CNS & neurological disorders drug targets最新文献

Depression is a serious mental health disorder that impacts more than 350 million individuals globally. While the roles of serotonin and norepinephrine in depression have been extensively studied, the importance of dopaminergic pathways-essential for mood, cognition, motor control, and endocrine function-often gets overlooked. This review focuses on four major dopamine (DA) circuits: the mesolimbic (MLP), mesocortical (MCP), nigrostriatal (NSP), and thalamictuberoinfundibular pathways (TTFP), and their roles in depression. The MLP, which is key to reward processing, is linked to anhedonia, a primary depression symptom. The MCP, projecting to the prefrontal cortex, affects cognitive issues like impaired attention and decision-making. The NSP, mainly responsible for motor control, is related to psychomotor retardation in depression, while the TTFP manages neuroendocrine responses, which are often disrupted in stress-related depressive conditions. Current antidepressant treatments mainly target serotonin and norepinephrine systems but tend to be less effective for patients with DArgic dysfunction, leading to treatment resistance. This review underscores emerging evidence that suggests targeting DArgic pathways could improve treatment outcomes, especially for symptoms like anhedonia and cognitive deficits that conventional therapies often fail to address. Future research should aim to combine advancements in neuroimaging, optogenetics, and genetic studies to better map DArgic pathways and create personalized treatment plans. This review highlights the potential for new therapies that focus on DA systems, which could pave the way for more effective and tailored approaches to treating depression.

Alzheimer's disease is an ailment that is linked with the degeneration of the brain cells, and this illness is the main cause of dementia. Metabolic stress affects the activity of the brain in AD via FOXO signaling. The occurrence of AD will significantly surge as the world's population ages, along with lifestyle changes perceived in current decades, indicating a main contributor to such augmented prevalence. Similarly, metabolic disorders of current adulthood, such as obesity, stroke, and diabetes mellitus, have been observed as the risk-causing factors of AD. Environmental influences induce genetic mutations that result in the development of several diseases. Metabolic disorders develop when individuals are exposed to an environment where food is easily accessible and requires minimal energy expenditure. Obesity and diabetes are among the most significant worldwide health concerns. Obesity arises because of an imbalance between the amount of energy consumed and the amount of energy expended, which is caused by both behavioral and physiological factors. Obesity, insulin resistance syndrome, hypertension, and inflammation are factors that contribute to the worldwide risk of developing diabetes mellitus and neurodegenerative diseases. FOXO transcription factors are preserved molecules that play an important part in assorted biological progressions, precisely in aging as well as metabolism. Apoptosis, cell division and differentiation, oxidative stress, metabolism, and lifespan are among the physiological processes that the FOXO proteins are adept at controlling. In this review, we explored the correlation between signaling pathways and the cellular functions of FOXO proteins. We have also summarized the intricate role of FOXO in AD, with a focus on metabolic stress, and discussed the prospect of FOXO as a molecular link between AD and metabolic disorders.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease worldwide and presents as a progressive motor disorder. Gene mutations play a pivotal role in the degeneration of dopaminergic neurons in the substantia nigra region. Mutations in the Leucine rich repeat kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of PD. LRRK2 is a multi-functional protein involved in several critical cellular processes, including mitochondrial function, autophagy, vesicular trafficking, and immune system regulation. Dysregulation of these processes due to aberrant LRRK2 activity contributes to neuronal degeneration, particularly in dopaminergic neurons, which are most affected in PD. The current review discusses the structure of LRRK2, its function, and pathogenic mutations in the context of PD. However, significant challenges remain, particularly in terms of ensuring drug specificity, minimizing off-target effects, and understanding the long-term safety and efficacy of these treatments. As we advance our understanding of LRRK2 biology, it remains a highly promising target for therapeutic strategies aimed at modifying the course of Parkinson's disease.

Sitagliptin is a dipeptidyl peptidase-IV inhibitor approved for treating type 2 diabetes mellitus. It increases the active form of incretin Glucagon-like Peptide-1 (GLP-1). The GLP-1 peptide prevents damage to neurons due to its anti-inflammatory and anti-apoptotic activities. This article summarizes the studies assessing the neuroprotective properties of sitagliptin, especially through the GLP-1 pathway. The outcomes of experimental research indicate that sitagliptin has a decreasing effect on inflammation response. Sitagliptin decreases proinflammatory factors, such as Glial Fibrillary Acidic Protein (GFAP), Nuclear factor kappa B (NF-κB), Tumor Necrosis Factor-α (TNF- α), and Interleukin-6 (IL-6). It also decreases glutamate levels, the primary excitatory neurotransmitter. Furthermore, sitagliptin shows antioxidative and antiapoptotic effects. Lastly, sitagliptin may provide a novel agent for the management of neurological disease.

