Pharmacotherapeutic potential of Vitis vinifera(grape) in age-related neurological diseases / Potencial farmacoterapéutico de Vitis vinifera(uva) en enfermedades neurológicas asociadas a la edad

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are complex illnesses with an increasing risk with advancing years. The central nervous system's neuropathological conditions, including oxidative stress, neuroinflammation, and protein misfolding, are what define ANDs. Due to the rise in age-dependent prevalence, efforts have been made to combat ANDs. Vitis viniferahas a long history of usageto treat a variety of illness symptoms. Because multiple ligand sites may be targeted, Vitis viniferacomponents can be employed to treat ANDs. This is demonstrated by the link between the structure and action of these compounds. This review demonstrates that Vitis viniferaand its constituents, including flavonoids, phenolic compounds, stilbenoidsandaromatic acids, are effective at reducing the neurological symptoms and pathological conditions of ANDs. This is done by acting as an antioxidant and anti-inflammatory. The active Vitis vinifera ingredients have therapeutic effects on ANDs, as this review explains.

Las enfermedades neurológicas asociadas a la edad (AND, por su sigla en inglés) incluyendo las enfermedades neurodegenerativas, son enfermedades complejas con un riesgo creciente con la edad. Las condiciones neuropatológicas del sistema nervioso central, que incluyen el estrés oxidativo, la neuro inflamación, y el plegado erróneo de proteínas, son lo que define las AND. Debido al aumento en la prevalencia dependiente de la edad, se han hecho esfuerzos para combatir las AND. Vitis vinifera tiene una larga historia de uso para el tratamiento de síntomas. Puesto que puede hacer objetivo a muchos sitios ligando, los componentes de Vitis viniferase pueden utilizar para tratar AND. Esto se demuestra por el vínculo entre la estructura y la acción de estos compuestos. Esta revisión demuestra que la Vitis viniferay sus constituyentes, incluídos los flavonoides, componentes fenólicos, estilbenoides, y ácidos aromáticos, son efectivos para reducir los síntomas neurológicos y las condiciones patológicas de AND. Esto se produce por su acción como antioxidante y antiinflamatorio. Los ingredientes activos de Vitis vinifera tienen efectos terapéuticos en AND, y esta revisión lo explica.

PET brain imaging in neurological disorders.

Brain disorders are a series of conditions with damage or loss of neurons, such as Parkinson's disease (PD), Alzheimer's disease (AD), or drug dependence. These individuals have gradual deterioration of cognitive, motor, and other central nervous system functions affected. This degenerative trajectory is intricately associated with dysregulations in neurotransmitter systems. Positron Emission Tomography (PET) imaging, employing radiopharmaceuticals and molecular imaging techniques, emerges as a crucial tool for detecting brain biomarkers. It offers invaluable insights for early diagnosis and distinguishing brain disorders. This article comprehensively reviews the application and progress of conventional and novel PET imaging agents in diagnosing brain disorders. Furthermore, it conducts a thorough analysis on merits and limitations. The article also provides a forward-looking perspective in the future development directions of PET imaging agents for diagnosing brain disorders and proposes potential innovative strategies. It aims to furnish clinicians and researchers with an all-encompassing overview of the latest advancements and forthcoming trends in the utilization of PET imaging for diagnosing brain disorders.

Microalgae Octapeptide IIAVEAGC Alleviates Oxidative Stress and Neurotoxicity in 6-OHDA-Induced SH-SY5Y Cells by Regulating the Nrf2/HO-1 and Jak2/Stat3 Pathways.

