Treatment Of Neurodegenerative Diseases Research Articles

Dynamic mitophagy trajectories hallmark brain aging.

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.

In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.

Effective Nose-to-Brain Delivery of Blood-Brain Barrier Impermeant Anti-IL-1β Antibody via the Minimally Invasive Nasal Depot (MIND) Technique.

Treatment of neuroinflammation and neurodegenerative diseases using biologic therapies is limited due to the blood-brain barrier (BBB). This study explores a clinically validated approach to bypass the BBB for the purposes of direct central nervous system (CNS) delivery of antibodies using the Minimally Invasive Nasal Depot (MIND) technique. Using a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation, we evaluated the efficacy of MIND in delivering a BBB impermeant full-length anti-IL-1β antibody. The results demonstrated that MIND delivery resulted in a significant reduction in IL-1β levels and microglial activation in relevant brain regions, notably outperforming conventional intravenous (IV) administration. These results underscore the ability of the MIND approach to transform the treatment landscape for a range of neurodegenerative diseases by enabling the targeted delivery of otherwise BBB impermeant therapeutics.

Microglia programmed cell death in neurodegenerative diseases and CNS injury.

Programmed cell death (PCD) has emerged as a critical regulatory mechanism in the initiation and progression of various pathological conditions. PCD in microglia, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, occurs in a variety of central nervous system (CNS) diseases. Dysregulation of microglia can lead to excessive tissue damage or neuronal death in CNS injury. Various injury stimuli trigger aberrant activation of the PCD pathway of microglia, which then further leads to inflammatory cascades that exacerbates CNS pathology in a vicious cycle. Therefore, targeting PCD in microglia is considered an important avenue for the treatment of various neurodegenerative diseases and CNS injury. In this review, we summarize the major and recent findings focusing on the mechanisms of PCD in microglia modulating functions in neurodegenerative diseases and CNS injury and provide a systematic overview of the current inhibitors targeting various PCD pathways, which may provide important therapeutic targets that merit further investigation.

Biological activities of astaxanthin in the treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) develop with the gradual advancement of neuronal damage and dysfunction in the central nervous system (CNS). These disorders are mostly the outcomes of the improper sedimentation and accumulation of proteins, such as amyloid-β (Aβ), α-synuclein, and prions. Astaxanthin (AST) exists in different types of living organisms and displays antioxidant and anti-inflammatory functions. This review has concentrated on the therapeutic characteristics of AST on NDs. Data was collected by searching Scopus, PubMed, and Google Scholar databases. Articles selected for this review reported results on the neuroprotective properties of AST on NDs of studies conducted during the years 2000 to 2024. AST decreases soluble Aβ levels by stimulating the Aβ degradation enzyme. It also reduces inflammation in the substantia nigra (SN) by decreasing IBA1 expression, thereby lessening microglia activity. This carotenoid reduces demyelination by increasing the survival of oligodendrocytes cells and increasing the number of their progenitor cells. AST has antioxidant, anti-inflammatory, and anti-apoptotic properties and can play a role in the treatment of many NDs. There is no definitive treatment for some NDs. The use of AST and natural compounds can be an optimal method for preventing and treating NDs with few side effects.

Erinacine A-Enriched Hericium erinaceus Mycelium Ethanol Extract Lessens Cellular Damage in Cell and Drosophila Models of Spinocerebellar Ataxia Type 3 by Improvement of Nrf2 Activation

