Central Nervous System Therapy Research Articles

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.

Experience with a hybrid recruitment approach of patient-facing web portal screening and subsequent phone and medical record review for a neurosurgical intervention trial for chronic ischemic stroke disability (PISCES III)

BackgroundRecruitment of participants is the greatest risk to completion of most clinical trials, with 20–40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent.MethodsTwo tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted.ResultsThe approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19.ConclusionsA tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells.Trial registrationClinicalTrials.gov Identifier: NCT03629275

The impact of burn injury on the central nervous system.

Burn injuries can be devastating, with life-long impacts including an increased risk of hospitalization for a wide range of secondary morbidities. One area that remains not fully understood is the impact of burn trauma on the central nervous system (CNS). This review will outline the current findings on the physiological impact that burns have on the CNS and how this may contribute to the development of neural comorbidities including mental health conditions. This review highlights the damaging effects caused by burn injuries on the CNS, characterized by changes to metabolism, molecular damage to cells and their organelles, and disturbance to sensory, motor and cognitive functions in the CNS. This damage is likely initiated by the inflammatory response that accompanies burn injury, and it is often long-lasting. Treatments used to relieve the symptoms of damage to the CNS due to burn injury often target inflammatory pathways. However, there are non-invasive treatments for burn patients that target the functional and cognitive damage caused by the burn, including transcranial magnetic stimulation and virtual reality. Future research should focus on understanding the mechanisms that underpin the impact of a burn injury on the CNS, burn severity thresholds required to inflict damage to the CNS, and acute and long-term therapies to ameliorate deleterious CNS changes after a burn.

An Ultrasmall Cu/Cu2O Nanoparticle-Based Diselenide-Bridged Nanoplatform Mediating Reactive Oxygen Species Scavenging and Neuronal Membrane Enhancement for Targeted Therapy of Ischemic Stroke.

Ischemic stroke is one of the major causes of death and disability worldwide, and an effective and timely treatment of ischemic stroke has been a challenge because of the narrow therapeutic window and the poor affinity with thrombus of the thrombolytic agent. In this study, rPZDCu, a multifunctional nanoparticle (NP) with the effects of thrombolysis, reactive oxygen species (ROS) scavenging, and neuroprotection, was synthesized based on an ultrasmall Cu4.6O NP, the thrombolytic agent rt-PA, and docosahexaenoic acid (DHA), which is a major component of the neuronal membrane. rPZDCu showed strong thrombus-targeting ability, which was achieved by the platelet cell membrane coating on the NP surface, and a good thrombolytic effect in both the common carotid artery clot model and embolic middle cerebral artery occlusion (MCAO) model of rats. Furthermore, rPZDCu exhibited a good escape from the phagocytosis of macrophages, effective promotion of the polarization of microglia, and efficient recovery of neurobiological and behavioral functions in the embolic MCAO model of rats. This is a heuristic report of (1) the Cu0/Cu+ NP for the treatments of brain diseases, (2) the integration of DHA and ROS scavengers for central nervous system therapies, and (3) diselenide-based ROS-responsive NPs for ischemic stroke treatments. This study also offers an example of cell membrane-camouflaged stimuli-responsive nanomedicine for brain-targeting drug delivery.

Impact of Central Nervous System (CNS) Leukemia Status-Based Therapeutic Protocol Change on the Incidence of CNS2 Diagnosis in Pediatric B-Lymphoblastic Acute Leukemia