Neurodegenerative diseases are characterized by the progressive loss of selectively vulnerable populations of neurons, and many factors are involved in its causes. Neurotoxicity and oxidative stress, are the main related factors. The octapeptide Ile-Ile-Ala-Val-Glu-Ala-Gly-Cys (IEC) was identified from the microalgae Isochrysis zhanjiangensis and exhibited potential anti-oxidative stress activity. In this study, the stability of α-synaptic protein binding to IEC was modeled using molecular dynamics, and the results indicated binding stabilization within 60 ns. Oxidative stress in neurons is the major cause of α-synaptic protein congestion. Therefore, we next evaluated the protective effects of IEC against oxidative stress and neurotoxicity in 6-ohdainduced Parkinson's disease (PD) model SH-SY5Y cells in vitro. In oxidative stress, IEC appeared to increase the expression of the antioxidant enzymes HO-1 and GPX through the antioxidant pathway of Nrf2, and molecular docking of IEC with Nrf2 and GPX could generate hydrogen bonds. Regarding apoptosis, IEC protected cells by increasing the Bcl-2/Bax ratio, inhibiting the caspase cascade, acting on p53, and modulating the Jak2/Stat3 pathway. The results indicated that IEC exerted neuroprotective effects through the inhibition of α-synaptic protein aggregation and antioxidant activity. Therefore, microalgal peptides have promising applications in the pre-vention and treatment of neurodegenerative diseases.

Prominent Perspective on Existing Biological Hallmarks of Alzheimer's Disease.

Biomarkers are the most significant diagnosis tools tending towards unique approaches and solutions for the prevention and cure of Alzheimer's Disease (AD). The current report provides a clear perception of the concept of various biomarkers and their prominent features through analysis to provide a possible solution for the inhibition of events in AD. Scientists around the world truly believe that crucial hallmarks can serve as critical tools in the early diagnosis, cure, and prevention, as well as the future of medicine. The awareness and understanding of such biomarkers would provide solutions to the puzzled mechanism of this neuronal disorder. Some of the argued biomarkers in the present article are still in an experimental phase as they need to undergo specific clinical trials before they can be considered for treatment.

Alleviating Neurodegenerative Diseases Associated with Mitochondrial Defects by Therapeutic Biomolecules.

Neurodegenerative diseases are emerging as a global health concern in the current sce-nario, and their association with mitochondrial defects has been a potential area of research. Mi-tochondria, one of the essential organelles of the cell, serve as the cell's powerhouse, producing energy and ensuring cellular health. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and Pelizaeus-Merzbacher disease have been found to be primarily triggered by mitochondrial malfunction. One of the key byproducts of mitochondrial respiration, reactive oxygen species, also contributes significantly to mitochondrial DNA muta-tions that eventually cause mitochondrial breakdown. This review paper comprehensively examines the potential of therapeutic biomolecules, specifi-cally mitochondria-specific antioxidants, in mitigating the impact of mitochondrial defects on neurodegenerative diseases. It provides a detailed analysis of the mechanisms involved in mito-chondrial dysfunction, the potential therapeutic targets of these biomolecules, and their structure-activity relationship information are also discussed in this review. Various research articles and publications were used extensively in compiling the data, and the structures of biomolecules were prepared using software such as ChemDraw and ChemSketch. Crucial elements triggering mitochondrial abnormalities were identified and a tabular compilation of bioactive antioxidant compounds along with their therapeutic targets, was presented. Mitochondria-specific antioxidant therapy is an innovative and promising strategy for the man-agement of neurodegenerative diseases associated with mitochondrial defects. This review pro-vides a thorough summary of the current state of research and promising avenues of research and development in this field, emphasizing the importance of further investigations and clinical trials to elucidate their therapeutic benefits.

Optogenetics in chronic neurodegenerative diseases, controlling the brain with light: A systematic review.