The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

Repurposing drugs (DR) has become a viable approach to hasten the search for cures for neurodegenerative diseases (NDs). This review examines different off-target and on-target drug discovery techniques and how they might be used to find possible treatments for non-diagnostic depressions. Off-target strategies look at the known or unknown side effects of currently approved drugs for repositioning, whereas on-target strategies connect disease pathways to targets that can be treated with drugs. The review highlights the potential of experimental and computational methodologies, such as machine learning, proteomic techniques, network and genomics-based approaches, and in silico screening, in uncovering new drug-disease correlations. It also looks at difficulties and failed attempts at drug repurposing for NDs, highlighting the necessity of exact and standardised procedures to increase success rates. This review's objectives are to address the purpose of drug repurposing in human disorders, particularly neurological diseases, and to provide an overview of repurposing candidates that are presently undergoing clinical trials for neurological conditions, along with any possible causes and early findings. We then include a list of drug repurposing strategies, restrictions, and difficulties for upcoming research.

Parkinson's disease (PD) is a neurodegenerative disorder that results from the progressive loss of neurons in the brain followed by symptoms such as slowness and rigidity in movement, sleep disorders, dementia and many more. The different mechanisms due to which the neuronal degeneration occurs have been discussed, such as mutation in PD related genes, formation of Lewy bodies, oxidation of dopamine. This review discusses current surgical treatment and gene therapies with novel developments proposed for PD. Gene therapy based on novel approaches will possess more potential advantages over the conventional methods. Currently, gene therapy for such disorders is still under the process of clinical trials and approval. The pathogenesis comes from the breakdown of dopaminergic neurons within substantia nigra (SN) by the action of tyrosinase enzyme and subsequent accumulation of α-synuclein within the neurons. These dopaminergic neurons are the main source of dopamine, the decline of which is responsible for the symptoms. So, gene therapy can possibly provide more stable supplementation and regulate the expression of tyrosinase enzyme, providing better symptomatic relief and lesser side effects. Dopamine replacement therapy is a wellstudied gene therapy method for PD. Another approach involves introducing functional genes for enzymes such as tyrosine hydroxylase, cyclohydrolases, and decarboxylases with the help of engineered vectors such as AAV and LV. Further, the potential application of nanoparticles in gene therapy as an efficient gene delivery and imaging system has been discussed. Among these, lipidbased nanoparticles such as PILs offer important benefits in terms of enhanced bioavailability, permeability to the cells, and solubility. So, this review paper summarizes some of the advanced gene therapy approaches for PD and the current status of clinical research in the development of gene therapy using nanoparticles.

Background: AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives.

Objectives: This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments.

Methods: The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR).

Results: Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. RT-qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD.

Conclusion: This research provides a new perspective for personalized clinical management and treatment of AD.

Neurological conditions resulting from severe spinal cord injuries, brain injuries, and other traumatic incidents often lead to the loss of essential bodily functions, including sensory and motor capabilities. Traditional prosthetic devices, though standard, have limitations in delivering the required dexterity and functionality. The advent of neuroprosthetics marks a paradigm shift, aiming to bridge the gap between prosthetic devices and the human nervous system. This review paper explores the evolution of neuroprosthetics, categorizing devices into sensory and motor neuroprosthetics and emphasizing their significance in addressing specific challenges. The discussion section delves into long-term challenges in clinical practice, encompassing device durability, ethical considerations, and issues of accessibility and affordability. Furthermore, the paper proposes potential solutions with a specific focus on enhancing sensory experiences and the importance of user-friendly interfaces. In conclusion, this paper offers a comprehensive overview of the current state of neuroprosthetics, outlining future research and development directions to guide advancements in the field.

Cerebral or brain infarction is a pathological process that restricts or blocks the supply of blood to the brain due to occlusion or narrowing of cerebral blood vessels. At present, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used to image cerebral infarction. Along with imaging, numerous non-invasive external brain monitoring tools are being developed that use a variety of technologies to act as sensors for neurological disorders, including stroke. This review briefly discussed the recent biomarkers for cerebral infarction and its diagnostic system through different biosensors.