Spinocerebellar ataxia type 3 (SCA3), caused by the abnormal expansion of polyglutamine (polyQ) in the ataxin-3 protein, is one of the inherited polyQ neurodegenerative diseases that share similar genetic and molecular features. Mutant polyQ-expanded ataxin-3 protein is prone to aggregation in affected neurons and is predominantly degraded by autophagy, which is beneficial for neurodegenerative disease treatment. Not only does mutant polyQ-expanded ataxin-3 increase susceptibility to oxidative cytotoxicity, but it also hampers antioxidant potency in neuronal cells. Nuclear factor erythroid-derived 2-like 2 (Nrf2), a master transcription factor that controls antioxidant and detoxification gene expression, plays a crucial role in neuroprotection in SCA3 and other neurodegenerative diseases. The present data showed that treatment with erinacine A-enriched Hericium erinaceus mycelium ethanol extract (HEME) extended longevity and improved locomotor activity in ELAV-SCA3tr-Q78 transgenic Drosophila. Moreover, HEME treatment enhanced antioxidant potency and autophagy, which, in turn, corrected levels of mutant polyQ-expanded ataxin-3 and restrained protein aggregation in both cell and Drosophila models of SCA3. Markedly, HEME increased the activation of Nrf2. Silencing Nrf2 protein expression negated most of the promising effects of HEME on SK-N-SH-MJD78 cells, highlighting the critical role of increased Nrf2 activation in the efficacy of HEME treatment. These findings suggest that HEME has therapeutic potential in SCA3 by enhancing autophagic and Nrf2-mediated antioxidant pathways, which may also influence neurodegenerative progression in other polyQ diseases.

Promoting stem cells activity using Chinese medicine herbs in treatment of neurological disorder: A review on novel therapeutic approaches

Stem cell therapy represents a burgeoning and swiftly advancing modality for the treatment of a diverse array of neurological disorders. However, despite continued clinical trials, the underlying mechanisms of action often remain elusive. Traditional Chinese medicine (TCM), with its holistic approach, provides a valuable resource for the identification and evaluation of potential neuroprotective agents. Research has shown that TCM, including herbs, herbal extracts, and specific Chinese herbal constituents, can modulate the proliferation and differentiation of neural stem cells (NSCs) to some extent. This review examines the potential of TCM as a treatment for neurodegenerative diseases. Given the limitations of current therapies due to a lack of understanding of disease pathogenesis, a holistic approach to TCM offers a promising alternative. This paper also summarizes the role of stem cells in the management of neurological disorders and evaluates prior studies concerning stem cell transplantation. In addition, it explores the capacity of TCM to influence the proliferation and differentiation of NSCs. The ultimate aim of this review is to enhance our understanding of how TCM can be utilized to influence stem cell behavior and potentially treat neurodegenerative diseases.

Design, Synthesis, and Biological Evaluations of 5-aryl-pyrazole-3-carboxamide Derivatives as Selective CB2 Receptor Agonists for the Treatment of Colitis

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC50, CB2 = 16.2 nM, EC50, CB1 > 105 nM). Furthermore, 33 treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis.

Neuroimaging in Dementia.

This article captures the current literature regarding the use of neuroimaging measures to study neurodegenerative diseases, including early- and late-onset Alzheimer disease, vascular cognitive impairment, frontotemporal lobar degeneration disorders, dementia with Lewy bodies, and Parkinson disease dementia. In particular, the article highlights significant recent changes in novel therapeutics now available for the treatment of Alzheimer disease and in defining neurodegenerative disease using biological frameworks. Studies summarized include those using structural and functional MRI (fMRI) techniques, as well as metabolic and molecular emission tomography imaging (ie, positron emission tomography [PET] and single-photon emission computerized tomography [SPECT]). Neuroimaging measures are considered essential biomarkers for the detection and diagnosis of most neurodegenerative diseases. The recent approval of anti-amyloid antibody therapies has highlighted the importance of MRI and PET techniques in treatment eligibility and monitoring for associated side effects. Given the success of the initial biomarker-based classification system for Alzheimer disease (the amyloid, tau, neurodegeneration [A/T/N] framework), researchers in vascular cognitive impairment have created similar techniques for biomarker-based diagnosis. Further, the A/T/N framework for Alzheimer disease has been updated to include several pathologic targets for biomarker detection. Neurodegenerative diseases have a major health impact on millions of patients around the world. Neuroimaging biomarkers are rapidly becoming major diagnostic tools for the detection, monitoring, and treatment of neurodegenerative diseases. This article educates readers about the current literature surrounding the use of neuroimaging tools in neurodegenerative diseases along with recent important developments in the field.