B-lymphoblastic acute leukemia (B-ALL) is the most prevalent cancer among children, and prophylactic central nervous system (CNS) therapy has significantly contributed to high cure rates for the past 50 years. However, relapses in bone marrow and/or CNS continue to pose challenges to achieving cure for all patients, especially in those with high-risk disease. CNS status at diagnosis, defined as CNS1 (no blasts present), CNS2 (blasts with <5 total white blood cells [WBC] per mm 3 in a cerebrospinal fluid [CSF] sample), and CNS3 (blasts with ≥5 total WBC per mm 3 or grossly traumatic), plays a crucial role in determining treatment stratification. In the past, patients with CNS1 and CNS2 received similar therapy, but evidence suggested that those with CNS2 were at a higher risk for marrow and/or CNS relapse. As a result, the Children's Oncology Group (COG) frontline trials AALL1131 and AALL0932 implemented additional CNS therapy for CNS2 patients beginning in 2012 and 2016, respectively, specifically twice weekly intrathecal chemotherapy until CSF cleared of disease 3 consecutive times. This change highlighted the necessity for accurate identification of CNS2. Based on anecdotal observation, we hypothesized that the incidence of CNS2 among pediatric B-ALL patients at diagnosis was higher after this therapeutic change due to pathologist awareness of its implications for patient management. The electronic medical records of all consecutive pediatric patients diagnosed with B-ALL at Children's Hospital Los Angeles (CHLA) from September 2008 to December 2019 were reviewed. CSF WBC count and blast involvement were used to calculate CNS status. Blast involvement was determined by one or more pathologists per case by morphologic review of cytocentrifuged CSF material. The patients were divided into two cohorts, one before (cohort A) and one after (cohort B) the COG AALL0932 protocol change (May 20, 2016). Differences between cohorts were evaluated via Fisher's exact test and Wilcoxon rank sum test. All tests were two-sided, except for CNS2 status, and significance level was set a priori at 0.05. During the study period, 391 patients were diagnosed with B-ALL at CHLA. These included 192 patients prior to the CNS status-based therapeutic change (cohort A) and 199 patients after the therapeutic change (cohort B). The incidence of CNS2 status was higher in cohort B (20%) than in cohort A (13%) (p=0.052). Conversely, the incidence of CNS1 status was lower in cohort B (77%) than in cohort A (85%), while the incidence of CNS3 was similar before (5%) and after (4%) the protocol change. There were no differences between the cohorts in patient age at diagnosis [cohort A: mean age 8.91 years (SD 5.67 years) vs. cohort B: mean age 8.10 (SD 5.62 years); p=0.20], sex (cohort A: 59.9% male vs. cohort B: 58.8% male; p=0.80), or ethnicity (cohort A: 76.0% Hispanic vs. cohort B: 67.7% Hispanic; p=0.09). These data suggest that the incidence of CNS2 status in pediatric patients with B-ALL at our institution was higher after (20%) than before (13%) the COG protocol changes that began treating CNS2 patients more intensively than CNS1 patients. In addition to increased frequency of intrathecal chemotherapy, in the ongoing frontline COG standard-risk ALL trial, patients with CNS2 status and neutral cytogenetics are upstaged to higher-risk therapy irrespective of end-induction response. A limitation of this study is that pathologist reviewers of CSF cytospin morphology at the time of CNS assignment differed during the two time periods, such that an observational bias cannot be entirely excluded. Notably, flow cytometry - a more sensitive methodology than cytospin morphology for detection of leukemic cells in CSF material - was not used in these cohorts, but increasingly widespread adoption of such techniques may further increase the incidence of CNS2, including in patients who would otherwise have been diagnosed with CNS1 disease (by cytospin morphology) and as such may be overtreated. Future directions of our study include examination of clinical outcome as well as recent (2021-present) patterns of flow cytometry use in CSF specimens and associated diagnoses of CNS disease in pediatric patients with B-ALL at diagnosis.

CNS Prophylaxis in Adult ALL Patients after Stem Cell Transplantation: An EBMT Survey on General Practice

