostly in late summer/early fall, and genomic sequencing of new strains can contribute to understanding the epidemiology of HPeV infections globally.

Polygala tenuifolia root extract attenuates ischemic stroke by inhibiting HMGB1 trigger neuroinflammation

Polygala tenuifolia Willd., a famous traditional Chinese medicine, has been widely applied to treat central nervous system diseases. In this study, P. tenuifolia root extract exhibited a moderate anti-ischemic effect on in-vitro oxygen-glucose deprivation/reperfusion (OGD/R) model. In transient middle cerebral artery occlusion (tMCAO) rats, P. tenuifolia root extract significantly attenuated brain infarction and neurological deficits in a dose-dependent manner. Compared with the sham group, the release of damage-associated molecular patterns (DAMPs)-HMGB1 in the ischemic brain was significantly higher, which was inhibited by P. tenuifolia root extract. To further explore such neuroprotective effects whether associated with aseptic inflammation, HMGB1-activated BV2 microglial cells model was established. The extract of P. tenuifolia was found to inhibit the downstream inflammatory response driven by HMGB1, with an IC50 value of 49.46 μg/mL. In addition, the extract was also found to be able to directly interact with HMGB1 in the surface plasmon resonance (SPR) experiment. Phytochemical studies showed that the extract of P. tenuifolia root contains a large number of terpenoids, oligosaccharides and phenolic compounds, which likely contribute to the above observed biological activities. Our results not only provide some data support for the clinical application of P. tenuifolia against cerebral ischemia, but also clarify the potential target of P tenuifolia's anti-inflammatory properties.

Mechanism of Gastrodin against neurotoxicity based on network pharmacology, molecular docking and experimental verification

BackgroundDisorders of glutamate metabolism and excessive release participat in multiple neuronal pathologies including ischemic stroke (IS), Alzheimer's disease (AD), or Parkinson's disease (PD). Recently, herbal medicines have been widely used and have shown satisfactory results in the treatment of neurological disorders. Gastrodin is a traditional Chinese medicine (TCM) used for the treatment of nerve injuries, spinal cord injuries, and some central nervous system diseases as well. This research examines the neuroprotective effects of Gastrodin against glutamate-induced neurotoxicity in neuronal cells. MethodsThe HERB database was used to explore the active ingredients and target genes of Gastrodia Elata. The STRING database and Cytoscape software were used to screen and construct the Protein-Protein Interaction (PPI). Furthermore, we used molecular docking to predict the potential targets of Gastrodin. The effects of Gastrodin were revealed by western blot, calcium imaging, membrane clamp, CCK8 and flow cytometry. Neuronal oxidative stress and damage were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Neuronal morphology was examined using Golgi-Cox staining. Finally, animal behavior was examined using novel object recognition and fear conditioning tests. ResultsWe have obtained 22 components such as TM10, TM17, TM25 (Gastrodin), and 281 targets such as AKT, EGFR, and CDK1 through network pharmacology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed these genes were significantly enriched in protein phosphorylation, protein serine/threonine/tyrosine kinase activity, apoptosis and HIF-1 signaling pathways, etc. A higher affinity between Gastrodin and AKT was revealed by PPI analysis and molecular docking. Further, Gastrodin significantly inhibited Ca2+ influxes and excitatory synaptic transmission in cortical neurons. In addition, Gastrodin effectively alleviated neuron apoptosis, oxidative stress and damage. ConclusionGastrodin has neuroprotective effects against glutamate-induced neurotoxicity.

Ultrasound Neuromodulation for Sleep and Neurological Disorder Therapy: A Path to Clinical Translation.

Ultrasound neuromodulation is a promising noninvasive technique capable of penetrating the skull and precisely targeting deep brain regions with millimeter accuracy. Recent studies have demonstrated that transcranial ultrasound stimulation (TUS) of sleep-related brain areas can induce sleep in mice and even trigger a reversible, hibernation-like state without causing damage. Beyond its utility in preclinical models of central nervous system diseases, such as epilepsy, tremors, Alzheimer's disease, and depression, TUS holds significant potential for clinical translation. Given that many neurological disorders, including Alzheimer's and Parkinson's disease, are associated with sleep abnormalities, leveraging clinical TUS applications for these diseases also creates a pathway for translating this technology to sleep modulation in human use. These findings highlight the potential for ultrasound neuromodulation to advance neuroscience research and clinical applications in sleep control.

