CNS & neurological disorders drug targets最新文献

Alzheimer's disease (AD), the leading cause of dementia, is characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. While Aβ-targeting therapies have been a primary focus of drug development, their long-term efficacy remains uncertain. Emerging evidence suggests that tauopathy is more closely linked to cognitive decline, positioning tau as a promising therapeutic target. Tauopathies, a group of neurodegenerative disorders marked by tau dysfunction and aggregation, were historically attributed to a toxic gain-of-function. However, clinical trials targeting tau have yielded limited success, likely due to the heterogeneity of tau pathology, variable patient responses, and suboptimal therapeutic strategies. Here, we underline the need for a refined understanding of tau biology to develop effective interventions. Advancing precision medicine approaches and identifying optimal tau species for therapeutic intervention could transform tau-targeting therapies into a cornerstone in managing tauopathies. By integrating insights from genetics, pathology, and translational research, future efforts may overcome current challenges and unlock novel treatment avenues, ultimately improving patient outcomes.

Salsolinol (SAL), an endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline, is a dopamine metabolite that has been implicated in the pathogenesis of Parkinson's disease (PD) due to its selective toxicity toward dopaminergic (DA) neurons. Experimental studies have demonstrated that SAL induces DA neuronal injury both in vitro and in vivo, thereby contributing to the PD pathogenesis. Given its specificity for nigral DA neurons, SAL serves as a more relevant model for studying PD-associated brain waste clearance and neurotoxicity, as it recapitulates the progressive nature of the disease. Emerging evidence indicates that SAL exerts its neurotoxic effects primarily through the induction of oxidative stress and regulated cell death in DA neurons. With the escalating global burden of PD and unmet need for therapies targeting multifactorial mechanisms, the dual role of SAL as both a dopamine derivative and mediator of protein aggregation links metabolic dysfunction to neurodegeneration, positioning it as a pivotal target for understanding sporadic PD and therapeutic development. In this review, we summarize current knowledge on the molecular mechanisms underlying SAL-induced neurotoxicity and its pathophysiological role in PD. By elucidating these mechanisms, this review provides valuable insights for future research in uncovering underestimated molecular targets for therapeutic intervention in PD.

The normal cellular prion protein (PrPC) can misfold into an infectious and pathogenic form (PrPSc) to produce prion diseases, also known as transmissible spongiform encephalopathies (TSEs), which are rare and deadly neurodegenerative conditions. The conversion of PrPC to PrPSc, which builds up as toxic aggregates in the central nervous system, is caused by sporadic, inherited, or acquired pathways. PrPSc-induced proteostasis failure, oxidative stress, neuronal toxicity, and progressive neurodegeneration are characteristics of pathogenesis. Due to their overlap with other neurodegenerative illnesses, prion diseases are still difficult to diagnose, even with breakthroughs in our knowledge of the molecular causes. Cerebrospinal fluid biomarkers, neuroimaging, EEG, and genetic testing are utilized in the diagnostic process. Methods like real-time quaking-induced conversion (RT-QuIC) provide high sensitivity. As there are currently no cures, the main goals of management are palliative care and symptom alleviation. Research is currently being conducted on experimental strategies that target PrP misfolding. These strategies include autophagy enhancers, monoclonal antibodies, antisense oligonucleotides, and small compounds. Artificial intelligence (AI) shows revolutionary promise by enhancing early diagnosis through biomarker analysis, neuroimaging interpretation, and EEG pattern identification. AI also improves clinical trial design, identifies tailored treatment approaches, and accelerates drug discovery. Furthermore, advancements in AI-based bioinformatics technologies have led to a better understanding of prion biology and strain diversity. The future holds promise for utilising cutting-edge treatment techniques, such as CRISPR and gene therapy, for targeted interventions, as well as combining AI with multimodal data to enhance diagnostic capabilities. There is optimism that the burden of prion disorders can be reduced, and the treatment of neurodegenerative illnesses can be improved through the integration of molecular research, novel treatments, and AI technology.

TAR DNA-binding protein 43 (TDP-43) is a vital RNA/DNA-binding protein involved in RNA metabolism, playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Approximately 97% of sporadic ALS (sALS), familial ALS (fALS) and FTLD cases are associated with pathological inclusions of hyperphosphorylated and ubiquitinated TDP-43 and genetic mutations in TAR DNA binding protein (TARDBP). Besides TARDBP, mutations in other genes such as C9ORF72, SOD1, FUS, and NEK1 are also linked to other fALS cases. Cytoplasmic mislocalization, aberrant post-translational modifications, and amyloid- like aggregation characterize TDP-43 pathology. These pathological changes impair essential cellular processes, including gene expression, mRNA stability, and RNA metabolism. Mechanisms of TDP-43-induced toxicity include disruption of endocytosis, mitochondrial dysfunction, and progressive cellular damage. Additionally, liquid-liquid phase separation (LLPS) and prion-like propagation are emerging as central features of its pathological spread. This review summarizes advances in understanding TDP-43's physiological functions and pathological mechanisms in ALS and FTLD. It highlights key processes underlying TDP-43 toxicity, such as aggregation, selective neuronal vulnerability, and regional susceptibility. Finally, this review summarizes evolving therapeutic strategies aimed at mitigating TDP-43-related toxicity through disaggregation, targeting mislocalization, and addressing upstream dysfunctions and challenges faced in the development of effective therapies for ALS and FTLD.

