CNS & neurological disorders drug targets最新文献

Motor neuron disorders (MNDs), including ALS, are deadly neurodegenerative conditions that cause progressive motor neuron degeneration. With neuroprotection and the potential for neuron regeneration employing MSCs, ESCs, iPSCs, and NSCs, stem cell treatment presents a viable alternative to current medicines, which only control a limited number of symptoms. Following PRISMA criteria, this narrative review methodically screened 1248 records from the Cochrane, Web of Science, PubMed, and Scopus databases. Following a thorough screening process, 22 studies, including preclinical models and 19 clinical trials, were analysed to assess the therapeutic mechanisms, safety, and efficacy of stem cell therapies for MNDs. Mesenchymal stem cell (MSC) therapy has shown a promising safety profile and possible therapeutic efficacy in ALS, with no substantial transplant-related toxicity noted. ALS functional rating scale-revised (ALSFRS-R) scores and forced vital capacity (FVC) assessments from clinical trials, such as those evaluating autologous bone marrow-derived MSCs, demonstrated stabilisation in ALS development. Studies have also emphasised as to how immunomodulation and neurotrophic factors play a part in MSC-based therapies. Recent data indicate that repeated intrathecal MSC injection could extend the duration of therapeutic advantages. Clinical trials have shown safety and early efficacy signals for motor neurons produced from embryonic stem cells (ESCs), especially using AstroRx®. This suggests that ESCs could be a viable option for regenerative medicine. Nonetheless, issues, like host integration and differentiation optimisation, still exist. Although clinical translation is still in its early stages, induced pluripotent stem cells (iPSCs) and their derivatives provide disease modelling and patient-specific therapeutic applications. Stem cell therapy holds promise for treating MND, with MSCs leading the way in current trials. It is necessary to enhance ESC- and iPSC-based techniques to tackle integration issues. To ensure long-term safety and efficacy, therapies must be developed using standardised protocols, patient stratification, optimised delivery, and large-scale studies.

Autophagy is a catabolic process that helps maintain cellular homeostasis by degrading damaged proteins and organelles while recycling essential biomolecules. Neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders, have been linked to autophagy dysregulation. In this manuscript, we review the complex role of autophagy in the neurobiology of these disorders, encompassing neuronal function, neurodevelopment, and neuroplasticity. The molecular mechanisms by which autophagy dysregulation contributes to the manifestation and progression of neuropsychiatric diseases, including those related to autophagy genes and pathways, are also discussed. Additionally, potential entry points for autophagytargeted therapy in these disorders, such as modulating mTOR and combining autophagy modulators with existing treatments, are also explored. We also specifically examine the neuroprotective effects of lithium, a mood stabilizer, through its influence on autophagy pathways. Overall, understanding the intricate relationship between autophagy and neuropsychiatric disorders provides new avenues for developing new treatments for these devastating conditions.

Introduction: Neuroinflammation plays a pivotal role in diabetes-associated cognitive dysfunction. Icariin (ICA), a bioactive flavonoid from Epimedium, shows neuroprotective potential, though its mechanism remains unclear.

Methods: Potential ICA targets and diabetic cognitive impairment-related genes were identified through database mining. A protein-protein interaction network was constructed (STRING database) and analyzed (Cytoscape) to identify hub genes. Molecular docking and dynamics simulations validated key targets, followed by in vitro validation using high glucose-induced HT22 cells.

Results: Network pharmacology suggested ICA's neuroprotection involves MAPK pathway modulation and anti-inflammatory effects. In vitro studies confirmed ICA suppressed pro-inflammatory cytokine release and regulated MAPK signaling.

Discussion: ICA's neuroprotection aligns with known flavonoid anti-inflammatory properties. However, limitations include single-cell line use and potentially non-physiological concentrations. Future studies should assess ICA in diabetic animal models, blood-brain barrier penetration, and synergy with antidiabetic drugs.

Conclusion: ICA protects HT22 cells from high glucose-induced damage via MAPK signaling and reduces inflammation, suggesting therapeutic potential for diabetic cognitive impairment. Further in vivo validation is warranted.

Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.

Introduction: Although motor neuron inclusions that contain hyperphosphorylated TDP- 43 protein (p-TDP-43) are considered an important clue in the pathophysiology of ALS, the main determinants of the neuronal dysfunction remain unknown.

Method: The spinal cords and motor cortex of 17 people (n=60 tissues) who died of ALS, with 10 controls were tested for p-TDP-43/neurofibrillary tangles (NFTs), biomarkers of neuroinflammation (GFAP, TMEM 119, miR-155, IL6, TNFα, IL1β, NF-κβ), neurodegeneration (NeuN, myelin basic protein) and BCL2 family proteins (BCL2, BCLW, BCLXL, and MCL1 each pro-survival as well as BIM, PUMA, NOXA, BAK, BAX each anti-survival) using in situ based methods including immunohistochemistry.

Results: p-TDP-43 detection was strongly correlated with neuroinflammation and neurodegeneration in both humans and in a mouse model of ALS with the mutant human TDP-43 gene (B6.Cg- Tg(Prnp-TARDBP*A315T)95Balo/J). The expression of each BCL2 family protein was significantly increased compared to the controls and co-localized with p-TDP-43 in both human and mouse models.