Risk of Inflammatory Central Nervous System Diseases After Tumor Necrosis Factor–Inhibitor Treatment for Autoimmune Diseases

Tumor necrosis factor (TNF) inhibitors have been used extensively to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) disease events following TNF inhibitor therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF-blocking agents. To evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases or TNF inhibitors. Separate searches were conducted across PubMed, Embase, and the Cochrane Library from inception until March 1, 2024. Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group. Study eligibility assessment and data extraction were independently conducted by 2 investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis. The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors. Eighteen studies involving 1 118 428 patients with autoimmune diseases contributing more than 5 698 532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10 000 person-years. Overall, exposure to TNF inhibitors was associated with a 36% increased risk of any inflammatory CNS disease compared to conventional therapies (RR, 1.36; 95% CI, 1.01-1.84; I2, 49%), mainly attributed to demyelinating diseases (RR, 1.38; 95% CI, 1.04-1.81; I2, 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR, 1.36; 95% CI, 0.84-2.21; inflammatory bowel disease 1.49; 95% CI, 0.93-2.40; P for subgroup = .74) and TNF inhibitors (anti-TNF monoclonal antibodies vs etanercept: RR, 1.04; 95% CI, 0.93-1.15; I2, 0%). Compared to conventional therapies, exposure to TNF inhibitors was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune disease or TNF inhibitor type.

Long-term follow-up of methotrexate and cytarabine in adult patients with Langerhans cell histiocytosis.

The optimal treatment strategy for adult Langerhans cell histiocytosis (LCH) remains unclear. Our previous study demonstrated the remarkable efficacy of combined methotrexate and cytarabine (Ara-C) [MA] therapy in patients newly diagnosed with LCH, with a median follow-up of 2 years. The present article reports long-term follow-up data spanning a median of 78 months (6.5 years) from a single-arm, single-centre, prospective phase 2 clinical trial (NCT02389400) conducted between January 2014 and December 2020. Ninety-five adults with newly diagnosed LCH exhibiting multisystem disease or multifocal single-system involvement underwent MA therapy every 35 days for six cycles. Methotrexate (1 g/m2) was administered by 24 h infusion on day 1 and AraC (0.1 g/m2) by 24 h infusion for 5 days. The primary end-point was event-free survival (EFS). The median patient age was 32 years (range 18-65 years). The overall response rate was 89.5%. Seven patients in this cohort died, and 38 experienced disease reactivation. No degenerative central nervous system diseases were observed. The estimated 6-year overall survival (OS) and EFS rates were 93.2% and 55.2% respectively. Multivariate analysis revealed that risk organ (RO) involvement at baseline (hazard ratio [HR] 6.135 [95% confidence interval (CI) 1.185-32.259]; p = 0.031) and age >40 years at diagnosis (HR 7.299 [95% CI 1.056-21.277]; p = 0.042) were associated with inferior OS. RO (HR 2.604 [95% CI 1.418-4.762]; p = 0.002) and skin (HR 2.232 [95% CI 1.171-4.255]; p = 0.015) involvement at baseline were poor prognostic factors for EFS. Regarding adverse events, four patients developed a second primary malignancy. In conclusion, the MA regimen was a valid and safe therapeutic approach for adult patients newly diagnosed with LCH.

The corticospinal tract in multiple sclerosis: correlation between cortical excitability and magnetic resonance imaging measures.