Employing spectroscopic, calorimetric and structural bioinformatics approaches to decipher the binding mechanism of mangiferin with human transferrin.

In recent times, neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD) and others, represent a major global health challenge with increasing prevalence and significant socio-economic impact. These diseases, characterized by progressive neuronal loss, currently lack effective therapies. Phytochemicals offer promising therapeutic potential due to their diverse bioactive properties. Mangiferin, a glucosylxanthone found in mangoes and other plants, has shown significant therapeutic potential in NDs. Human transferrin (Tf), an iron-binding protein crucial for iron homeostasis, is implicated in ND pathogenesis. This study delineates the interaction between Mangiferin and Tf. Molecular docking revealed Mangiferin predominantly interacts with Tf's binding site, engaging critical residues. Molecular dynamics simulations over 200 ns demonstrated the stability of the Tf-Mangiferin complex without major deviations. Fluorescence binding assays confirmed the strong binding affinity of Mangiferin to Tf. Additionally, ITC validated the spontaneous binding of Mangiferin with Tf, providing detailed thermodynamic parameters. The findings highlight the therapeutic potential of Mangiferin in NDs treatment through its interaction with Tf, offering insights into novel mechanisms of action and pathways for disease modification.

Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment

Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment

Theoretical investigation of selective inhibitory activity of chromone-based compounds against monoamine oxidase (MAO)-A and -B

Monoamine oxidase (MAO) is crucial for the breakdown of monoamine neurotransmitters, making it a promising target for treating neurodegenerative disorders, such as depression, Alzheimer’s disease, and Parkinson’s disease. In this study, we investigated the selective inhibitory activity of chromone-based compounds against MAO-A and MAO-B for neurodegenerative disease treatment. In literary sources, thirty chromone derivatives have been identified as potential ligands for MAO-A and MAO-B inhibitors. We utilized molecular docking to evaluate how the most active compound interacted with the targeted MAO-A and MAO-B. Compound 2 g, the most active for MAO-A, demonstrated a lower CDOCKER energy compared to the co-crystallized ligand. Meanwhile, compound 2f, the most active for MAO-B, showed a CDOCKER energy similar to the co-crystallized ligand and exhibited similar binding patterns. Furthermore, we constructed a quantitative structure-activity relationship (QSAR) model to predict the properties and estimate IC50 values for 30 chromone derivatives functioning as MAO-A and MAO-B inhibitors. The model predictions were validated against experimental measurements. Our 2D QSAR model demonstrated robustness, with a statistically significant non-cross-validated coefficient (r2 < 0.9), cross-validated correlation coefficient (q2 < 0.6), and predictive squared correlation coefficient (r2 pred < 0.8). Additionally, MD simulations confirmed the stable binding of compounds 2 g and 2f with MAO-A and MAO-B, respectively, displaying substantial binding energy. The most effective pharmacophore model identified key features, such as hydrogen bond acceptors and hydrophobic interactions, that contribute significantly to inhibitory potency. This study offers valuable insight into the selection of compounds with improved selectivity for MAO inhibition.

Investigating the Possibilities of Applying the TENS as a Neurostimulation Method

Transcranial electrical stimulation (TES) is a non-invasive technology used to change the functions of the nervous system as one of the methods of neuromodulation. This method modulates brain activity by applying low-intensity electrical current to different regions of the brain. The use of transcranial electrical stimulation has shown promising results in the treatment of depression, chronic pain, neurodegenerative diseases and other neurological problems. Research shows that the application of transcranial electrical stimulation can be effective in areas such as improving memory, developing motor skills and increasing cognitive functions. However, safety, efficacy, and individual differences should be considered when using this method in clinical practice. The article examines the clinical and scientific basis, applications, and potential benefits of transcranial electrical stimulation. It is very important to study the parameters such as the shape, amplitude and frequency of the influencing signal used for the optimal solution of the treatment process. In the article, the types of the effective signal in transcranial electrical stimulation were investigated. The role of different forms of affective signals on the effectiveness of neurostimulation was investigated. In addition, it was concluded that electroacupuncture stimulation belongs to neurostimulation in terms of its essence and parameters.