Neurodegenerative diseases are progressive disorders characterized by synaptic loss and neuronal death. Optogenetics combines optical and genetic methods to control the activity of specific cell types. The efficacy of this approach in neurodegenerative diseases has been investigated in many reviews, however, none of them tackled it systematically. Our study aimed to review systematically the findings of optogenetics and its potential applications in animal models of chronic neurodegenerative diseases and compare it with deep brain stimulation and designer receptors exclusively activated by designer drugs techniques. The search strategy was performed based on the PRISMA guidelines and the risk of bias was assessed following the Systematic Review Centre for Laboratory Animal Experimentation tool. A total of 247 articles were found, of which 53 were suitable for the qualitative analysis. Our data revealed that optogenetic manipulation of distinct neurons in the brain is efficient in rescuing memory impairment, alleviating neuroinflammation, and reducing plaque pathology in Alzheimer's disease. Similarly, this technique shows an advanced understanding of the contribution of various neurons involved in the basal ganglia pathways with Parkinson's disease motor symptoms and pathology. However, the optogenetic application using animal models of Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis was limited. Optogenetics is a promising technique that enhanced our knowledge in the research of neurodegenerative diseases and addressed potential therapeutic solutions for managing these diseases' symptoms and delaying their progression. Nevertheless, advanced investigations should be considered to improve optogenetic tools' efficacy and safety to pave the way for their translatability to the clinic.

The Role of Vitamin K in the Development of Neurodegenerative Diseases.

Neurodegenerative diseases are a growing global health problem with enormous consequences for individuals and society. The most common neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, can be caused by both genetic factors (mutations) and epigenetic changes caused by the environment, in particular, oxidative stress. One of the factors contributing to the development of oxidative stress that has an important effect on the nervous system is vitamin K, which is involved in redox processes. However, its role in cells is ambiguous: accumulation of high concentrations of vitamin K increases the content of reactive oxygen species increases, while small amounts of vitamin K have a protective effect and activate the antioxidant defense systems. The main function of vitamin K is its involvement in the gamma carboxylation of the so-called Gla proteins. Some Gla proteins are expressed in the nervous system and participate in its development. Vitamin K deficiency can lead to a decrease or loss of function of Gla proteins in the nervous system. It is assumed that the level of vitamin K in the body is associated with specific changes involved in the development of dementia and cognitive abilities. Vitamin K also influences the sphingolipid profile in the brain, which also affects cognitive function. The role of vitamin K in the regulation of biochemical processes at the cellular and whole-organism levels has been studied insufficiently. Further research can lead to the discovery of new targets for vitamin K and development of personalized diets and therapies.

G-Quadruplexes as Sensors of Intracellular Na+/K+ Ratio: Potential Role in Regulation of Transcription and Translation.

Data on the structure of G-quadruplexes, noncanonical nucleic acid forms, supporting an idea of their potential participation in regulation of gene expression in response to the change in intracellular Na+i/K+i ratio are considered in the review. Structural variety of G-quadruplexes, role of monovalent cations in formation of this structure, and thermodynamic stability of G-quadruplexes are described. Data on the methods of their identification in the cells and biological functions of these structures are presented. Analysis of information about specific interactions of G-quadruplexes with some proteins was conducted, and their potential participation in the development of some pathological conditions, in particular, cancer and neurodegenerative diseases, is considered. Special attention is given to the plausible role of G-quadruplexes as sensors of intracellular Na+i/K+i ratio, because alteration of this parameter affects folding of G-quadruplexes changing their stability and, thereby, organization of the regulatory elements of nucleic acids. The data presented in the conclusion section demonstrate significant change in the expression of some early response genes under certain physiological conditions of cells and tissues depending on the intracellular Na+i/K+i ratio.

Analysis of Human Peripheral Blood Mononuclear Cells in Patients with Neurodegenerative Diseases.

The role of immune system in the progression of neurodegenerative diseases has been studied for decades in animal models. However, invasive studies in human subjects remain controversial due to the heterogeneity of the presentation of different diagnostic categories at different stages of the disease. Peripheral blood mononuclear cells (PBMCs) contain immune cells including dendritic cells (DCs), monocytes, macrophages, and T lymphocytes. Isolating PBMCs from whole blood samples collected from patients provides a minimally invasive method for analyzing the immune system's function in patients with neurodegenerative diseases. By isolating single cell types from patients' peripheral blood, in vitro analyses can be conducted including RNA sequencing, immunofluorescence, and phagocytic analysis. In this chapter, we discuss PBMC separation and isolation of macrophages in pure culture in vitro. We also outline methods for performing RNA-seq on cultured macrophages and other techniques for investigating the role of macrophages in neurodegenerative disease pathophysiology.