Multiple sclerosis (MS) is a central nervous system disease involving gray and white matters. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) could help identify potential markers of disease evolution, disability, and treatment response. This work evaluates the relationship between intracortical inhibition and facilitation, motor cortex lesions, and corticospinal tract (CST) integrity. Consecutive adult patients with progressive MS were included. Sociodemographic and clinical data were collected. MRI was acquired to assess primary motor cortex lesions (double inversion and phase-sensitive inversion recovery) and CST integrity (diffusion tensor imaging). TMS outcomes were obtained: motor evoked potentials (MEP) latency, resting motor threshold, short-interval intracortical facilitation (ICF) and inhibition. Correlation analysis was performed. Twenty-five patients completed the study (13 females, age: 55.60 ± 11.49 years, Expanded Disability Status Score: 6.00 ± 1.25). Inverse correlations were found between ICF mean and each of CST radial diffusivity (RD) (ρ =-0.56; p < 0.01), CST apparent diffusion coefficient (ADC) (ρ=-0.44; p = 0.03), and disease duration (ρ=-0.46; p = 0.02). MEP latencies were directly correlated with disability scores (ρ = 0.55; p < 0.01). High ADC/RD and low ICF have been previously reported in patients with MS. While the former could reflect structural damage of the CST, the latter could hint towards an aberrant synaptic transmission as well as a depletion of facilitatory compensatory mechanisms that helps overcoming functional decline. The findings suggest concomitant structural and functional abnormalities at later disease stages that would be accompanied with a heightened disability. The results should be interpreted with caution mainly because of the small sample size that precludes further comparisons (e.g., treated vs. untreated patients, primary vs. secondary progressive MS). The role of these outcomes as potential MS biomarkers merit to be further explored.

Phenolic-enabled nanotechnology: a new strategy for central nervous system disease therapy.

Polyphenolic compounds have received tremendous attention in biomedicine because of their good biocompatibility and unique physicochemical properties. In recent years, phenolic-enabled nanotechnology (PEN) has become a hotspot of research in the medical field, and many promising studies have been reported, especially in the application of central nervous system (CNS) diseases. Polyphenolic compounds have superior anti-inflammatory and antioxidant properties, and can easily cross the blood‒brain barrier, as well as protect the nervous system from metabolic damage and promote learning and cognitive functions. However, although great advances have been made in this field, a comprehensive review regarding PEN-based nanomaterials for CNS therapy is lacking. A systematic summary of the basic mechanisms and synthetic strategies of PEN-based nanomaterials is beneficial for meeting the demand for the further development of novel treatments for CNS diseases. This review systematically introduces the fundamental physicochemical properties of PEN-based nanomaterials and their applications in the treatment of CNS diseases. We first describe the different ways in which polyphenols interact with other substances to form high-quality products with controlled sizes, shapes, compositions, and surface chemistry and functions. The application of PEN-based nanomaterials in the treatment of CNS diseases is then described, which provides a reference for subsequent research on the treatment of CNS diseases.

Relationship of cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 with the progression and prognosis of viral encephalitis in children

To investigate the relationship of cerebrospinal fluid and serum levels of soluble interleukin-2 receptor (SIL-2R), endothelial nitric oxide synthase (eNOS), and cluster of differentiation 93 (CD93) with the progression and prognosis of viral encephalitis (VE) in children. Prospectively, 102 children with VE admitted from January 2021 to January 2024 were selected as the VE group. The patients were divided into a mild subgroup (64 patients) and a severe subgroup (38 patients) according to disease progression. The patients were also divided into a good prognosis subgroup (29 patients) and a poor prognosis subgroup (73 patients) according to prognosis. A control group of 102 children with central nervous system diseases who were examined and found not to have VE during the same period was selected. The factors contributing to the poor prognosis of children with VE and the predictive value of SIL-2R, eNOS, and CD93 in cerebrospinal fluid and serum for the poor prognosis of children with VE were evaluated. Cerebrospinal fluid and serum SIL-2R, eNOS, and CD93 levels were significantly increased in the VE group, severe subgroup, and poor prognosis subgroup (P<0.05). Multivariate logistic regression analysis showed that high SIL-2R, eNOS, and CD93 levels in cerebrospinal fluid and serum were risk factors for poor prognosis in children with VE (P<0.05). Receiver operating characteristic curve analysis showed that the combination of cerebrospinal fluid SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). Similarly, the combination of serum SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). The cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 are significantly elevated in children with VE, and they are associated with VE progression and prognosis.