Alzheimer's disease (AD) is a typical neurodegenerative illness, and it is a main cause of dementia, affecting millions of older populations throughout the world. Although the exact causes of AD are still not clear, the disorder is known to be considered by the accumulation of amyloid plaques and tau tangles in the neuronal cells. Currently, available drugs such as cholinesterase inhibitors and NMDA antagonists can help manage symptoms but don't address the underlying causes of the disease. New experimental treatments targeting amyloid and tau proteins show promise but are still in clinical trials. Recently, β-Amyloid has gained attention as an emerging target to develop new medications as it is strongly involved in the pathophysiology of AD. β-Amyloidpathies are directly or indirectly linked with multiple pathways, including GSK3β, insulin resistance, NMDA dysfunction, AMP-activated kinase, cholesterol mechanism, mitochondrial dysfunction, neuroinflammation, and SIRT1. However, several β-Amyloid targeting therapies employing various mechanisms have shown partial success in clinical trials, possibly due to a lack of understanding of the molecular link of this peptide with other pathways. Therefore, this paper has discussed the β- Amyloid molecular mechanisms involved in pathophysiological pathways to manage neuronal disorders and intracellular signal transduction effectively.

Introduction: The polyol pathway is responsible for the metabolism of almost one-third of the total glucose in people with chronic diabetes. Moreover, it causes complications in organs that rely on aldose reductase (AR) as an enzyme. The purpose of this research was to examine the in vitro and in vivo effects of a flavonoid-rich ethyl acetate fraction of a methanolic extract of Ficus carica Lam. leaves (FCEA) on the aldose reductase gene AKR1B1. The complicated relation of AR for target confirmation and analysis of the flavonoids of FCEA, quercetin, kaempferol, and chrysin was explored by building a flavonoid-protein complex network utilizing GeneCards®, String, and Cytoscape Networking.

Method: The examination of ADMET was carried out after docking on the active sites of AR. By the binding and scoring abilities, the analysis was carried out. The ADMET characteristics demonstrated that these flavonoids had excellent solubility, absorption, and oral bioavailability, and the results demonstrate that they have potential. An additional in-vivo investigation was conducted on rats using a model induced by streptozotocin (STZ). Hence, upon induction, the rats' sciatic nerves were removed and prepared for an RT-PCR analysis of the AKR1B1 gene.

Result: Compared to the diabetic normal group and the metformin group, rats treated with FCEA had lower levels of messenger RNA and AKR1B1 gene expression.

Conclusion: This proves that FCEA has effectively blocked AR. It is highly likely to suggest FCEA as a potent aldose reductase inhibitor, as it considerably reduces the mRNA level of AKR1B1 gene expression in the sciatic nerve of sick rats, according to a combined bioinformatics prediction and RT-PCR analysis.

Introduction: Functional reserve, the process that warrants the brain to have resources to maintain key functions and processes when facing neurodegeneration, may be strengthened in nominally healthy subjects by measures that prompt neural plasticity throughout life.

Method: In this work, we administered Chlorogenic Acid (CGA) to evaluate its ability to promote functional morphological plasticity in the frontal cortical-striatal circuit of healthy mice, a pathway exposed constantly to oxidative challenges, excitotoxicity, and neuroinflammation. The magnitude of neural plasticity was estimated by assessing spontaneous motor behavior (open field), the relative magnitude of neuronal activation (number of c-Fos positive neurons), dendritic remodeling (Golgi- Cox impregnation), the availability of Brain-Derived Neurotrophic Factor (BDNF) (semiquantitative Western blotting), and lipid peroxidation (TBARS assay) in CGA- or vehicle-administered C57BL/6 male mice.

Results: CGA administration increased c-Fos in the Dorsal striatum (Ds), changed the availability of BDNF and Pro-BDNF in the Frontal Cortex (FC) and DS, induced dendritic remodeling in FC and DS neurons, and reduced FC and DS lipid peroxidation without affecting motor performance or the availability of TrkB receptor isoforms.

Conclusion: Our findings suggest that CGA increases functional reserve by promoting neuronal plasticity in healthy male mice. Future research should determine whether these additional resources indeed protect against neurodegeneration.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Emerging evidence highlights the significant role of glial cells, particularly astrocytes and microglia, in the pathophysiology of ASD. Glial cells are crucial for maintaining homeostasis, modulating synaptic function, and responding to neural injury. Dysregulation of glial cell functions, including altered cytokine production, impaired synaptic pruning, and disrupted neuroinflammatory responses, has been implicated in ASD. Molecular mechanisms underlying these disruptions involve aberrant signaling pathways, such as the mTOR pathway, and epigenetic modifications, leading to altered gene expression profiles in glial cells. Moreover, microglial activation and reactive astrocytosis contribute to an inflammatory environment that exacerbates neural circuit abnormalities. Understanding these molecular mechanisms opens avenues for therapeutic interventions. Current therapeutic approaches targeting glial cell dysfunction include anti-inflammatory agents, modulators of synaptic function, and cell-based therapies. Minocycline and ibudilast have shown potential for modulating microglial activity and reducing neuroinflammation. Additionally, advancements in gene editing and stem cell therapy hold promise for restoring normal glial function. This abstract underscores the importance of glial cells in ASD. It highlights the need for further research to elucidate the complex interactions between glial dysfunction and ASD pathogenesis, aiming to develop targeted therapies that can ameliorate the clinical manifestations of ASD.

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.