Models Of Neurodegenerative Diseases Research Articles

Efficient and Rapid Generation of Neural Stem Cells by Direct Conversion Fibroblasts with Single microRNAs.

Neural stem cells (NSCs) have great potentials in the application of neurodegenerative disease therapy, drug screening, and disease modeling. However, current approaches for induced NSCs (iNSCs) generation from somatic cells are still slow and inefficient. Here we establish a rapid and efficient method of iNSCs generation from human and mouse fibroblasts by single microRNAs (miR-302a). These iNSCs exhibited morphological, molecular and functional properties resembling those of adult human and mouse NSCs, and human iNSCs can be expanded for more than 20 passages in vitro. Furthermore, miR-302a alone was demonstrated to be sufficient to reprogram both human and mouse fibroblasts into iNSCs. Our results showed that direct conversion of autologous fibroblasts with miR-302a into iNSCs, which provides a rapid and efficient strategy to generate iNSCs for both basic research and clinical applications.

Versatility of Caenorhabditis elegans as a Model Organism for Evaluating Foodborne Neurotoxins and Food Bioactive Compounds in Nutritional Neuroscience.

Epidemiological evidence has shown that the regular ingestion of vegetables and fruits is associated with reduced risk of developing chronic diseases. The introduction of the 3Rs (replacement, reduction, and refinement) principle into animal experiments has led to the use of valid, cost-effective, and efficient alternative and complementary invertebrate animal models which are simpler and lower in the phylogenetic hierarchy. Caenorhabditis elegans (C. elegans), a nematode with a much simpler anatomy and physiology compared to mammals, share similarities with humans at the cellular and molecular levels, thus making it a valid model organism in neurotoxicology. This review explores the versatility of C. elegans in elucidating the neuroprotective mechanisms elicited by food bioactive compounds against neurotoxic effects of food- and environmental-related contaminants. Several signaling pathways linked to the molecular basis of neuroprotection exerted by bioactive compounds in chemically induced or transgenic C. elegans models of neurodegenerative diseases are also discussed. Specifically, the modulatory effects of bioactive compounds on the DAF-16/FoxO and SKN-1/Nrf2 signaling pathways, stress resistance- and autophagy-related genes, and antioxidant defense enzyme activities were highlighted. Altogether, C. elegans represent a valuable model in nutritional neuroscience for the identification of promising neuroprotective agents and neurotherapeutic targets which could help in overcoming the limitations of current therapeutic agents for neurotoxicity and neurodegenerative diseases.

The neuroprotective effects of cholecystokinin in the brain: antioxidant, anti-inflammatory, cognition, and synaptic plasticity.

Cholecystokinin (CCK) is a major neuropeptide in the brain that functions as a neurotransmitter, hormone, and growth factor. The peptide and its receptors are widely expressed in the brain. CCK signaling modulates synaptic plasticity and can improve or impair memory formation, depending on the brain areas studies and the receptor subtype activated. Studies have shown in a series of animal models of neurodegenerative diseases that CCK receptor agonists show neuroprotective effects and can effectively alleviate oxidative stress, alleviate chronic inflammation of the central nervous system, improve neuronal synaptic plasticity, prevent neuronal loss, and improve cognitive dysfunction in Alzheimer's disease (AD) model mice and motor activity in animal models of Parkinson's disease. In addition, CCK plays important roles in the amygdala to regulate anxiety and depressive states. Activation of interneurons or inhibition of excitatory neurons can improve anxiety levels. This review summarizes the effects on memory formation andsynaptic plasticity, the neuroprotective effects of cholecystokinin and its analogs in neurological diseases such as Alzheimer and Parkinson's disease, and the effects on anxiety and neuronal activity in the amygdala.

C16 peptide and angiopoietin-1 alleviate the side effects of glucocorticoids in a rat multiple sclerosis model.