TTR associated leptomeningeal amyloidosis in a Sri Lankan patient

ObjectivesThis case report aims to contribute to the expanding genotypic-phenotypic spectrum of TTR associated leptomeningeal amyloidosis. MethodsNeuroimaging and targeted TTR Sanger sequencing were performed on a 52-year-old female presenting with cognitive and motor symptoms. ResultsThe proband, a Sri Lankan woman, presented with a gradually progressive cognitive decline, followed by a rapid deterioration in motor function and level of consciousness. She had a significant family history of an undiagnosed neurological disorder, characterized by cognitive impairment and early death occurring in the fifth decade of life. Analysis of cerebrospinal fluid (CSF) demonstrated elevated protein levels. CT scan of the brain showed extensive leptomeningeal calcifications and hydrocephalus, and gadolinium enhanced magnetic resonance imaging (MRI) demonstrated extensive leptomeningeal enhancement in the brain and spinal cord.Genetic analysis revealed c.113 A > G, p.D38G mutation in TTR, a rare mutation with characteristic clinic-radiological central nervous system features. DiscussionLeptomeningeal amyloidosis represents the least common subtype of familial transthyretin amyloidosis, which is a life-threatening condition. Among the over 150 identified mutations, few are specifically associated with central nervous system disease. The genetic spectrum and clinical phenotypes including neuroimaging findings continue to expand. It is important to maintain a high index of suspicion for leptomeningeal amyloidosis, particularly when the presentation is not acute or when there are relapsing-remitting symptoms. Consideration of family history and early genetic testing are essential to facilitate appropriate treatment and genetic counselling.

Of potential new treatment targets and polythetic approach in meningoencephalitis of unknown origin: a review.

Meningoencephalitis of unknown origin (MUO) represents an umbrella term for inflammatory, non-infectious central nervous system (CNS) diseases in dogs. Current therapeutic approaches, involving long-term glucocorticosteroid use, often fail to provide adequate relief or cure, and the effectiveness of additional immunosuppressive medications remains uncertain. Future advancements in MUO treatment may benefit from patient-specific therapies, potentially enhancing treatment precision, efficacy, and minimizing side effects. However, significant challenges impede this progress, including ambiguity in MUO subtype classification, uncertainties regarding the autoimmune nature vs. infectious triggers, and the lack of reliable diagnostic biomarkers. Clinical heterogeneity and overlapping signs with other encephalopathies further complicate diagnosis and treatment. This review gives an overview about diagnostic findings and immunological features of MUO. It advocates for a more overall characterization of MUO by using a polythetic system to better characterize MUO subtypes, identify immunological treatment targets, and establish a conceptual foundation for future therapeutic trials. Addressing these themes may lead to more effective and less burdensome treatments, improving the quality of life for dogs afflicted with MUO and their owners.

An In Vitro Platform for Pharmacokinetic Quantification and Optimization of Cerebrospinal Fluid Filtration and Drug Circulation

Abstract Background: Modification of cerebrospinal fluid (CSF) transport dynamics is an expanding method for treating central nervous system injury and diseases. One application of this route is to modify the distribution of solutes in the CSF, however few tools currently exist for this purpose. The present study describes the use of a subject-specific in-vitro CSF phantom to perform a parametric evaluation of the Neurapheresis? CSF Management System (NP) for both CSF filtration and intrathecal drug circulation. Methods: An in-vitro CSF phantom was constructed which included realistic anatomy for the complete subarachnoid space. This platform was configured to test multiple parametric modifications of a dual-lumen catheter and filtration system. Calibrated mapping of tracer distribution and area under the curve (AUC) measurements were used to compare filtration and intrathecal-circulation schemes using the NP device versus the clinical standards of care. Results: The NP device showed potential advantages over lumbar drain (LD) for clearance of simulated subarachnoid hemorrhage, especially in the spinal canal. Use of the NP device in combination with simulated intracerebroventricular drug infusion (ICV) resulted in an increased extent and uniformity of tracer spread compared to ICV alone. Conclusion: NP improved clearance of simulated subarachnoid hemorrhage compared to LD and increased uniformity of tracer concentration via simulated ICV, providing support for NP use in these scenarios. The in-vitro CSF phantom system presented here quantitatively described the effects of parametric boundary modification on solute distribution in the intrathecal space.