Increasing Risk of Dementia Among Patients with Subsequent Epilepsy Within 2 Years Post-Traumatic Brain Injury: A Population-Based Case-Control Study.

Background: Although the association between neurodegenerative diseases, such as dementia, and traumatic brain injury (TBI) has long been known, the association between dementia and TBI with epilepsy has been controversial. Aim: This data-driven population-based study is designed to investigate the association between dementia and epilepsy after TBI within a 2-year period. Methods: This case-control cohort study was conducted using the Longitudinal Health Insurance Database 2000 (LHID2000). We included 784 individuals ambulatory or hospitalized for TBI with epilepsy from 2001 to 2011, compared with 2992 patients with TBI without epilepsy who were matched for characteristics including sex, age, and healthcare resource use index date. Every participant was followed up for 5 years to ascertain any dementia development. Data were stratified and analyzed using the Cox proportional hazards regression. Results: Through the 5-year follow-up period, 39 patients (5.21%) with TBI with epilepsy and 55 (1.53%) with TBI without epilepsy developed dementia. TBI with epilepsy was independently associated with a >3.03 times risk of dementia after correcting for age, sex, and comorbidities. Conclusion: These findings suggest an increased risk of dementia in patients with TBI with epilepsy. Our research recommends that individuals with TBI and epilepsy be monitored more intensively.

A Novel Computerized Flexible Attention Test in Detecting Executive Dysfunction of Patients with Early-Onset Cognitive Impairment and Dementia.

OBJECTIVE: The number of computer-based cognitive tests has increased in recent years, but there is a need for tests focusing on the assessment of executive function (EF), as it can be crucial for the identification of early-onset neurodegenerative disorders. This study aims to examine the ability of the Flexible Attention Test (FAT), a new computer-based test battery for detecting executive dysfunction of early-onset cognitive impairment and dementia patients. METHOD: We analyzed the FAT subtask results in memory clinic patients with cognitive symptom onset at ≤65 years. The patients were divided into four groups: early onset dementia (EOD, n = 48), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes (MCI-o, n = 99), and subjective cognitive decline (SCD, n = 14). The test accuracy to distinguish EOD patients from other groups was examined, as well as correlations with pen-and-paper EF tests. We also reported the 12-months follow-up results. RESULTS: The EOD and MCI-n patients performed significantly poorer (p ≤ .002) than those in the MCI-o and SCD groups in most of the FAT subtasks. The accuracies of the FAT subtasks to detect EOD from other causes were mainly moderate (0.34 ≤ area under the curve < 0.74). The FAT subtasks correlated logically with corresponding pen-and-paper EF tests (.15 ≤ r ≤ .75). No systematic learning effects were detected in the FAT performance at follow-up. CONCLUSIONS: The FAT appears to be a promising method for the precise evaluation of EF and applicable distinguishing early-onset neurodegenerative disorders from patients with other causes of cognitive problems.

Modulation of Gut Microbiota Through Dietary Intervention in Neuroinflammation and Alzheimer's and Parkinson's Diseases.

PURPOSE OF REVIEW: The gut microbiota plays a crucial role in the pathogenesis of neuroinflammation and Alzheimer's and Parkinson's diseases. One of the main modulators of the gut microbiota is the diet, which directly influences host homeostasis and biological processes. Some dietary patterns can affect neurodegenerative diseases' progression through gut microbiota composition, gut permeability, and the synthesis and secretion of microbial-derived neurotrophic factors and neurotransmitters. This comprehensive review critically assesses existing studies investigating the impact of dietary interventions on the modulation of the microbiota in relation to neurodegenerative diseases and neuroinflammation. RECENT FINDINGS: There are limited studies on the effects of specific diets, such as the ketogenic diet, Mediterranean diet, vegetarian diet, and Western diet, on the progression of neuroinflammation and Alzheimer's and Parkinson's diseases through the gut-brain axis. The ketogenic diet displays promising potential in ameliorating the clinical trajectory of mild cognitive impairment and Alzheimer's disease. However, conflicting outcomes were observed among various studies, highlighting the need to consider diverse types of ketogenic diets and their respective effects on clinical outcomes and gut microbiota composition. Vegetarian and Mediterranean diets, known for their anti-inflammatory properties, can be effective against Parkinson's disease, which is related to inflammation in the gut environment. On the other hand, the westernization of dietary patterns was associated with reduced gut microbial diversity and metabolites, which ultimately contributed to the development of neuroinflammation and cognitive impairment. Various studies examining the impact of dietary interventions on the gut-brain axis with regard to neuroinflammation and Alzheimer's and Parkinson's diseases are thoroughly reviewed in this article. A strong mechanistic explanation is required to fully understand the complex interactions between various dietary patterns, gut microbiota, and microbial metabolites and the effects these interactions have on cognitive function and the progression of these diseases.

