Central Nervous Disorders Research Articles

MSC Secretome as a Promising Tool for Neuroprotection and Neuroregeneration in a Model of Intracerebral Hemorrhage.

Multipotent mesenchymal stromal cells (MSCs) are considered to be critical contributors to injured tissue repair and regeneration, and MSC-based therapeutic approaches have been applied to many peripheral and central neurologic disorders. It has been demonstrated that the beneficial effects of MSC are mainly mediated by the components of their secretome. In the current study, we have explored the neuroprotective potential of the MSC secretome in a rat model of intracerebral hemorrhage and shown that a 10-fold concentrated secretome of human MSC and its combination with the brain-derived neurotrophic factor (BDNF) provided a better survival and neurological outcome of rats within 14 days of intracerebral hemorrhage compared to the negative (non-treated) and positive (BDNF) control groups. We found that it was due to the ability of MSC secretome to stimulate neuron survival under conditions of glutamate-induced neurotoxicity. However, the lesion volume did not shrink in these rats, and this also correlated with prominent microglia activation. We hypothesize that this could be caused by the species-specificity of the used MSC secretome and provide evidence to confirm this. Thus, we have found that allogenic rat MSC secretome was more effective than xenogenic human MSC secretome in the rat intracerebral hemorrhage model: it reduced the volume of the lesion and promoted excellent survival and neurological outcome of the treated rats.

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders.

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

Comparison of Static, Dynamic Balance, Knee Joint Position Among Healthy Women and Those Infected with COVID-19

Background and Aims: The Coronavirus disease 2019 (COVID-19) pandemic has created widespread and long-lasting impacts on human health. Infection induces harm and damage to various systems, including the respiratory, digestive, kidney, and central nervous systems. Hence, considering its effects on the central nervous system (CNS) and nervous disorders and the fact that the CNS can impact balance and “position sense”, the objective of this study was to compare static balance, dynamic balance, and knee joint position sense among women (with COVID-19 and healthy subjects). Methods: In this study, 15 women infected with COVID-19 (age: 47.73±3.44 years, height: 162.53±4.17 cm, mass: 70.33±4.67 kg, and body mass index (BMI): 26.63±1.62 kg/m2) and 15 healthy women (age:47.53±3.27 years, height: 161.13±4.56 cm, and mass: 67.66±4.25 kg, and BMI: 26.11±2.10 kg/m2) were analyzed. Sharpendromberg and time up and go tests were utilized to respectively evaluate static and dynamic balance as well as knee joint position sense. The data were recorded by angular reconstruction and via a digital camera. Balance and sense of status tests were performed for both groups, and ultimately, the results were evaluated utilizing an independent t-test. Results: The findings revealed a significant difference between static and dynamic balance among the two groups of women (with COVID-19 & healthy) (P<0.05). Moreover, there was a significant difference between knee joint position sense (P<0.05), where the COVID group had 2.64 degrees more reconstruction error than the healthy group. Conclusion: The static, dynamic balance, and knee joint position sense of the COVID group decreased, which can lead to an increase in the contingency of dropping/falling among these individuals.

Effects of age, sex and education on verbal fluency tasks in a normal Saudi sample

ABSTRACT Introduction This study’s purpose is to describe the performance of healthy community dwelling Saudi Arabians on fluency tasks and explore the effects of age, sex and education. Methods Arabic-speaking Saudi Arabians > 18 were chosen through convenience sampling. Included were healthy community members whose first language is Arabic. Excluded were anyone with a past history of psychiatric or central neurological diseases, or who was taking medications that affect the central nervous system. Information regarding the variables sex, age, and education was collected. Participants were required to name as many words as they could that started with the letters Ain (ع), Sheen (ش), and Qaf (ق) (letter task), and words that belonged to the categories “countries,” “boy names,” “girl names,” and “four-legged animals” (categorical task). Mean scores were derived for the three letters (ASQ) and four categories (TC). Descriptive statistics, percentile curves, and quantile regressions (0.05, 0.25, 0.5, 0.75, and 0.95) were conducted to determine performance range. Results The study included 301 participants, comprising 162 (53.47%) females. The M(SD) for age was 46.74 (16) and for years of education 14 (4.78). The M(SD) for ASQ was 26.26 (10.01), and for TC, 81.56 (20.77). Percentile curves demonstrated an initial increase, followed by a decrease, in performance with increasing age on letter and categorical fluency tasks. Performance scores showed an increase of 1 to 1.5 and 2 to 3.5 words in the letter and categorical tasks, respectively, for each additional year of education across the quantiles (both with p < 0.0001). Males scored higher in the 0.05 and 0.95 quantiles of the letter fluency task only. Conclusion We demonstrated a range of normative performance from a Saudi Arabian community, with varying age and education levels. The assessment demonstrated the importance of education as a major variable linearly associated with performance, influencing both tasks.