Pregnancy-related intracranial venous sinus thrombosis secondary to cryptococcal meningoencephalitis: a case report and literature review

BackgroundCerebral venous sinus thrombosis (CVST), a serious cerebrovascular and neurological emergency, is common in pregnant individuals and accounts for approximately 0.5–1.0% of all cerebrovascular diseases. However, CVST with cryptococcal meningoencephalitis in immunocompetent pregnant patients is rare.Case presentationA 30-year-old woman who was 33 weeks pregnant presented with recurrent dizziness, headache, and vomiting as the main clinical manifestations, all of which were initially nonspecific. After assessment of the cerebrospinal fluid, skull computerized tomography, magnetic resonance imaging, and other laboratory and imaging examinations, the patient was diagnosed with secondary pregnancy-related CVST with cryptococcal meningoencephalitis. Despite receiving potent anticoagulant and antifungal treatment, the patient’s condition deteriorated, and the patient’s family opted to cease treatment.ConclusionsWe present a rare case of CVST with cryptococcal meningoencephalitis in an immunocompetent pregnant patient. The difficulty of diagnosing and treating secondary pregnancy-related CVST caused by cryptococcal meningoencephalitis, as well as the great challenges faced at present are highlighted. One crucial lesson from the present case is that when clinical and imaging signs are unusual for CVST during pregnancy, it is essential to account for the possibility of other central nervous system (CNS) diseases, such as CNS infections with Cryptococcus, which may cause CVST.

Edaravone Dexborneol provides neuroprotective effect by inhibiting neurotoxic activation of astrocytes through inhibiting NF-κB signaling in cortical ischemia

Edaravone Dexborneol (EDB), comprised of edaravone and (+)- bornel, has been demonstrated to have synergistic effects of antioxidant and anti-inflammatory, which makes it to be applied for stroke as a protectant. However, the underlying mechanism of neuroprotection of EDB has not been fully elucidated. Increasing evidence has shown that neurotoxic A1 astrocytes were closely related to neuronal death after cerebral ischemia. However, whether EDB could provide neuroprotection by modulating the activation of astrocytes has not yet been elucidated. The present study aimed to explore whether EDB afforded neuroprotection by modulating A1 polarization of astrocytes and the down-stream signaling after cerebral ischemia. We first validated the neuroprotective effects of EDB in mice suffering focal cerebral ischemia via evaluating behavioral test, infarct volumes and neuronal survival. As for the down-stream signaling, our data further showed that EDB alleviated neuronal death by suppressing activation of neurotoxic A1 astrocytes via inhibition of NF-κB signaling pathway in vitro. Additionally, administration of EDB reduced the number of A1 reactive astrocytes in mice of focal cerebral ischemia. The above findings demonstrated that EDB provided neuroprotective effect by inhibiting neurotoxic activation of A1 astrocytes in animal model of cerebral ischemia, which indicated that EDB-mediated phenotypic regulation of astrocytes is a potential research direction to promote neurological recovery in central nervous system (CNS) diseases.

Choroid Plexus Pathophysiology.

This review examines the crucial roles of the choroid plexus (ChP) in central nervous system (CNS) pathology, emphasizing its involvement in disease mechanisms and therapeutic potential. Structural changes in the human ChP have been reported across various diseases in case reports and descriptive work, but studies have yet to pin down the physiological relevance of these changes. We highlight primary pathologies of the ChP, as well as their significance in neurologic disorders, including stroke, hydrocephalus, infectious diseases, and neurodegeneration. Synthesizing recent research, this review positions the ChP as a critical player in CNS homeostasis and pathology, advocating for enhanced focus on its mechanisms to unlock new diagnostic and treatment strategies and ultimately improve patient outcomes in CNS diseases. Whether acting as a principal driver of disease, a gateway for pathogens into the CNS, or an orchestrator of neuroimmune processes, the ChP holds tremendous promise as a therapeutic target to attenuate a multitude of CNS conditions.