Natural glucocorticoids (GCs) have been widely used to treat acute multiple sclerosis (MS) attacks. However, they also cause significant side effects related to immunosuppression. Our previous study found that C16 peptide combined with angiopoietin-1 (Ang-1) inhibited inflammatory cell infiltration and protected blood vessels in animal models of inflammatory neurodegenerative diseases. An acute experimental autoimmune encephalomyelitis model was established in Lewis rats to explore the effects of these drugs on MS. One hundred rats were equally and randomly assigned into five groups: normal control, vehicle, low-dose methylprednisolone (MP), high-dose MP, and C16+Ang-1 (C+A). Histological examinations, behavioral tests, and high-throughput 16S rRNA gene sequencing were conducted to determine inflammation levels in the central nervous system, neuronal survival, functional recovery and gut microbiota. The results illustrated that C+A exerted a neuroprotective effect in MS rats, with fewer side effects observed in the C+A group than in the high-dose MP group. The abundance of Campylobacter was increased in vehicle-treated rats, indicating an imbalance of the gut microbiota after MS. The abundance of probiotic Lactobacillus plantarum was increased in the C+A group. Low-dose MP failed to reverse the gut microbiota imbalance, whereas both the C+A and high-dose MP groups exhibited gut microbiota profiles more similar to those of the normal controls, with C+A displaying superior efficacy. C16 plus Ang-1 might serve as a complement to GCs for the treatment of MS. Changes in the abundance of Campylobacter and L. plantarum suggest their essential roles in the pathogenesis of MS.

Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF‐1R

ABSTRACTA growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro‐inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF‐1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF‐1R. Pharmacological inhibition of CSF‐1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF‐1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

Mechanisms and clinical applications of palmitoylethanolamide (PEA) in the treatment of neuropathic pain.

Palmitoylethanolamide (PEA) is emerging as a promising therapeutic agent for neuropathic and other pain-related conditions. This naturally occurring fatty acid has drawn interest because of its ability to regulate pain and inflammation. Initially identified in food sources, PEA has been the subject of extensive research to elucidate its properties, efficacy, and clinical applications. PEA primarily exerts its effects through interaction with its primary receptor PPAR α, this interaction influences pain signalling pathways and neuroinflammatory processes by modulating the synthesis of pro-inflammatory cytokines, mast cell degranulation, microglial activation, and decrease of oxidative stress. PEA's interaction with endocannabinoid receptors decreases the inflammatory cytokine and chemokine production and thereby a descending pain sensation. The pharmacological and pharmacokinetic characteristics of PEA are examined in this paper, along with its potential for efficiency when used in in combination additional therapies in a variety of neurodegenerative disease models, including multiple sclerosis, Parkinson's disease, and Alzheimer's. Experimental evidence shows that PEA not only reduces pain and inflammation but also lowers the need for higher dosages of other drugs hence minimizing the risk of drug toxicity. The bioavailability of PEA has been enhanced by recent technological developments, which emphasize continuous research efforts to maximize PEA's therapeutic potential in pain treatment and associated medical sectors.

Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study.

Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55years) volunteers. This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing. The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine. Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity-and the overarching brain protection it offers-provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available.

Innovative approaches to genome editing in the treatment of neurodegenerative diseases

The purpose of this review is to analyze current advances in the field of genome editing, their application for the modeling and treatment of neurodegenerative diseases, as well as to discuss current limitations and prospects for overcoming barriers in clinical practice. Materials and methods. To achieve this goal, a systematic analysis of literature over the past nine years (2016–2024) was conducted in the databases CyberLeninka, eLibrary, PubMed, Cochrane Library, SAGE Premier, Springer and Wiley Journals. The main provisions. Neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases remain a serious challenge for modern medicine, characterized by progressive loss of neurons and the lack of effective therapeutic methods capable of stopping or reversing the pathological process. In recent years, genome editing technologies, including CRISPR-Cas9, TALEN and ZFN, have opened up new horizons in the treatment of these diseases. However, their clinical application is associated with a number of limitations, including problems of delivering editing tools to cells of the central nervous system, the risk of non-target mutations, and ethical issues. In this regard, the improvement of genome editing methods is one of the key areas. Modern methods such as CRISPR-Cas9, basic and prime editing, as well as epigenomic and RNA editing, have demonstrated high potential for accurate correction of genetic defects and modification of pathogenetic processes. Improvements in delivery systems, including viral and non-viral methods, have made it possible to overcome barriers such as low permeability of the blood-brain barrier and increase the effectiveness of therapy. Conclusion. In recent years, significant progress has been made in the development of methods aimed at improving the safety of genomic editing in the nervous system. Despite significant advances, genome editing technologies face a number of challenges, including the need to increase specificity, minimize non-targeted effects, improve editing in postmitotic neurons and develop long-term safety monitoring methods, as well as address ethical issues related to the clinical application of these technologies.