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome.

The incidence and prevalence of metabolic syndrome has steadily increased worldwide. As a major risk factor for various diseases, metabolic syndrome has come into focus in recent years. Some natural aporphine alkaloids are very promising agents in the prevention and treatment of metabolic syndrome and its components because of their wide variety of biological activities. These natural aporphine alkaloids have protective effects on the different risk factors characterizing metabolic syndrome. In this review, we highlight the activities of bioactive aporphine alkaloids: thaliporphine, boldine, nuciferine, pronuciferine, roemerine, dicentrine, magnoflorine, anonaine, apomorphine, glaucine, predicentrine, isolaureline, xylopine, methylbulbocapnine, and crebanine. We particularly focused on their impact on metabolic syndrome and its components, including insulin resistance and type 2 diabetes mellitus, endothelial dysfunction, hypertension and cardiovascular disease, hyperlipidemia and obesity, non-alcoholic fatty liver disease, hyperuricemia and kidney damage, erectile dysfunction, central nervous system-related disorder, and intestinal microbiota dysbiosis. We also discussed the potential mechanisms of actions by aporphine alkaloids in metabolic syndrome.

Tick-borne encephalitis in a dog

Tick-borne encephalitis (TBE) is an infectious disease transmitted by ticks and rarely diagnosed in dogs. The diagnosis of a TBE virus infection in a living animal is based on the simultaneous presence of typical clinical-neurological signs, an acute and rapidly progressive course of the disease, the detection of TBE-specific antibodies (in the cerebrospinal fluid) or virus detection (in blood or cerebrospinal fluid), as well as the presence of pleocytosis in the cerebrospinal fluid. In the case described, the results of the performed tests led to the assumption of the presence of TBE. In addition to hyperthermia and central nervous disorders (ataxia, hyperaesthesia, seizures, changes in behavior) the classic symptoms of clinically overt TBE frequently include neck pain on flexion of the cervical spine. In the case described, a chronic form of the disease with a regeneration period of several months is documented. Treatment is based on symptomatic measures, as there is no specific therapy to date. In contrast to human medicine, there is no vaccine against TBE currently approved for use in the veterinary field. Therefore, tick prophylaxis is the only possibility to prevent TBE in dogs.

DIAGNOSTIC ROLE OF EXOSOMES IN VARIOUS DISEASES

Exosomes are lipid bilayer- enclosed membrane bound extracellular vesicles (EVs) that secreted by cells under physiological conditions called extracellular vesicles (EV). EVs participate in are natural carrier which can transfer DNAs, RNAs, proteins, and lipids in autocrine, paracrine and endocrine manner. Exosome cargo having cell cycle related mRNA from cancer promotes proliferation of vascular endothelial cells and exosome play a significant role in angiogenesis by vascular endothelial cells. Exosome cargos showed significant role in pathogenesis of central nervous system related disease and exosomal content can act as biomarkers for specific central nervous system related disorders. It has been observed that viral infected cell release exosome more frequently as compared to non- infected cells; which might be act as indicator of viral infection. It was found that exosomes act as extracellular communicator in ischemic signaling and myocardial repair and several studies evidently prove that in adult heart, exosome secreted by myocardial tissue involved in hetero-cellular communication. It has been suggested that exosomes could play an important role in prognosis of various disease like cancer, disease related to nervous system, infections disease and cardiovascular disease. Exosomes secretion plays important role in disease pathogenesis and may be serve as an important biomedical tool as a biomarker in early detection of various disease.