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute lymphoblastic leukemia (ALL) resulting in long-term remission. Despite advances in therapy, disease progression remains the major cause of mortality following HSCT accounting for 20-50% of all deaths. The central nervous system (CNS) is the most common extra-medullary site of disease progression after transplant in ALL. The established practice of CNS prophylaxis for ALL has largely been modeled in the pediatric population, given the higher incidence of ALL in this age group compared with adults. Although the use of CNS prophylaxis as part of the upfront treatment for ALL has led to significant decreases in CNS relapse and improved outcomes overall, the routine use of post-HSCT prophylactic CNS therapy as a strategy to prevent CNS relapse after transplant in adult patients is still controversial. Studies that utilized post-HSCT CNS prophylaxis have reported disparate results and there is no generalized consensus regarding the use of post-transplant CNS prophylaxis to prevent relapse. Methods In order to assess the current practice of post-HSCT prophylactic CNS therapy in preventing CNS relapse in ALL patients, we carried out a survey among EBMT centres to describe intrathecal (i.t.) prophylaxis or irradiation in HSCT for ALL in both patients with or without CNS manifestations at any time of disease (first or second complete remission [CR1, CR2] and relapsed/refractory [R/R] ALL). EBMT centres were asked whether they usually give i.t. prophylaxis or cranial irradiation before and after HSCT, and which drugs they use. Results Of 410 invited centres, 55 (13%) replied to the survey. Tables 1 shows the number of centres which use i.t. prophylaxis or cranial irradiation. Most of the 55 centres used both pre-and post i.t. prophylaxis and triple prophylaxis (steroids, cytarabine [AraC] and methotrexate [MTX]) was the most frequently adopted. As expected in the pre-transplant phase, almost 70% of centres use i.t. chemotherapy irrespective of the phase of the disease or of the use of total body irradiation (TBI) as conditioning regimen. In the post-transplant phase, the rate of i.t prophylaxis varies according to disease phase, TBI use, and history of CNS involvement pre HSCT. In patients w/o history of CNS involvement in CR1, i.t. prophylaxis is given in 23.6% and 21.5% (with or w/o TBI use, respectively). Notably in CR2 pts, i.t. prophylaxis is given in 20% of cases if the conditioning regimen includes TBI, and in 74.5% of cases if TBI is not used; 32.7% and 46.9% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. In the setting of patients with history of CNS involvement in CR1, i.t. prophylaxis is given in and 30.9% and 38.2% (with or without TBI use, respectively); in CR2 pts, i.t. prophylaxis is given in 38.9% of cases if the conditioning regimen does not include TBI, and in 29.1% of cases if TBI is used; 38.9% and 45.3% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. Pre-transplant cranial irradiation is planned in less than 10% of centres in CR1 and CR2 patients without CNS involvement, irrespective of the use of TBI in the conditioning regimen, while it is used in 22.4% and 25% of patients with R/R disease with or without TBI use for transplant, respectively. In the setting of patients with CNS involvement, among those in CR1 and CR2, approximately 30% receive pre-transplant cranial irradiation irrespective of TBI use, while 32.7% and 34.6% of patients receive cranial irradiation (with or without TBI use, respectively). Its use after transplant is uncommon irrespective of disease status at treatment. Conclusions CR2 pts (without CNS involvement) seem to be at higher risk of CNS relapse if TBI is not included in the conditioning regimen. R/R pts are always considered at higher risk for CNS relapse if TBI is not included in the conditioning regimen. Cranial irradiation before treatment is used in almost 1 out of 3 pts with CNS involvement despite the use of TBI as the conditioning regimen, and 1 out 4 R/R pts without CNS involvement at transplant. The rate of cranial irradiation after transplant is extremely low, irrespective of diseases status, previous CNS involvement or TBI use. In conclusion, the use of i.t. prophylaxis after HSCT in patients with or without CNS involvement is variable among European transplant centres, also in the era of novel therapies for patients with ALL.

O-GlcNAcylation is essential for therapeutic mitochondrial transplantation

BackgroundTransplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals.MethodsMitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc. O-GlcNAcylated mitochondrial proteins were identified by mass spectrometry and the antiglycation ability of O-GlcNAcylated DJ1 was determined by loss-of-function via mutagenesis. Therapeutic efficacy of O-GlcNAcylated mitochondria was assessed in a mouse model of transient focal cerebral ischemia-reperfusion. To explore translational potential, we evaluated O-GlcNAcylated DJ1 in CSF collected from patients with subarachnoid hemorrhagic stroke (SAH).ResultsWe show that isolated mitochondria are susceptible to advanced glycation end product (AGE) modification, and these glycated mitochondria induce the receptor for advanced glycation end product (RAGE)-mediated autophagy and oxidative stress when transferred into neurons. However, modifying mitochondria with O-GlcNAcylation counteracts glycation, diminishes RAGE-mediated effects, and improves viability of mitochondria recipient neurons. In a mouse model of stroke, treatment with extracellular mitochondria modified by O-GlcNAcylation reduces neuronal injury and improves neurologic deficits. In cerebrospinal fluid (CSF) samples from SAH patients, levels of O-GlcNAcylation in extracellular mitochondria correlate with better clinical outcomes.ConclusionsThese findings suggest that AGE-modification in extracellular mitochondria may induce danger signals, but O-GlcNAcylation can prevent glycation and improve the therapeutic efficacy of transplanted mitochondria in the CNS.

Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway.

Intranasal administration is a promising strategy to enhance the delivery of the sEVsomes-based drug delivery system to the central nervous system (CNS). This study aimed to explore central distributive characteristics of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) and underlying pathways. Here, we observed that intranasal MSC-sEVs were rapidly distributed to various brain regions, especially in the subcortex distant from the olfactory bulb, and were absorbed by multiple cells residing in these regions. We captured earlier transportation of intranasal MSC-sEVs into the perivascular space and found an increase in cerebrospinal fluid influx after intranasal administration, particularly in subcortical structures of anterior brain regions where intranasal sEVs were distributed more significantly. These results suggest that the perivascular pathway may underlie the rapid and widespread central delivery kinetics of intranasal MSC-sEVs and support the potential of the intranasal route to deliver MSC-sEVs to the brain for CNS therapy.