Characterization of neurologic disease-associated Streptococcus suis strains within the United States swine herd and use of diagnostic tools.

Streptococcus suis negatively impacts swine health, posing diagnostic and preventative challenges. S. suis can induce disease and also quietly reside on mucosal surfaces. The limited use of diagnostic tools to identify disease-associated strains and rule out differential diagnoses, alongside the complex ecology of S. suis, poses significant challenges in comprehending this important pathogen and defining pathotypes. This study evaluated 2,379 S. suis central nervous system (CNS) isolates from diagnostic submissions between 2015 and 2019. Isolates originating from submissions with histologic evidence of CNS infection (n = 1,032) were further characterized by standard and advanced diagnostic techniques. We identified 29 S. suis serotypes and 4 reclassified serotypes as putative causes of CNS disease. Among these, serotypes 1 and 7 emerged as the predominant putative causes of CNS infection (32% of submissions). Furthermore, 51 sequence types (STs), of which 15 were novel, were detected with ST1 predominating. Through whole-genome sequencing of 145 isolates, we observed that five commonly used virulence-associated genes (VAGs; epf, mrp, sly, ofs, and srtF) were not present in most disease-associated isolates, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) yielded false-positive results in 7% of isolates. These data indicate that (i) clinical signs and site of isolation alone are insufficient for defining a pathotype, (ii) S. suis serotypes and STs associated with CNS infection are more diverse than previously reported, (iii) MALDI-TOF MS may need to be supplemented with additional diagnostic tools for precise S. suis identification, and (iv) VAGs remain an unreliable means for identifying isolates associated with CNS disease.IMPORTANCEStreptococcus suis is an important and complex systemic bacterial pathogen of swine. Characterization of S. suis strains originating from pigs with histologic confirmation of neurologic disease is limited. Review of swine diagnostic submissions revealed that fewer than half of cases from which S. suis was isolated from the brain had histologic evidence of neurologic disease. This finding demonstrates that clinical signs and site of isolation alone are not sufficient for identifying a neurologic disease-associated strain. Characterization of strains originating from cases with evidence of disease using classic and advanced diagnostic techniques revealed that neurologic disease-associated strains are diverse and commonly lack genes previously associated with virulence.

BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway

Background and purposeOxidative stress plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The small molecule ULK1 agonist, BL-918, demonstrated neuroprotective effects in other central nervous system diseases; however, its role in SAH has not yet been explored. This study aimed to evaluate whether BL-918 could provide neuroprotective effects in rats following SAH. MethodsAn SAH model was established in Sprague-Dawley rats using endovascular perforation. BL-918 was administered intraperitoneally after SAH, while the ULK1 inhibitor SBI was given intraperitoneally prior to SAH modeling. PINK1 siRNA was administered into the lateral ventricle before SAH induction. The neuroprotective effects and mechanisms of BL-918 were assessed through SAH grading, brain water content measurement, blood-brain barrier permeability, neurobehavioral tests, Western blot, immunofluorescence, TUNEL staining, DHE staining, and transmission electron microscopy (TEM). ResultsAfter SAH, the expression levels of p-ULK1, PINK1, Parkin, and LC3Ⅱ increased, peaking at 24 h post-SAH. BL-918 treatment improved neurological function in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Western blot analysis revealed that BL-918 increased the expression of p-ULK1, PINK1, Parkin, LC3Ⅱ, Bcl-xl, and Bcl-2 while inhibiting the expression of Bax and Cleaved Caspase-3. Oxidative stress-related indicators showed that BL-918 alleviated oxidative stress. Immunofluorescence and TEM results demonstrated that BL-918 promoted mitophagy and preserved mitochondrial morphology. Furthermore, the positive effects of BL-918 were reversed by SBI and PINK1 siRNA, respectively. ConclusionBL-918 improved both short-term and long-term neurological impairments in rats after SAH and reduced oxidative stress by promoting mitophagy, at least partially through the ULK1/PINK1/Parkin signaling pathway.