Importance des troubles cognitifs en médecine interne : physiopathologie, évaluation, prise en charge. L’exemple du lupus systémique

Systemic diseases, which are in France mainly monitored in internal medicine, affect multiple organs or tissues. While cutaneous or articular manifestations are the most common, neurological involvement is often associated with severity. Diagnosis of peripheral (e.g, neuropathies) or central (e.g, myelitis) nervous disorders is quite easy through clinical examination and dedicated complementary tests. However, neuropsychological manifestations that affect cognition, including memory, attention, executive functions or reasoning, are difficult to diagnose, sometimes trivialized by practitioners. Their causes are often numerous and interrelated. Nevertheless, these cognitive manifestations are closely related to patients’ quality of life, affecting their social life, family dynamics and professional integration but also the treatment adherence. The purpose of this review, focused on the example of systemic lupus erythematosus, is to raise awareness of cognitive dysfunction in systemic diseases including their management from diagnosis to treatments. The final aim is to go further into setting up research groups and care programs for patients with cognitive impairment followed in internal medicine.

Sedative-hypnotic, anxiolytic and possible side effects of Salvia limbata C. A. Mey. Extracts and the effects of phenological stage and altitude on the rosmarinic acid content

Ethnopharmacological relevanceSalvia limbata C. A. Mey. (Persian name: Maryam Goli-e-labeh dar) has been used for treating central nervous disorders such as insomnia, anxiety and depression in Persian traditional medicine. S. limbata is known for its pharmacological activities which could be at least in a part, upon the presence of rosmarinic acid (RA). However, the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extract has not yet been examined. Aim of the studyIn the current study the sedative-hypnotic effect, anxiolytic activity, possible side effects, and the mechanism of action of S. limbata extracts were evaluated. Besides, the effects of altitude and phenological stage on the RA content of S. limbata were investigated. Materials and methodsSedative-hypnotic and anxiolytic effects were evaluated through the pentobarbital induced loss of righting reflex test and open field test, respectively. Flumazenil was used to reveal the mechanism of action. Possible side effects were investigated in the passive avoidance and grip strength tests. Besides, the effects of altitude and phenological stage (vegetative, flowering, and seed setting) on the RA content of S. limbata were evaluated using reversed-phase high-performance liquid chromatography (RP-HPLC). ResultsFollowing behavioral tests, sedative-hypnotic and anxiolytic effects were observed. Since the observed effects were reversed by flumazenil and no side effect on the memory and muscle strength was reported, modulation of the α1-containing GABA-A receptors could be proposed as one of the involved mechanisms. According to the RP-HPLC analysis, harvesting S. limbata in the vegetative stage at the altitude of 2500 m led to the highest content of RA (8.67 ± 0.13 mg/g dry matter). Among different extract of the plant samples collected in the vegetative stage at the altitude of 2500 m, the hydroalcoholic extract showed the highest rosmarinic acid content. ConclusionThe obtained results help to find the optimum situation to gain the highest content of RA as well as the pharmacological activity that could be economically important for the pharmaceutical industries.

Clinical assessment of upper limb hypertonia in central neurological diseases

The clinical assessment of a hypertonic upper limb in central neurological diseases should be analytical, systematic (shoulder, elbow, extrinsic and intrinsic hand) and focused on the patient or caregiver’s wishes and on the expected objectives (esthetic, hygienic, functional). Nerve blocks can help to separate mixed contractures, show the existence of antagonist muscles or find a starter muscle in dystonia patterns. The etiology (especially the evolving nature of the disease), general health condition (especially in older adults), associated deficits (cerebellar, sensory and cognitive; hemineglect) are considered together to arrive at a contract with patients and/or caregivers.

