CNS & neurological disorders drug targets最新文献

Background: Gliomas are the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy is an established procedure for tumor cell sampling that aids diagnosis, tumor grading, and prediction of prognosis.

Materials and methods: We studied and compared the levels of liquid biopsy markers in patients with different grades of glioma. Also, we tried to prove the potential association between glioma and specific blood group antigens.

Results: 78 patients were found, among whom the maximum percentage with glioblastoma had blood group O+ (53.8%). The second highest frequency had blood group A+ (20.4%), followed by B+ (9.0%) and A- (5.1%), and the least with O-. Liquid biopsy biomarkers included Alanine Aminotransferase (ALT), Lactate Dehydrogenase (LDH), lymphocytes, Urea, Alkaline phosphatase (AST), Neutrophils, and C-Reactive Protein (CRP). The levels of all the components increased significantly with the severity of the glioma, with maximum levels seen in glioblastoma (grade IV), followed by grade III and grade II, respectively.

Conclusion: Gliomas have significant clinical challenges due to their progression with heterogeneous nature and aggressive behavior. A liquid biopsy is a non-invasive approach that aids in setting up the status of the patient and figuring out the tumor grade; therefore, it may show diagnostic and prognostic utility. Additionally, our study provides evidence to prove the role of ABO blood group antigens in the development of glioma. However, future clinical research on liquid biopsy will improve the sensitivity and specificity of these tests and confirm their clinical usefulness to guide treatment approaches.

Introduction: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment of these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC).

Case presentation: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures.

Conclusion: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.

The current landscape of therapeutic strategies for subarachnoid hemorrhage (SAH), a significant adverse neurological event commonly resulting from the rupture of intracranial aneurysms, is rapidly evolving. Through an in-depth exploration of the natural history of SAH, historical treatment approaches, and emerging management modalities, the present work aims to provide a broad overview of the shifting paradigms in SAH care. By synthesizing the historical management protocols with contemporary therapeutic advancements, patient-specific treatment plans can be individualized and optimized to deliver outstanding care for the best possible SAH-related outcomes.

Background and objective: The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. Hence, we conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.

Methods: Identifying relevant studies was carried out by searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.

Results: This review included a total of 23 studies and more than 2177 epilepsy patients. It was found that the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, whereas the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It was also observed that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.

Conclusion: Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.

Background: The aetiology of fibromyalgia is unknown; its symptoms may be related to a T-lymphocyte-mediated response to infectious organisms.

Objectives: First, to test the hypothesis that fibromyalgia is associated with increased interferon (IFN)-γ-secreting T-lymphocytes after stimulation with Anaplasmataceae-related major surface proteins (MSPs) and the macromolecular translocation type IV secretion system effector ankyrin repeat domain-containing protein A (AnkA). Second, to ascertain the relationship in fibromyalgia between (i) the IFN-γ-secreting T-lymphocyte response to stimulation with Anaplasmataceae-related MSPs and AnkA, and (ii) co-infection by Borrelia and Yersinia spp., and antinuclear antibodies.

Methods: Using a case-control design, patients fulfilling the American College of Rheumatology revised criteria for fibromyalgia, and controls, underwent the following blinded assessments: (i) enzyme- linked immune absorbent spot (ELISpot) IFN-γ release assay of T-lymphocyte reactivity to Anaplasmataceae-related MSPs and AnkA; (ii) ELISpot IFN-γ release assays of T-lymphocyte reactivity to three Borrelia antigens, namely Borrelia burgdorferi full antigen (B31); peptide mix (from Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii); and Borrelia burgdorferi lymphocyte function-associated antigen-1; (iii) immunoglobulin (Ig) A assay by enzyme-linked immunosorbent assay (ELISA) of antibodies to Yersinia spp.; (iv) IgG (ELISA) antibodies to Yersinia spp.; (v) serum antinuclear antibodies (immunofluorescence).

Results: The groups were age- and sex-matched. The mean (standard error) value of IFN-γ release for the fibromyalgia group was 1.52 (0.26), compared with 1.00 (0.22) for the controls. Generalised linear modelling (p<0.001) of IFN-γ release in the fibromyalgia patients showed significant main effects of all three indices of Borrelia infection and of antinuclear antibodies.

