CNS & neurological disorders drug targets最新文献

Autophagy is a self-destructive cellular process that removes essential metabolites and waste from inside the cell to maintain cellular health. Mitophagy is the process by which autophagy causes disruption inside mitochondria and the total removal of damaged or stressed mitochondria, hence enhancing cellular health. The mitochondria are the powerhouses of the cell, performing essential functions such as ATP (adenosine triphosphate) generation, metabolism, Ca²⁺ buffering, and signal transduction. Many different mechanisms, including endosomal and autophagosomal transport, bring these substrates to lysosomes for processing. Autophagy and endocytic processes each have distinct compartments, and they interact dynamically with one another to complete digestion. Since mitophagy is essential for maintaining cellular health and using genetics, cell biology, and proteomics techniques, it is necessary to understand its beginning, particularly in ubiquitin and receptor-dependent signalling in injured mitochondria. Despite their similar symptoms and emerging genetic foundations, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have all been linked to abnormalities in autophagy and endolysosomal pathways associated with neuronal dysfunction. Mitophagy is responsible for normal mitochondrial turnover and, under certain physiological or pathological situations, may drive the elimination of faulty mitochondria. Due to their high energy requirements and post-mitotic origin, neurons are especially susceptible to autophagic and mitochondrial malfunction. This article focused on the importance of autophagy and mitophagy in neurodegenerative illnesses and how they might be used to create novel therapeutic approaches for treating a wide range of neurological disorders.

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

Background: The work proposes a new mathematical model of dynamic processes of a typical spatially heterogeneous biological system, and sets and solves a mathematical problem of modeling the dynamics of the system of neurovascular units of the brain in conditions of ischemic stroke. There is a description of only a small number of mathematical models of stroke in the literature. This model is being studied and a numerical and software implementation of the corresponding mathematical problem is proposed.

Methods: This work is the first attempt ever aiming to employ a Monte Carlo computational approach for In Silico simulation of the most critical parameters in molecular and cellular pathogenesis of the brain ischemic stroke. In this work, a new mathematical model of the development of ischemic stroke is proposed in the form of a discrete model based on neurovascular units (NVU) as elements.

Results: As a result of testing the program with the assignment of empirically selected coefficients, data were obtained on the evolution of the states of the lattice of the cellular automaton of the model for the spread of stroke in a region of the brain tissue. A resulting new theoretical model of the particular pathologically altered biosystem might be taken as a promising tool for further studies in neurology; general pathology and cell biology.

Conclusion: For the first time, a mathematical model has been constructed that allows us to represent the spatial dynamics of the development of the affected area in ischemic stroke of the brain, taking into account neurovascular units as single morphofunctional structures.

Background: Neutrophils and Lipocalin-2 (LCN2) play pivotal roles in cerebral ischemiareperfusion (I/R) injury. However, their contribution is not fully clarified.

Objective: This study aimed to explore the role of LCN2 and its association with neutrophil polarization in I/R injury.

Methods: A mouse model of middle cerebral artery occlusion (MCAO) was used to induce cerebral ischemia. LCN2mAb was administered 1 h and Anti-Ly6G was administered for 3d before MCAO. The role of LCN2 in the polarity transition of neutrophils was explored using an in vitro HL-60 cell model.

Results: LCN2mAb pretreatment had neuroprotective effects in mice. The expression of Ly6G was not significantly different, but the expression of N2 neutrophils was increased. In the in vitro study, LCN2mAb-treated N1-HL-60 cells induced N2-HL-60 polarization.

Conclusion: LCN2 may affect the prognosis of ischemic stroke by mediating neutrophil polarization.

Background: Vitamin D is implicated in many processes in the central nervous system (CNS), such as neurogenesis, neurotransmitter synthesis, synaptogenesis and protection against oxidative stress, thereby exerting a neuroprotective effect.

Objective: In the present review, we aimed to evaluate the potential benefit(s) of vitamin D supplementation for CNS aging in different clinical contexts.

Methods: We performed a literature search, looking for clinical trials and randomized clinical trials evaluating the effect of vitamin D supplementation on different endpoints related to cognitive outcomes.

Results: Firstly, we identified 16 papers dealing with the impact of vitamin D supplementation on cognitive function in healthy subjects; the current literature suggests a real role for vitamin D supplementation in the prevention of cognitive decay in this clinical setting. Conversely, two papers suggest that vitamin D supplementation may be beneficial in patients with mild cognitive impairment (MCI). Finally, current data on vitamin D in Alzheimer's disease are contradictory.

Conclusion: Vitamin D supplementation may improve the cognitive outcomes of patients with MCI, whereas there is no evidence that it may prevent dementia or modulate the course of Alzheimer's disease.

Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen (O₂). ROS sources can be endogenous, such as cellular organelles and inflammatory cells, or exogenous, such as ionizing radiation, alcohol, food, tobacco, chemotherapeutical agents and infectious agents. Oxidative stress results in damage of several cellular structures (lipids, proteins, lipoproteins, and DNA) and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging. A large body of studies showed that ROS plays an important role in carcinogenesis. Indeed, increased production of ROS causes accumulation in DNA damage leading to tumorigenesis. Various investigations demonstrated the involvement of ROS in gliomagenesis. The most common type of primary intracranial tumor in adults is represented by glioma. Furthermore, there is growing attention on the role of the Nerve Growth Factor (NGF) in brain tumor pathogenesis. NGF is a growth factor belonging to the family of neurotrophins. It is involved in neuronal differentiation, proliferation and survival. Studies were conducted to investigate NGF pathogenesis's role as a pro- or anti-tumoral factor in brain tumors. It has been observed that NGF can induce both differentiation and proliferation in cells. The involvement of NGF in the pathogenesis of brain tumors leads to the hypothesis of a possible implication of NGF in new therapeutic strategies. Recent studies have focused on the role of neurotrophin receptors as potential targets in glioma therapy. This review provides an updated overview of the role of ROS and NGF in gliomagenesis and their emerging role in glioma treatment.

Parkinson's disease (PD) is one of the most frequent degenerative central nervous system disorders affecting older adults. Dopaminergic neuron failure in the substantia nigra is a pathological sign connected with the motor shortfall of PD. Due to their low teratogenic and adverse effect potential, medicinal herbs have emerged as a promising therapy option for preventing and curing PD and other neurodegenerative disorders. However, the mechanism through which natural compounds provide neuroprotection against PD remains unknown. While testing compounds in vertebrates such as mice is prohibitively expensive and time-consuming, zebrafish (Danio rerio) may offer an appealing alternative because they are vertebrates and share many of the same characteristics as humans. Zebrafish are commonly used as animal models for studying many human diseases, and their molecular history and bioimaging properties are appropriate for the study of PD. However, a literature review indicated that only six plants, including Alpinia oxyhylla, Bacopa monnieri, Canavalia gladiate, Centella asiatica, Paeonia suffruticosa, and Stachytarpheta indica had been investigated as potential PD treatments using the zebrafish model. Only C. asiatica and B. monnieri were found to have potential anti-PD activity. In addition to reviewing the current state of research in this field, these plants' putative mechanisms of action against PD are explored, and accessible assays for investigation are made.

Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD.

Cerebral palsy (CP) is part of a group of nonprogressive motor disorders. The disease affects movement and posture and constitutes the most frequent cause of motor disability in childhood. CP is characterized by spasticity, reflecting lesions in the pyramidal pathway. Treatment is currently focused on physical rehabilitation, and the annual progression of the disease is 2-3%. About 60% of these patients present severe degrees of malnutrition associated with dysphagia, gastrointestinal abnormalities, malabsorption, increased metabolism, and depression. These alterations promote sarcopenia functional dependence and affect the quality of life and delay the evolution of motor skills. Currently, there is evidence that the supplementation of several nutrients, dietary correction, and probiotics can improve neurological response by stimulating neuroplasticity, neuroregeneration, neurogenesis, and myelination. This therapeutic strategy could shorten the response period to treatment and increase both gross and fine motor skills. The interaction of nutrients and functional foods integrating a Nutritional Support System (NSS) has shown greater efficiency in neurological stimulation than when nutrients are supplied separately. The most studied elements in the neurological response are glutamine, arginine, zinc, selenium, cholecalciferol, nicotinic acid, thiamine, pyridoxine, folate, cobalamin, Spirulina, omega-3 fatty acids, ascorbic acid, glycine, tryptophan, and probiotics. The NSS represents a therapeutic alternative that will restore neurological function in patients with spasticity and pyramidal pathway lesions, both characteristics of patients with CP.

Monoamine oxidase B is a crucial therapeutic target for neurodegenerative disorders like Alzheimer's and Parkinson's since they assist in disintegrating neurotransmitters such as dopamine in the brain. Pursuing efficacious monoamine oxidase B inhibitors is a hot topic, as contemporary therapeutic interventions have many shortcomings. Currently available FDA-approved monoamine oxidase inhibitors like safinamide, selegiline and rasagiline also have a variety of side effects like depression and insomnia. In the quest for a potent monoamine oxidase B inhibitor, sizeable, diverse chemical entities have been uncovered, including chalcones. Chalcone is a renowned structural framework that has been intensively explored for its monoamine oxidase B inhibitory activity.The structural resemblance of chalcone (1,3-diphenyl-2-propen-1-one) based compounds and 1,4-diphenyl- 2-butene, a recognized MAO-B inhibitor, accounts for their MAO-B inhibitory activity. Therefore, multiple revisions to the chalcone scaffold have been attempted by the researchers to scrutinize the implications of substitutions onthe molecule's potency. In this work, we outline the docking investigation results of various chalcone analogues with monoamine oxidase B available in the literature until now to understand the interaction modes and influence of substituents. Here we focused on the interactions between reported chalcone derivatives and the active site of monoamine oxidase B and the influence of substitutions on those interactions. Detailed images illustrating the interactions and impact of the substituents or structural modifications on these interactions were used to support the docking results.