The spectrum of Epstein-Barr virus infections of the central nervous system after organ transplantation

BackgroundEpstein-Barr virus (EBV)-related neurologic complications have a diverse presentation in transplant recipients, creating diagnostic and therapeutic challenges for clinicians. In this case series, we report unique manifestations of EBV related neurologic complications following solid organ transplant and highlight pitfalls in management.Case presentationsA retrospective search of the electronic medical record of all patients from January 2015 to December 2020 who underwent solid organ transplantation and had central nervous system complications as determined by ICD-10 codes were included. Three patients with unique manifestation of EBV-related neurologic complications after liver transplantation were identified. The first was a 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and several lesions on brain MRI; he was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. The second patient was a 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency and was found to have a stroke; he was diagnosed with EBV encephalitis. The final patient was a 75-year-old woman with a deceased-donor liver transplant six years prior for primary biliary cirrhosis who presented with four months of gait instability; she was diagnosed with EBV myelitis. A review of the literature was performed to supplement description of the different diseases.ConclusionsEBV-related central nervous infection in post-transplant patients can manifest in a variety of neurologic syndromes, which can be challenging to diagnose. Careful correlation of clinical, pathologic, and radiologic findings and a high index of suspicion are crucial in identification and appropriate management.

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

Background and purposeCerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS‐CoV‐2. The clinical characteristics of 213 post‐vaccination CVST cases notified to the European Medicines Agency are reported.MethodsData on adverse drug reactions after SARS‐CoV‐2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term ‘Central nervous system vascular disorders’ were obtained from the EudraVigilance database. Post‐vaccination CVST was compared with 100 European patients with CVST from before the COVID‐19 pandemic derived from the International CVST Consortium.ResultsIn all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov‐19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA‐1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%–64%) in the ChAdOx1 nCov‐19 group, in none in the mRNA vaccine group (0%, 95% CI 0%–13%) and in 7/100 (7%, 95% CI 3%–14%) in the pre‐COVID‐19 group. In the ChAdOx1 nCov‐19 group, 39 (21%) reported COVID‐19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov‐19 group, 44 (38%, 95% CI 29%–47%) had died, compared to 2/10 (20%, 95% CI 6%–51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%–8%) in the pre‐COVID‐19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov‐19 group was 49% (95% CI 39%–60%).ConclusionsCerebral venous sinus thrombosis occurring after ChAdOx1 nCov‐19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov‐19 vaccination was associated with thrombocytopenia.

Late Primary B Cell Cerebral Lymphoma After Kidney Transplant: A Case Report and Literature Review

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a serious and uncommon complication which can be developed months or years after a Kidney transplant. Immunosuppressive agents administered before and after transplantation to minimize the chances of allograft rejection has proved to be a double-edged sword that puts the host at risk of infectious, neoplastic and vascular diseases, including PCNS-PTLD. The immunosuppressive therapy leads to decreased innate malignant and viral immune surveillance and this has been shown to play a role in lymphoproliferative diseases after transplantation. In most cases, PCNS-PTLD is Epstein–Barr virus related. Case Description: A 60-year-old female with history of kidney transplant presented to the emergency room with history of low fever, dizziness nausea and vomiting for 1 month. MRI and CT scans showed a mass cerebellar lesion and a biopsy revealed Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD). Conclusion: This case highlights the need for a careful long-term follow up of patients with kidney transplant. PCNS-PTLD represents a continuing long-term risk after transplantation, although less common. This case report supports observational data that suggests that peripheral blood screening for EBV DNA does not seem helpful for identification of PCNS-PTLD. Suspicion of PCNS PTLD should be considered when patients with long-term history of kidney transplant present neurological complaints.

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases.

ObjectiveTo identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases.MethodsTwo distinct approaches (immunoprecipitation/mass spectrometry–based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples.ResultsUsing the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments.ConclusionsAGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder.Classification of EvidenceThis study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.