Simple methods for cerebrospinal fluid collection in fetal, neonatal, and adult rat

BackgroundCerebrospinal fluid (CSF) collection and its analysis are common medical practices useful in the diagnosis, therapy, and prevention of central nervous system (CNS) disorders. In recent years, several types of research have improved our insight into CSF and its role in health and disease. Yet, many characteristics of this fluid remain to be fully understood. New methodsHere, we describe how to collect CSF from embryonic, postnatal, and adult stages of the rat. In adults, CSF can be collected through simple stereotaxic surgery to expose the membrane overlying the cisterna magna (CM) of an anesthetized rat and collection of CSF through micropipette puncture through the membrane. In embryos and pups, CSF is aspirated, using a fire-polished micro-capillary pipette, from the CM of animals. ResultsApplication of these methods provides the maximum volume of pure, uncontaminated CSF (embryonic day 19: 10–15 microliter, postnatal day 5: 20–30 microliter, adults: 100–200 microliter) with a success rate of approximately 95% in every age. Comparison with existing methodsCompared to the existing protocols, these methods obtain considerable volumes of CSF, which may accelerate the measurement of biological markers in this fluid. Also, these techniques do not require surgical skills and according to the practical points mentioned during sampling, the procedures can be performed in rapid fashion. ConclusionWe describe simple methods for collecting CSF in live rats. These protocols provide clean, uncontaminated CSF for experiments to understand the exact role of this fluid in the development and maintenance of the CNS health.

TIPS-10 FEASIBILITY OF A MULTI-MODALITY CENTRAL NERVOUS SYSTEM SCREENING EVALUATION IN HER2+ BREASTCANCER PATIENTS

Abstract BACKGROUND Breast cancer is the most common cancer in the world and the second most common to metastasize to the central nervous system (CNS). CNS-metastases are the most common type of brain tumor and have a rising incidence. They are associated with neurologic morbidity and mortality and remain a major clinical challenge. Survival withCNS-metastases is short with a median survival in the order of months. The incidence of CNS-metastases is 5.1% in breast cancer however true prevalence is not known; at autopsy this incidence ranges between 20-40%. One contributing factor towards the development of CNS-metastases in breast cancer is HER2-positivity. Between 25%-48% of patients with HER2-positive metastatic breast cancer develop CNS-metastases. Currently, routine CNS surveillance imaging is not recommended, however guidelines suggest having a low threshold for evaluation with imaging and/or cerebrospinal fluid (CSF) analysis because of the high rate of CNS-metastases. The clinical relevance of occult CNS-metastases, survival after identification of occult CNS-metastases and the importance of earlier initiation of CNS therapy are unknown. Existing treatment strategies for CNS-metastases rely on a combinatorial approach of chemotherapy, radiotherapy and/or surgery which typically affords limited disease control. This trial seeks to study if surveillance imaging and CSF analysis are feasible as early disease detection mechanisms. METHODS This is a two-cohort study to establish feasibility of multi-modality CNS surveillance. Patients with HER2+ metastatic breast cancer patients (with no known CNS-metastases) who are either Stage IV (Cohort A) or Stage II/III are eligible (Cohort B). On study, patients will undergo MRI Brain and CSF analysis at 6 monthly intervals. CSF analysis includes cytology, circulating tumor cells and cell-free DNA analysis. We plan to enroll 20 patients (10 onto each cohort). 1 of 20 patients have enrolled. This is the first multi-modality screening feasibility study for patients HER2-positive breast cancer.

Novel therapeutic delivery for neurodegenerative diseases: Strategies to overcome CNS barriers

The incidence of central nervous system (CNS) diseases is expected to rise significantly due to increasing lifespan and changing population demographics. Among CNS diseases, neurodegenerative diseases (ND’s) entail a significant challenge since they frequently involve neuronal loss and age-related progressive deterioration in brain function. Although the mechanisms and pathogenesis of neuronal disorders including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease (HD) have been extensively studied, effective treatment strategies remain limited. Drug delivery to the CNS is particularly challenging and poses a significant obstacle in the management of neurodegeneration. The present review focuses on the challenges associated with neuronal disorders, especially concerning the delivery of macro molecules containing proteins and nucleic acid. Additionally, we highlight opportunities to enhance therapeutic delivery for the treatment of ND’s. As our understanding of the biological aspects of ND’s continues to grow, there is a growing potential for therapeutic interventions. Therefore, these delivery strategies play a vital role for the future transition of CNS therapies from research labs to clinical practices.