Necropolitics of Death in Neurodegeneration.

Neurodegenerative diseases (ND) pose significant challenges for biomedicine in the twenty-first century, particularly considering the global demographic ageing and the subsequent increase in their prevalence. Characterized as progressive, chronic and debilitating, they often result in higher mortality rates compared with the general population. Research agendas and biomedical technologies are shaped by power relations, ultimately affecting patient wellbeing and care. Drawing on the concepts of bio- and necropolitics, introduced by philosophers Foucault and Mbembe, respectively, this perspective examines the interplay between the territoriality and governmentality around demographic ageing, ND and death, focussing on knowledge production as a dispositif of power by highlighting the marginal role that the phenomenon of mortality plays in the ND research landscape. We propose a shift into acknowledging the coloniality of knowledge and embracing its situatedness to attain knowledge 'from death', understood as an epistemic position from which novel approaches and practices could emerge.

Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases.

N-methyl-d-aspartate receptors (NMDARs) are the main class of ionotropic receptors for the excitatory neurotransmitter glutamate. They play a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of several subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, and excitotoxicity. The present review will detail the structure, composition, and localization of NMDARs, their role and regulation at the glutamatergic synapse, and their impact on cognitive processes and in neurodegenerative diseases (Alzheimer's, Huntington's, and Parkinson's disease). The pharmacology of different NMDAR antagonists and their therapeutic potentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising development as a neuroprotective agent in Alzheimer's disease, in complement to its reported efficacy as a tomography radiotracer for NMDARs and an anxiolytic drug in post-traumatic stress disorder.

Nervonic Acid Synthesis Substrates as Essential Components in Profiled Lipid Supplementation for More Effective Central Nervous System Regeneration.

Central nervous system (CNS) damage leads to severe neurological dysfunction as a result of neuronal cell death and axonal degeneration. As, in the mature CNS, neurons have little ability to regenerate their axons and reconstruct neural loss, demyelination is one of the hallmarks of neurological disorders such as multiple sclerosis (MS). Unfortunately, remyelination, as a regenerative process, is often insufficient to prevent axonal loss and improve neurological deficits after demyelination. Currently, there are still no effective therapeutic tools to restore neurological function, but interestingly, emerging studies prove the beneficial effects of lipid supplementation in a wide variety of pathological processes in the human body. In the future, available lipids with a proven beneficial effect on CNS regeneration could be included in supportive therapy, but this topic still requires further studies. Based on our and others' research, we review the role of exogenous lipids, pointing to substrates that are crucial in the remyelination process but are omitted in available studies, justifying the properly profiled supply of lipids in the human diet as a supportive therapy during CNS regeneration.

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond.

Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease.

Alzheimer's disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aß) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression. Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention. The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aß-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.

Alzheimer's disease cerebrospinal fluid biomarkers and kidney function in normal and cognitively impaired older adults.

INTRODUCTION: Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown. METHODS: Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center (N = 973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR. RESULTS: Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aß)42/tau ratio (p < 0.0001) and Aß42 (p = 0.002) and higher tau (p < 0.0001) and p-tau (p = 0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p-values were < 0.005). DISCUSSION: The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed. Highlights: There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function.