Morpholine Anchored Fluorogenic Toolkit: Unveiled Disease Allied Protein Fibrillation in Lysosomal Compartment of Live-Cell and Drosophila Models.

The aberrant accumulation of cytotoxic protein aggregates is a hallmark of various neurodegenerative and non-neurodegenerative ailments, necessitating the development of sensitive and selective tools for their detection. Herein, we report a series of morpholine-anchored fluorescent probes, denoted as SC-nmor (n = 2, 4, 6), designed for facile visualization of protein aggregates. These probes display notable changes in their photophysical properties upon binding with protein aggregates, owing to their high sensitivity to the fibrillar microenvironment. Specifically, the SC-4mor probe demonstrates strong selectivity for aggregated insulin proteins over native insulin, accompanied by a significant enhancement in fluorescence lifetime. Live-cell imaging reveals an exclusive localization at the lysosomal compartment. This feature enables the visualization of lysosomal accumulated protein fibrils induced with pepstatin A. Additionally, in vivo assessments on genetically mutated and dietary-modified Drosophila melanogaster, representing neurodegenerative and non-neurodegenerative disease models, demonstrate staining of protein aggregates. The enhanced emission from the eye lobes of Aβ-mutated and HSD brain samples, suggesting that SC-4mor can exhibit adequate retention in the brain with minimal biological toxicity. SC-4mor also shows its capability to cross the blood-brain barrier in mice model. Consequently, SC-4mor emerges as a promising marker for detecting and monitoring neurotoxic protein fibrillation in live cells and animal models, offering potential insights into the pathogenesis and progression of protein aggregation.

Mitigating neurodegenerative diseases: the protective influence of baicalin and baicalein through neuroinflammation regulation.

Neurodegenerative diseases (NDDs) represent a category of serious illnesses characterized by the progressive deterioration of neuronal structure and function. The exploration of natural compounds as potential therapeutic agents has gained increasing attention in recent years owing to their wide range of pharmacological activities and minimal side effects. Baicalin (BAI) and baicalein (BE), polyphenolic flavonoids, derived from the root of Scutellaria baicalensis, evidently show potential in treating NDDs. This review provides an overview of the current understanding of the roles of BAI and BE in alleviating neuroinflammation, a pivotal pathological process implicated in various NDDs. Studies conducted prior to clinical trials have shown that BAI and BE exert protective effects on the nervous system in different animal models of NDDs. Furthermore, mechanistic studies indicate that BAI and BE exert anti-inflammatory effects by inhibiting pro-inflammatory cytokines, suppressing microglial activation, and regulating microglial phenotypes. These effects are mediated through the modulation of inflammatory signaling cascades, including Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), amp-activated protein kinase (AMPK), NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, and nuclear factor erythroid 2-related factor 2 (Nrf2)/hemoglobin oxygenase-1 (HO-1). Overall, BAI and BE exhibit promising potential as natural compounds with anti-inflammatory properties and offer innovative therapeutic approaches for managing NDDs.

Molecular chemiluminescence imaging of misfolded proteins with a versatile and highly sensitive probe in neurodegenerative disease models

Molecular chemiluminescence imaging of misfolded proteins with a versatile and highly sensitive probe in neurodegenerative disease models

Emerging Neuroprotective Strategies: Unraveling the Potential of HDAC Inhibitors in Traumatic Brain Injury Management.