Polymer-Formulated Nerve Growth Factor Shows Effective Therapeutic Efficacy for Cerebral Microinfarcts.

Cerebral microinfarcts represent the most prevalent form of ischemic brain injury in the elderly, particularly among those suffering from dementia, Alzheimer's disease, and vascular risk factors. Despite their commonality, effective treatments have remained elusive. Herein, a novel treatment utilizing a polymer-formulated nerve growth factor capable of crossing the blood-brain barrier is reported, which effectively reduced oxidative stress and neuronal apoptosis, reshaped microglia polarization at infarct sites, and decreased the overall microinfarct burden, leading to notable improvements in behavioral and cognitive functions in a mouse model. This work provides a promising new avenue for the treatment of cerebral microinfarcts and other neurodegenerative diseases.

Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.

Role of Neurotrophins in the Development and Treatment of Neurodegenerative Diseases: A Systematic Review

Role of Neurotrophins in the Development and Treatment of Neurodegenerative Diseases: A Systematic Review

Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.

Nanotechnological advancement for the treatment of neurodegenerative disorders

Neurodegenerative disorders are chronic and progressive conditions of the central nervous system. This review work focusses on some of the disorders like Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease which are some of the most prevalent neurodegenerative disorders presenting a substantial challenge on the global health care system. These disorders are characterized by the loss of neurons and the formation of protein aggregates leading to cognitive and motor impairments. The treatment options are available but due to the complex pathophysiology of the disease and the intricate structure of the brain, effective concentrations of drugs are not delivered to brain. Here we discuss some of the recent strategies employed by scientists to enhance the drug delivery and drug targeting to the site of action that is brain for these disorders. Further, nanotechnology-based carrier systems have been discussed which are developed using different natural and synthetic polymers and lipid materials. Owing to many beneficial properties like nanometric size range, physicochemical properties and tunable surface-modifying features, nanocarriers serve as potential systems in the treatment of neurodegenerative diseases as they can easily cross the BBB and reach to the brain in effective concentration. This review article describes neurodegenerative disorders and the limitations associated with their conventional application. Different arrays of nanocarriers such as polymeric nanoparticles, liposomes, Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, and Nanoemulsions have been extensively reviewed. To understand the nanomedicine market, the ongoing clinical trials for various nano-carriers employed to treat these disorders have been compiled and discussed.

A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.

Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.

Oxysophocarpine Prevents the Glutamate-Induced Apoptosis of HT-22 Cells via the Nrf2/HO-1 Signaling Pathway.

Oxysophocarpine (OSC), a quinolizidine alkaloid, shows neuroprotective potential, though its mechanisms are unclear. The aim of the present study was to investigate the neuroprotective effects of OSC through the nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway using the HT-22 cell line. Assessments of cell viability were conducted utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Assessments of oxidative stress (OS) were conducted through the quantification of reactive oxygen species (ROS). The integrity of the mitochondrial membrane potential (MMP) was scrutinized using fluorescent probe technology. Apoptosis levels were quantified using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The trafficking of Nrf2 within the cell nucleus was examined through immunofluorescence analysis. Furthermore, Western blotting (WB) was applied to evaluate the expression levels of proteins implicated in apoptosis and the Nrf2/HO-1 pathway. To further probe the influence of OSC on the overexpression of antioxidant enzymes, cells were subjected to transfection with HO-1 siRNA. The results showed that OSC inhibited glutamate-induced OS, as evidenced by reduced cell viability and ROS levels. Furthermore, the apoptotic condition induced by glutamate in HT-22 cells was significantly reduced following OSC treatment. More interestingly, the Nrf2/HO-1 signaling pathway was upregulated following OSC treatment. These results suggest that OSC can exert neuroprotective effects by regulating the Nrf2/HO-1 pathway to inhibit neuronal cell apoptosis, potentially aiding in the treatment of neurodegenerative diseases.