Gaining insights into the physicochemical properties and sequence space of blood–brain barrier penetrating peptides

The blood–brain barrier (BBB) poses a significant obstacle to the administration of drugs to the brain for the development of therapies of central nervous system (CNS) disorders. Blood-brain barrier penetrating peptides (BBBPps) are a group of peptides that can traverse the BBB by different processes without causing harm to the BBB. These peptides show promise as potential drugs for CNS ailments. Nevertheless, the process of identifying BBBPps using experimental approaches is both time-consuming and labour-intensive. To discover additional BBBPps as potential treatments for CNS diseases, it is critical to develop insilico methods that can distinguish BBBPps from non- BBBPps rapidly and precisely. In the current work, machine learning aided models are developed for accurate prediction of BBBPps using physicochemical and evolutionary information. The best model achieved an accuracy of 84.8 % by using 5-fold cross-validation and 79.8 % based on the holdout testing set on a reduced set of features. Further an extensive analysis is carried out for the black box models using model agnostic interpretation approaches to infer the physicochemical and sequence space of BBBPps. Basic amino acids and conservation of Arginine and Lysine are found to be more favoured in BBBPps. Further, basic amino acid property group and its interactions with other features are found to be prominent important interactions.

CXCR2 mediated trafficking of neutrophils and neutrophil extracellular traps are required for myelin clearance after a peripheral nerve injury

Neutrophils are a vital part of the innate immune system. Many of their functions eliminate bacteria & viruses, like neutrophil extracellular traps (NETs), which trap bacteria, enhancing macrophage phagocytosis. It was surprising when it was demonstrated that neutrophils are a part of Wallerian degeneration, a process that is essential for nerve regeneration after a nerve injury. It is not known what signals attract neutrophils into the nerve and how they aid Wallerian degeneration. Neutrophils accumulate in the distal nerve within one day after an injury and are found in the nerve from one to three days. We demonstrate that CXCR2 mediates the trafficking of neutrophils into the distal nerve, and without CXCR2 Wallerian degeneration, as indicated by luxol fast blue staining, was reduced seven days after a sciatic nerve crush or transection injury. NETs were detected in the distal nerve after a sciatic nerve transection. NET formation has been shown to require protein arginine deiminase 4 (PAD4), which citrullinates histone 3. Inhibiting PAD4 reduced NET formation significantly in the distal nerve at two days and myelin clearance at seven days indicating that NETs aid myelin clearance. These results demonstrate another function for NETs other than clearing pathogens. Neutrophils have been detected after injuries to the central nervous system and diseases in humans and animal models. Our results demonstrate neutrophils aid myelin clearance, suggesting a role for their presence in central nervous system injuries and diseases.

Morphological Evaluation of Corpus Callosum Atrophy Over Time in Relapsing Remitting Multiple Sclerosis

Objective: Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease that generally affects young adults and is marked by inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI) is widely used diagnosis tool for relapsing remitting MS (RRMS). Corpus callosum (CC), the largest commissural tract in brain which is associated with both cognitive and physical impairment by atrophy in MS. Our study aimed to evaluate CC in RRMS patients using MR images and compare it to measurements from healthy controls within the same age. Methods: We manually measured changes in CC thickness in T1 brain MR images of RRMS patients in 2017, 2019, and 2022. Results: Our results showed that control group had greater thickness, length, and index values in all CC sections compared to patient group. Additionally, a significant difference was observed in thickness of genu and splenium sections and CC index between patient and control groups. However, no significant difference was detected in truncus part of CC or overall CC length. CC measurements in patient group decreased over time, with 1st MRI showing greater values than 2nd and 3rd MRI scans. Furthermore, there was a statistically significant difference in thickness of truncus part of CC and volume values of subcortical areas between 2nd-3rd and 1st-3rd MRI measurements. Conclusion: As a result of these findings, our study provides important information about changes in CC measurements for MS patients.