Traumatic brain injury (TBI) is a significant global health problem, leading to high rates of mortality and disability. It occurs when an external force damages the brain, causing immediate harm and triggering further pathological processes that exacerbate the condition. Despite its widespread impact, the underlying mechanisms of TBI remain poorly understood, and there are no specific pharmacological treatments available. This creates an urgent need for new, effective neuroprotective drugs and strategies tailored to the diverse needs of TBI patients. In the realm of gene expression regulation, chromatin acetylation plays a pivotal role. This process is controlled by two classes of enzymes: histone acetyltransferase (HAT) and histone deacetylase (HDAC). These enzymes modify lysine residues on histone proteins, thereby determining the acetylation status of chromatin. HDACs, in particular, are involved in the epigenetic regulation of gene expression in TBI. Recent research has highlighted the potential of HDAC inhibitors (HDACIs) as promising neuroprotective agents. These compounds have shown encouraging results in animal models of various neurodegenerative diseases. HDACIs offer multiple avenues for TBI management: they mitigate the neuroinflammatory response, alleviate oxidative stress, inhibit neuronal apoptosis, and promote neurogenesis and axonal regeneration. Additionally, they reduce glial activation, which is associated with TBI-induced neuroinflammation. This review aims to provide a comprehensive overview of the roles and mechanisms of HDACs in TBI and to evaluate the therapeutic potential of HDACIs. By summarizing current knowledge and emphasizing the neuroregenerative capabilities of HDACIs, this review seeks to advance TBI management and contribute to the development of targeted treatments.

A tool to automate assessment of regional brain atrophy in mouse models of neurodegenerative disease.

As life expectancy rises, so too does the prevalence of neurodegenerative diseases. Neurodegeneration causes progressive regional brain atrophy, typically initiating prior to symptom onset. Researchers measure the impact of potential treatments on atrophy in mouse models to assess their effectiveness. This is important because treatments designed to combat neuropathology are more likely to modify the disease, per contra to symptom management. Magnetic resonance imaging, while accurate in measurement of brain region structure volumes, is prohibitively expensive. Conversely, stereological volume assessment, the process of estimating the volume of individual 3D brain regions from imaged 2D brain sections, is more commonly used. This involves manually tracing brain region(s) of interest in regularly spaced imaged cross-sections to determine their 2D area, followed by application of the Cavalieri principle to estimate the volume. The pertinent caveats of this approach are the labor-intensive manual tracing process, and potential inaccuracies that arise due to human variation. To overcome these challenges, we have created a Neuropathology Assessment Tool (NAT) to automate regional brain tracing and identification using artificial intelligence (AI) and concepts from topological data analysis. The NAT was validated by comparing manual and NAT analysis of striatal volume in Huntington disease model mice. The NAT detected striatal atrophy with higher efficiency, 93.8% agreement with manual measurements, and lower inter-group variability. The NAT will increase efficiency of preclinical neuropathology assessment, allowing for a greater number of experimental therapies to be tested and facilitating drug discovery intractable neurodegenerative diseases.

Rabies virus-mimicking liposomes for targeted gene therapy in Alzheimer’s disease

RNA interference (RNAi) harbors significant potential for treating neurological disorders; nevertheless, limited efficacy has been discerned. The presence of barriers within the central nervous system, coupled with the inherent instability of nucleic acids within biological conditions, poses formidable challenges in advancing effective gene delivery strategies. In this study, we designed and prepared a virus-mimic non-viral gene vector, rabies virus glycoprotein (RVG29)-decorated liposome (f(Lipo)-RVG29), to deliver small interfering RNAs to the brain. Alzheimer’s disease (AD) was chosen as a model of neurodegenerative disease in this context, and b-site APP cleaving enzyme silencing siRNA (siBACE1) was used. The developed liposomal delivery system has a particle size of under 80 nm with a spherical shape, positive zeta potential, and the ability to protect siRNA against nucleases. In vitro studies demonstrate that functionalizing the cationic liposome by the RVG29 targeting ligand significantly enhances the effectiveness of gene delivery and silencing. Examination through ex vivo imaging illustrates an increased deposition of fluorescent-labeled f(Lipo)-RVG29 within brain tissue after 12 h post application. Additionally, the in vivo delivery of f(Lipo)-RVG29 carrying siRNA has substantially suppressed BACE1 expression at both mRNA and protein levels within the brain tissue. Our results suggest that the developed non-viral vector could be a promising gene carrier system combining the synergistic effect of virus-mimic RVG29 ligand with bioinspired liposome that imitates the natural lipid bilayers of cell membranes for brain-targeted RNAi therapeutics.