A Mechanistic approach of Peroxisome Proliferator-Activated Receptors and its subtypes on Clinical and preclinical model of Neurodegenerative disorders

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, belonging to the nuclear receptor family, which has high expression of three structurally homologous PPARs isotypes (PPARα, PPARβ/δ, and PPARγ) in brain. Several studies have discovered role of PPARs in oxidative stress, mitochondrial dysfunction, neuroinflammation and production of the toxic proteins in various neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, Huntington disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis etc. Currently available drugs provide symptomatic relief, but disease progression cannot be stopped, because of their unclear molecular approach. The ability of PPAR to modulate the pathways involved in these conditions paved a path for future studies. Due to increasing challenges to treat central nervous system related disorders, hence PPARs have attracted much attention nowadays. In this review, we discussed various mechanisms of PPARs subtypes in neurodegenerative disorders. We congregate the molecular evidences which support PPARs as a therapeutic target to treat neurodegenerative disorders from preclinical and clinical studies and provide a basis for the potential therapeutic use of PPAR ligands in human diseases.

Abstract 1840: Isolation and evaluation of human nanobodies against hypoxanthine guanine phosphoribosyltransferase (HPRT) and their potential use for the detection and targeting of lung, breast and colon cancer cells

Abstract Since the clinical relevance of hypoxanthine guanine phosphoribosyltransferase (HPRT) as both a cancer biomarker and a potential tumor target is increasing, we isolated human nanobodies (Nbs) against HPRT and tested their potential to detect and target cytosolic and membrane associated HPRT in lung, breast and colon cancer cells. HPRT is a purine salvage pathway enzyme that catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. Until recently, HPRT was considered as a housekeeping gene and its clinical relevance was mainly limited to congenital central nervous disorders such as Lesch-Nyhan disease. However, recent gene expression analysis across all cancers in The Cancer Genome Atlas (TCGA) database and analysis of HPRT expression within cancer patients' tissues has revealed that the expression of HPRT is elevated in the majority of malignant tissues in comparison to normal tissues. Moreover, multiple studies have recently shown that HPRT may be associated with the cell membrane in lung, colon cancer and lymphoma cells, and not in normal cells. Thus, HPRT is a potential immunotherapeutic target for cancer. Using phage display technology we isolated 384 nanobody clones from the Christ human single domain antibody (dAb) library against human HPRT. Ten of the most sensitive Nbs were sequenced and evaluated to determine their sensitivity using dose response curves. Four parameter logistic regression analysis of the top 10 HPRT nanobodies showed R squared values ranging from 0.9388-0.9989 and a sigmoidal shape denoting a concentration-dependent antigen-ligand relationship. The anti-HPRT Nbs were able to detect minimum HPRT amounts ranging from 10-20 ng/ml. Validation of the anti-HPRT Nbs was conducted with a siRNA HPRT knockdown in A549 cells. A549 siRNA HPRT knockdown cell lysate showed at least a 5-fold reduction in the overall signal in phage ELISA compared to A549 wild type cell lysate (p&amp;lt;0.001) indicating the specificity of the Nbs to HPRT. In addition, flow cytometry analysis showed that the anti-HPRT Nbs were able to detect membrane associated HPRT on A549 (20%), NCI-H460 (23%), HT-29 (41%) , SW620 (46%) and MDA-MB-231 (32%) cancer cell lines. Anti-HPRT Nbs did not show significant binding to normal mononuclear cells compared to cancer cells (p&amp;lt;0.002). Anti-HPRT Nbs were successfully expressed and purified using the pET-scFv expression system. Human anti-HPRT Nbs may be used for the detection of both cytosolic and membrane associate HPRT. Future directions of this research will explore the uses of anti-HPRT-Nb-based therapies and their use in other applications such as chimeric antigen receptors (CARs) for cell adoptive therapies. Citation Format: Edwin J. Velazquez, Tyler B. Humpherys, Toni O. Mortimer, David M. Bellini, Kathryn R. Smith, Rachel M. Morris, Abigail Goodman, Kim L. O'Neill. Isolation and evaluation of human nanobodies against hypoxanthine guanine phosphoribosyltransferase (HPRT) and their potential use for the detection and targeting of lung, breast and colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1840.

Fractionating stem cells secretome for Parkinson's disease modeling: Is it the whole better than the sum of its parts?