A Radiologist's Guide to the 2021 WHO Central Nervous System Tumor Classification: Part 2-Newly Described and Revised Tumor Types.

The fifth edition of the World Health Organization classification of tumors of the central nervous system (CNS), published in 2021, introduces major shifts in the classification of brain and spine tumors. These changes were necessitated by rapidly increasing knowledge of CNS tumor biology and therapies, much of which is based on molecular methods in tumor diagnosis. The growing complexity of CNS tumor genetics has required reorganization of tumor groups and acknowledgment of new tumor entities. For radiologists interpreting neuroimaging studies, proficiency with these updates is critical in providing excellent patient care. This review will focus on new or revised CNS tumor types and subtypes, beyond infiltrating glioma (described in part 1 of this series), with an emphasis on imaging features.

Spatiotemporal tracking of gold nanorods after intranasal administration for brain targeting

Intranasal administration is becoming increasingly more attractive as a fast delivery route to the brain for therapeutics circumventing the blood-brain barrier (BBB). Gold nanorods (AuNRs) demonstrate unique optical and biological properties compared to other gold nanostructures due to their high aspect ratio. In this study, we investigated for the first time the brain region-specific distribution of AuNRs and their potential as a drug delivery platform for central nervous system (CNS) therapy following intranasal administration to mice using a battery of analytical and imaging techniques. AuNRs were functionalized with a fluorescent dye (Cyanine5, Cy5) or a metal chelator (diethylenetriaminepentaacetic dianhydride, DTPA anhydride) to complex with Indium-111 via a PEG spacer for optical and nuclear imaging, respectively. Direct quantification of gold was achieved by inductively coupled plasma mass spectrometry. Rapid AuNRs uptake in mice brains was observed within 10 min following intranasal administration which gradually reduced over time. This was confirmed by the 3 imaging/analytical techniques. Autoradiography of sagittal brain sections suggested entry to the brain via the olfactory bulb followed by diffusion to other brain regions within 1 h of administration. The presence of AuNR in glioblastoma (GBM) tumors following intranasal administration was also proven which opens doors for AuNRs applications, as nose-to-brain drug delivery carriers, for treatment of a range of CNS diseases.

Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Breast Cancer Brain Metastases: Achilles' Heel in Breast Cancer Patients' Care.

Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as amechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration. Other mechanisms of primary and secondary resistance are still unclear and may vary across the BC subtypes. New small molecules have demonstrated efficacy in BM, in particular for the HER2-positive subtype, with a benefit in survival. A new era has begun in the field of BM, and many trials specifically designed for this population are currently ongoing. The BC research community needs to address this call with the final aim of improving the efficacy of systemic therapy in CNS compartment and ultimately preventing the occurrence of BM.

Lipid nanoparticles for antisense oligonucleotide gene interference into brain border-associated macrophages.

A colloidal synthesis' proof-of-concept based on the Bligh-Dyer emulsion inversion method was designed for integrating into lipid nanoparticles (LNPs) cell-permeating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for mRNA interference. The GR@LNPs were formulated to target brain border-associated macrophages (BAMs) as a central nervous system (CNS) therapy platform for silencing neuroinflammation-related genes. We specifically aim at inhibiting the expression of the gene encoding for lipocalin-type prostaglandin D synthase (L-PGDS), an anti-inflammatory enzyme expressed in BAMs, whose level of expression is altered in neuropsychopathologies such as depression and schizophrenia. The GR@LNPs are expected to demonstrate a bio-orthogonal genetic activity reacting with L-PGDS gene transcripts inside the living system without interfering with other genetic or biochemical circuitries. To facilitate selective BAM phagocytosis and avoid subsidiary absorption by other cells, they were functionalized with a mannosylated lipid as a specific MAN ligand for the mannose receptor presented by the macrophage surface. The GR@LNPs showed a high GR-packing density in a compact multilamellar configuration as structurally characterized by light scattering, zeta potential, and transmission electronic microscopy. As a preliminary biological evaluation of the mannosylated GR@LNP nanovectors into specifically targeted BAMs, we detected in vivo gene interference after brain delivery by intracerebroventricular injection (ICV) in Wistar rats subjected to gene therapy protocol. The results pave the way towards novel gene therapy platforms for advanced treatment of neuroinflammation-related pathologies with ASO@LNP nanovectors.