Conclusion: Anaplasmataceae may play an aetiological role in fibromyalgia.

Apraxia can be detected when engaging in mental motor envisioning exercises. The nonverbal skills of manufacturing, representation, strategizing, arithmetic, visual sensitivity, and motor skills are all related to apraxia. Limb apraxia also negatively affects communication gestures and linguistic skills. The impairment of brain regions related to motion patterns is the primary cause of apraxia. People with apraxia may struggle to complete a variety of tasks because they are unable to focus on various movements. Apraxia can result from injury to the premotor cortex since it has a role in the left hemisphere-dependent selection of movements. Cognitive and complicated motor system deficits are hallmarks of the corticobasal syndrome. Apraxia of the limbs and visuospatial abnormalities are typical clinical types. TMS was used to study these problems; however, no research was done on the relationship between TMS parameters and clinical types. It is possible for changes in brain activity to last a long time when repetitive TMS (rTMS) is utilized. Electromyography shows that noninvasive TMS of the motor cortex causes target muscle spasms (MEP). The human motor cortex is a part of the cerebral cortex that is involved in the organization, management, and execution of voluntary movements. TMS and other neuroimaging techniques are frequently used to identify changes in this region. Cortical motor excitability varies among different diagnoses; therefore, it is important to determine the effectiveness of TMS. Therefore, this study aims to review the causes and neurophysiological simulation of apraxia along with the principles and effects of TMS on apraxia.

Background: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.

Objective: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.

Methods: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.

Results: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.

Conclusion: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

Objective: Non-traumatic subarachnoid hemorrhage (SAH) is associated with a high percentage of misdiagnosis and poor prognosis. Biomarkers could be useful in the identification, treatment/management guidance, and outcome improvement of SAH patients. The current systematic review aims to investigate the potential role of biomarkers GFAP (Glial Fibrillary Acidic Protein) and UCH-L1 (Ubiquitin C-Terminal Hydrolase L1) in the diagnosis and prognosis of non-traumatic SAH.

Methods: A systematic search of PubMed, Scopus, and Web of Science databases was conducted from their inception through February 2023.

Results: 17 studies met the inclusion criteria and were included in this review. The vast majority of the included studies (82%) were on GFAP. Most studies used blood and/or CSF samples and incorporated multiple measurements through the initial hospitalization days. The majority of identified studies reported significantly higher levels of GFAP and UCHL1 in SAH patients with poor outcomes. There was notable variation in the specimen type and the timing of sampling.

Conclusion: Quantification of GFAP and UCHL1 through the initial days of hospitalization shows promise in the prediction of SAH patient outcomes. Further research is nevertheless warranted to confirm these findings and further clarify the use of the two biomarkers in SAH diagnosis and the prediction of severity and secondary events.

In defiance of the vast amount of information regarding Alzheimer's disease (AD) that has been learned over the past thirty years, progress toward developing an effective therapy has been difficult. A neurological ailment that progresses and cannot be reversed is Alzheimer's disease, which shows neurofibrillary tangles, beta-amyloid plaque, and a lack of cognitive processes that is created by tau protein clumps with hyperphosphorylation that finally advances to neuronal damage without a recognized treatment, which has stimulated research into new therapeutic strategies. The protein CAS9 is linked to CRISPR, which is a clustered Regularly Interspaced Short Palindromic Repeat that inactivates or corrects a gene by recognizing a gene sequence that produces a doublestranded break has enchanted a whole amount of interest towards its potency to cure gene sequences in AD. The novel CRISPR-Cas9 applications for developing in vitro and in vivo models to the benefit of AD investigation and therapies are thoroughly analyzed in this work. The discussion will also touch on the creation of delivery methods, which is a significant obstacle to the therapeutic use of CRISPR/Cas9 technology. By concentrating on specific genes, such as those that are significant early- onset AD risk factors and late-onset AD risk factors, like the apolipoprotein E4 (APOE4) gene, this study aims to evaluate the potential application of CRISPR/Cas9 as a possible treatment for AD.