Human mesenchymal stem cells (hMSCs) secretome has been have been at the forefront of a new wave of possible therapeutic strategies for central nervous system neurodegenerative disorders, as Parkinson's disease (PD). While within its protein fraction, several promising proteins were already identified with therapeutic properties on PD, the potential of hMSCs-secretome vesicular fraction remains to be elucidated. Such highlighting is important, since hMSCs secretome-derived vesicles can act as biological nanoparticles with beneficial effects in different pathological contexts. Therefore, in this work, we have isolated hMSCs secretome vesicular fraction, and assessed their impact on neuronal survival, and differentiation on human neural progenitors' cells (hNPCs), and in a 6-hydroxydopamine (6-OHDA) rat model of PD when compared to hMSCs secretome (as a whole) and its protein derived fraction. From the results, we have found hMSCs vesicular fraction as polydispersity source of vesicles, which when applied in vitro was able to induce hNPCs differentiation at the same levels as the whole secretome, while the protein separated fraction was not able to induce such effect. In the context of PD, although distinct effects were observed, hMSCs secretome and its derived fractions displayed a positive impact on animals' motor and histological performance, thereby indicating that hMSCs secretome and its different fractions may impact different mechanisms and pathways. Overall, we concluded that the use of the secretome collected from hMSCs and its different fractions might be active modulators of different neuroregeneration mechanisms, which could open new therapeutical opportunities for their future use as a treatment for PD.

Discovery of HBW-3-20, the first potent reversible inhibitor of Bruton’s tyrosine kinase (BTK) with high brain exposure.

e15068 Background: It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, a critical property for extending its usages to treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is an aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, an irreversible BTK inhibitor with limited brain exposure, is the first BTK inhibitor approved for the treatment of recurrent or refractory primary central nervous system lymphoma recently. PRN2246 is another irreversible BTK inhibitor claimed to be of brain exposure, and is currently in clinical trials for the treatment of multiple sclerosis. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further measured for brain exposures in rats. Results: HBW-3-20 has excellent potency against both wild-type and C481S-mutated BTK, with IC50 of 2.5 and 3.8 nM, respectively. Its TMD8 cellular potency is 72 nM. In a head-to-head direct comparison of brain exposure experiment, HBW-3-20, tirabrutinib and PRN2246 were all dosed at 10mg/kg orally. The brain and plasma concentration were measured after 1 hour and the data are shown in the table below. The brain to plasma ratio for HBW-3-20, tirabrutinib and PRN2246 are 58%, 11.8% and 4.2% respectively. Our results show that HBW-3-20 has much greater brain permeability than tirabrutinib or PRN2246 in rats. Conclusions: HBW-3-20 is the first potent reversible BTK inhibitor that shows promisingly high brain permeability. HBW-3-20 provides a very valuable clinical candidate for treating B-cell malignancies in brain and autoimmune disorders![Table: see text]

COVID-19 and neuroinflammation: a literature review of relevant neuroimaging and CSF markers in central nervous system inflammatory disorders from SARS-COV2.

BackgroundThe literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19).MethodsWe screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; “SARS-CoV-2 and neurological complication”, “SARS-CoV-2 and CNS Complication” looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021.ResultsOur literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities.ConclusionTo our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.

Pannexin-1 Channels as Mediators of Neuroinflammation.

Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which alter the functionality of nearby tissues and might mediate the recruitment of leukocytes to the injury site. If this process persists or is exacerbated, it prevents the adequate resolution of the inflammation, and ultimately enhances secondary damage. Adenosine 5′ triphosphate (ATP) is among the molecules released that trigger an inflammatory response, and it serves as a chemotactic and endogenous danger signal. Extracellular ATP activates multiple purinergic receptors (P2X and P2Y) that have been shown to promote neuroinflammation in a variety of CNS diseases. Recent studies have shown that Pannexin-1 (Panx1) channels are the principal conduits of ATP release from dying cells and innate immune cells in the brain. Herein, we review the emerging evidence that directly implicates Panx-1 channels in the neuroinflammatory response in the CNS.