Discussion: To test whether altering BCL2 activity affects ALS pathophysiology, the FDAapproved drug venetoclax, which blocks BCL2, was started at age 3 mo IP in these mice and prevented clinical motor neuron dysfunction (n=5), whereas the untreated littermates (n=4) each died of end-stage paralysis at 5-7 mo. Blocking Bcl2 in the ALS mice reduced neurodegeneration 5-fold and neuroinflammation by 81%.

Conclusion: It is concluded that: 1) dysregulation of BCL2 family proteins is implicated in ALS, and 2) blocking Bcl2 alone in the mouse ALS model can markedly reduce the neurodegeneration.

CNS diseases have recently received a lot of focus. Glioblastoma multiforme (GBM) has the worst prognosis among various cancers. With its aggressive nature and potential for recurrence, GBM is a major concern in neuroscience. Radiotherapy, chemotherapy, and surgical removal are currently employed methods for treating GBM. The blood-brain barrier (BBB) is a major obstacle to effective medication delivery into the central nervous system (CNS), which is a major concern in the treatment of GBM. Nanotechnology helps transport active chemicals to brain tissue, a major glioma treatment challenge. Technology advancements in nanotechnology have the potential to facilitate the trans-BBB delivery of medicinal medications to the central nervous system. To treat illnesses associated with the central nervous system (CNS), it is possible to manage several types of nanoparticles (Nps). Novel therapeutic approaches are being explored, with NPs attracting interest as a potential tool for the targeted eradication of brain tumours. The review article reviewed the relevant literature on the utilisation of NPs for the treatment of Glioblastoma. The articles were obtained through various databases, including ScienceDirect, Scopus, PubMed and Google Scholar. It studies current treatment strategies for Glioblastoma, different NPs treating GBM with their mechanism by crossing the BBB, and various relevant patents of NPs drug delivery were analysed. This review article collects data about various nanoparticles used in GBM, with their mechanism of action. This review discusses the role of nanoparticulate systems in the effective treatment of GBM. It can be concluded from the literature that therapeutic agents can be delivered into the central nervous system through the blood-brain barrier with the use of nanotechnology, and so can be effectively used for the management of GBM.

Introduction: The mobility of people with multiple sclerosis (pwMS) is significantly limited due to the involvement of the musculoskeletal system, resulting in falls and a diminished quality of life. This study aimed to assess the risk of falls (utilizing the Downton scale) and its association with spasticity and other variables in pwMS and compare it with a group of healthy participants.

Methods: This descriptive and cross-sectional observational study involved 86 subjects, divided into two groups: cases (n=41) and controls (n=45). All participants completed the Spanish version of the Downton Scale.

Results: There was a significant statistical association (p<0.05) in all dimensions of the Downton Scale, except for medications (significant in antihypertensives), showing increased levels of disability and barriers in pwMS. The case group, comprising pwMS, exhibited a significantly higher risk of falls, with a mean score of 2.37 ± 1.76, whereas the healthy subjects scored significantly lower at 0.44 ± 0.62. Additionally, the pwMS displayed notably higher association levels of spasticity compared to the healthy group.

Discussion: The study emphasizes that spasticity significantly increases the risk of falls in pwMS, reinforcing the Downton scale's utility in identifying high-risk individuals. However, limitations such as a non-diverse sample and the absence of comparison with other neurological conditions suggest the need for broader, more inclusive future research.

Conclusion: This study confirms that pwMS face a greater risk of falls compared to their healthy counterparts. Factors such as spasticity, visual impairments, and hearing problems significantly contribute to this increased risk.

Introduction: Migraine is a common and debilitating neurological condition marked by recurring headaches and sensory disturbances. Although it poses a significant global health burden, its long-term management remains a challenge. Advances in pathophysiological insights have facilitated the development of more targeted treatment approaches. This review explores current and emerging strategies, including diagnostic methods, risk factors, and both pharmacological and nonpharmacological interventions.

Methods: An extensive literature review was conducted to evaluate both conventional and emerging treatment strategies for migraine. The analysis focused on the various phases of migraine, associated therapeutic options, underlying pathophysiological pathways, and existing treatment gaps. A comparative assessment of mechanisms of action, safety profiles, and treatment limitations was also conducted to identify current challenges and research needs.

Results: The literature highlights recent advances in both acute and preventive treatments for migraine. Key developments include the increasing use of CGRP antagonists (gepants), monoclonal antibodies, and non-invasive neuromodulation techniques. In addition, several FDA-approved drugs such as amitriptyline, ergotamine, flunarizine, and sumatriptan remain widely used. Novel agents, including topiramate, amiloride, and candesartan, are also being evaluated in clinical trials for their potential in migraine management.

Discussions: While conventional therapies like triptans, NSAIDs, and lifestyle interventions continue to serve as foundational treatments, the shift toward more personalized and mechanism-based approaches is evident. The integration of targeted therapies and neuromodulation reflects growing recognition of migraine's complex pathophysiology. Personalized care models and the exploration of newer pharmacological agents offer promising avenues for more effective and sustainable longterm management.

Conclusion: A variety of effective treatments are available for migraine, with choice dependent on severity, frequency, comorbidities, and individual tolerance. Gepants, Triptans, and Nutraceuticals represent a promising advancement in migraine therapy due to their targeted action and improved safety. Personalized treatment approaches are essential for optimal management outcomes.

Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer's and Parkinson's diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.