Morphological and functional characteristics of LPS-stimulated microglial cells under the action of orexin A

Interest to the orexin-containing neurons is caused by their recent discovery and perspectives of their usage for treatment of different diseases. The studies in this area were launched recently and are of special interest since the opportunity of modulating functional activity of the brain immune system is of pivotal significance for therapy of various central nervous system (CNS) disorders providing novel ways of search and promising data on therapeutic effects of orexins in inflammatory, autoimmune diseases as well as malignant tumors.
 Some data from literature show that orexins may exert therapeutic effects in different disorders caused by altered neuroimmune interactions. Participation of this neuromediator system is shown in pathogenesis of narcolepsia, obesity, multiple sclerosis, Alzheimer disease, intestinal disorders, septic shock and cancer, due to involvement of orexins in functional regulation of various components of immune syste, e.g., microglial cell populations. Despite only scarce data on these effects, some experimental results obtained over last years, add to our understanding of orexin effects upon functional activity of the brain immune system.
 A number of previous studies allowed to assess the orexin effects on morpho-functional features of microglial cells activated by lipopolysaccharide (LPS), thus presenting a prospective for development of novel approaches to therapy of infectious, inflammatory, neurodegenerative and autoimmune disorders affecting CNS. In the present study, we aimed for detecting the effects of neuromediator orexin A upon functional traits of of microglial cells activated by LPS (M1 phenotype) as evaluated by changes of their size and length of their processes, as well as density of cell distribution.
 We have studied the changes of microglia cell numbers following intraperitoneal LPS injection. It was shown that, the LPS causes higher activation degree of these cells, i.e., the contents of microglial cells becomes increased in somatosensory area of the brain cortex. A series of these studies allowed us to demonstrate that intracerebroventricular injection of orexin A in animals following LPS injection does not cause detectable changes of the processes initiated by LPS. The comparative analysis did not detect any changes in length of microglial processes localized in somatosensory or motor cortical areas, and corpus striatum. Other parameters of the microglial cell activation will be studied in future.

Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration.

The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease. From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, α-synuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.

Nanotechnology-Inspired Extracellular Vesicles Theranostics for Diagnosis and Therapy of Central Nervous System Diseases.

Shuttling various bioactive substances across the blood-brain barrier (BBB) bidirectionally, extracellular vesicles (EVs) have been opening new frontiers for the diagnosis and therapy of central nervous system (CNS) diseases. However, clinical translation of EV-based theranostics remains challenging due to difficulties in effective EV engineering for superior imaging/therapeutic potential, ultrasensitive EV detection for small sample volume, as well as scale-up and standardized EV production. In the past decade, continuous advancement in nanotechnology provided extensive concepts and strategies for EV engineering and analysis, which inspired the application of EVs for CNS diseases. Here we will review the existing types of EV-nanomaterial hybrid systems with improved diagnostic and therapeutic efficacy for CNS diseases. A summary of recent progress in the incorporation of nanomaterials and nanostructures in EV production, separation, and analysis will also be provided. Moreover, the convergence between nanotechnology and microfluidics for integrated EV engineering and liquid biopsy of CNS diseases will be discussed.

Integrating Lipidomics and Transcriptomics Reveals the Crosstalk Between Oxidative Stress and Neuroinflammation in Central Nervous System Demyelination.

Multiple sclerosis (MS) is an incurable and progressive neurodegenerative disease that affects more than 2.5 million people worldwide and brings tremendous economic pressures to society. However, the pathophysiology of MS is still not fully elucidated, and there is no effective treatment. Demyelination is thought to be the primary pathophysiological alteration in MS, and our previous study found abnormal lipid metabolism in the demyelinated corpus callosum. Growing evidence indicates that central nervous system (CNS) demyelinating diseases never result from one independent factor, and the simultaneous participation of abnormal lipid metabolism, oxidative stress, and neuroinflammation could potentiate each other in the pathogenesis of MS. Therefore, a single omics analysis cannot provide a full description of any neurodegenerative disease. It has been demonstrated that oxidative stress and neuroinflammation are two reciprocal causative reasons for the progression of MS disease. However, the potential crosstalk between oxidative stress and neuroinflammation remains elusive so far. With an integrated analysis of targeted lipidomics and transcriptomics, our research presents the potential interaction between abnormalities of lipid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in CNS demyelinating diseases. The findings of this paper may be used to identify possible targets for the therapy of CNS demyelinating diseases.