A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain

Mitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs.

Protective effect of Apelin-13 on D-glutamic acid-induced excitotoxicity in SH-SY5Y cell line: An in-vitro study

Excitotoxicity, resulting from excessive accumulation of glutamate in the extracellular space, leads to neuronal cell death. This study investigates the protective effects of Apelin-13 on D-Glutamic acid-induced excitotoxicity in SH-SY5Y human neuroblastoma cells, an in-vitro model for neurodegenerative diseases. Unlike the commonly studied L-glutamic acid, this research focuses on D-Glutamic acid to understand its specific impacts. SH-SY5Y cells were treated with varying concentrations of D-Glutamic acid and Apelin-13, followed by analyses at 12 and 24 h to evaluate cell viability, oxidative stress markers, and inflammatory cytokine levels. Cell viability assays revealed significant cytotoxic effects of D-Glutamic acid at doses of 10 mM and 20 mM, reducing viability by over 50 %. However, Apelin-13 treatment mitigated these effects, especially at 2 μg/ml, enhancing cell viability and reducing inflammatory cytokine levels (IL-1β and TNF-α). Apelin-13 also increased anti-inflammatory cytokine levels (IL-10 and TGF-β1) and brain-derived neurotrophic factor (BDNF), indicating its neuroprotective role. Oxidative stress markers, including ROS, AGE, AOPP, DT, T-SH, were significantly elevated by D-Glutamic acid but effectively reduced by Apelin-13. The neuroprotective mechanisms of Apelin-13 involve modulation of cAMP/PKA and MAPK signaling pathways, enhancing BDNF synthesis and suppressing oxidative stress and inflammatory responses. This study is the first to demonstrate the effects of D-Glutamic acid on SH-SY5Y cells. It highlights Apelin-13's potential as a therapeutic agent against excitotoxicity-induced neuronal damage, emphasizing its ability to modulate key molecular pathways involved in inflammation and oxidative stress. Further in-vivo studies are warranted to explore the long-term neuroprotective effects of Apelin-13 in treating neurodegenerative diseases.

Efficacy of Omega-5 NanoPSO Treatment in the Hippocampus, Through Antioxidant Mechanisms, After an Ischemia/Reperfusion Injury, in Murine Model.

Stroke is the third cause of death worldwide and a health problem, and current therapy continues to be very poor. It promotes an alteration associated with excitotoxicity, oxidative stress, and inflammatory processes, exacerbating the damage in the brain. Although cortical areas are the most affected by stroke, the hippocampus can be impacted in the long term through the pathways it connects with these areas, which are associated further with motor alterations; this encourages the search for new therapeutic approaches. Omega-5, being an antioxidant, participates in regulating oxidative stress. A recently designed nanoemulsified compound coupled with pomegranate seed oil (NanoPSO) maintains bioavailability in the body for longer. Omega-5 NanoPSO is more effective in different models of neurodegenerative diseases and metabolic disorders. Therefore, it is important to analyze the effect of omega-5 NanoPSO on ischemic damage through changes in the hippocampus, oxidative mechanisms, and behavioral outcomes. Male Wistar rats were used in five groups; three groups were subjected to an ischemic event through bilateral occlusion of the carotid arteries. An ischemia group received omega-5 NanoPSO after injury, and another group received omega-5 NanoPSO performed two weeks before the ischemic event and three weeks after the surgical process. The control and sham groups did not show changes in the hippocampus and behavior. In the ischemia group, neuronal loss, oxidative stress, and a higher expression of astrocytes were maintained in the hippocampal region, and behavior was modified. In the post and pre-treatment group with omega-5 NanoPSO, we observed reduced damage, glial proliferation, and oxidative stress. It increased neuron survival in the hippocampal region and improved the locomotion. These results highlight its promise for use in clinical settings to treat patients suffering from ischemic brain injury.

Synthesis and Evaluation of Glucosyl-, Acyl- and Silyl- Resveratrol Derivatives as Retinoprotective Agents: Piceid Octanoate Notably Delays Photoreceptor Degeneration in a Retinitis Pigmentosa Mouse Model.

Retinitis pigmentosa (RP), the leading cause of inherited blindness in adults, is marked by the progressive degeneration of rod photoreceptors in the retina. While gene therapy has shown promise in treating RP in patients with specific mutations, no effective therapies currently exist for the majority of patients with diverse genetic backgrounds. Additionally, no intervention can yet prevent or delay photoreceptor loss across the broader RP patient population. Resveratrol (RES), a naturally occurring polyphenol, has shown cytoprotective effects in various neurodegenerative disease models; however, its therapeutic potential is limited by low bioavailability. In this study, we synthesized novel RES derivatives and assessed their retinoprotective effects in a murine model of RP (rd10 mice). Among these derivatives, piceid octanoate (PIC-OCT) significantly delayed photoreceptor degeneration in the RP model, demonstrating superior efficacy compared to RES. PIC-OCT shows strong potential as a leading candidate for developing new therapeutic strategies for RP.

Spatial memory in Alzheimer's disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330.

The proteostatic decline in Alzheimer's disease is well established and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that XPO1 inhibitor KPT-330 (Selinexor), an FDA approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells and improves spatial memory performance in a murine model of Alzheimer's disease (5XFAD). Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

Evaluation of Alpha-Synuclein and Tau Antiaggregation Activity of Urea and Thiourea-Based Small Molecules for Neurodegenerative Disease Therapeutics.

Alzheimer's disease (AD) and Parkinson's disease (PD) are multifactorial, chronic diseases involving neurodegeneration. According to recent studies, it is hypothesized that the intraneuronal and postsynaptic accumulation of misfolded proteins such as α-synuclein (α-syn) and tau, responsible for Lewy bodies (LB) and tangles, respectively, disrupts neuron functions. Considering the co-occurrence of α-syn and tau inclusions in the brains of patients afflicted with subtypes of dementia and LB disorders, the discovery and development of small molecules for the inhibition of α-syn and tau aggregation can be a potentially effective strategy to delay neurodegeneration. Urea is a chaotropic agent that alters protein solubilization and hydrophobic interactions and inhibits protein aggregation and precipitation. The presence of three hetero atoms (O/S and N) in proximity can coordinate with neutral, mono, or dianionic groups to form stable complexes in the biological system. Therefore, in this study, we evaluated urea and thiourea linkers with various substitutions on either side of the carbamide or thiocarbamide functionality to compare the aggregation inhibition of α-syn and tau. A thioflavin-T (ThT) fluorescence assay was used to evaluate the level of fibril formation and monitor the anti-aggregation effect of the different compounds. We opted for transmission electron microscopy (TEM) as a direct means to confirm the anti-fibrillar effect. The oligomer formation was monitored via the photoinduced cross-linking of unmodified proteins (PICUP). The anti-inclusion and anti-seeding activities of the best compounds were evaluated using M17D intracellular inclusion and biosensor cell-based assays, respectively. Disaggregation experiments were performed with amyloid plaques extracted from AD brains. The analogues with indole, benzothiazole, or N,N-dimethylphenyl on one side with halo-substituted aromatic moieties had shown less than 15% cutoff fluorescence obtained with the ThT assay. Our lead molecules 6T and 14T reduced α-syn oligomerization dose-dependently based on the PICUP assays but failed at inhibiting tau oligomer formation. The anti-inclusion effect of our lead compounds was confirmed using the M17D neuroblastoma cell model. Compounds 6T and 14T exhibited an anti-seeding effect on tau using biosensor cells. In contrast to the control, disaggregation experiments showed fewer Aβ plaques with our lead molecules (compounds 6T and 14T). Pharmacokinetics (PK) mice studies demonstrated that these two thiourea-based small molecules have the potential to cross the blood-brain barrier in rodents. Urea and thiourea linkers could be further improved for their PK parameters and studied for the anti-inclusion, anti-seeding, and disaggregation effects using transgenic mice models of neurodegenerative diseases.