Flavonoids as a Natural Enhancer of Neuroplasticity—An Overview of the Mechanism of Neurorestorative Action

Neuroplasticity is a complex physiological process occurring in the brain for its entire life. However, it is of particular importance in the case of central nervous system (CNS) disorders. Neurological recovery largely depends on the ability to reestablish the structural and functional organization of neurovascular networks, which must be pharmacologically supported. For this reason, new forms of therapy are constantly being sought. Including adjuvant therapies in standard treatment may support the enhancement of repair processes and restore impaired brain functions. The common hallmark of nerve tissue damage is increased by oxidative stress and inflammation. Thus, the studies on flavonoids with strong antioxidant and anti-inflammatory properties as a potential application in neuro intervention have been carried out for a long time. However, recent results have revealed another important property of these compounds in CNS therapy. Flavonoids possess neuroprotective activity, and promote synaptogenesis and neurogenesis, by, among other means, inhibiting oxidative stress and neuroinflammation. This paper presents an overview of the latest knowledge on the impact of flavonoids on the plasticity processes of the brain, taking into account the molecular basis of their activity.

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The restless brain: how intrinsic activity organizes brain function

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0172 ◽

2015 ◽

Vol 370 (1668) ◽

pp. 20140172 ◽

Cited By ~ 183

Author(s):

Marcus E. Raichle

Keyword(s):

Brain Function ◽

Functional Organization ◽

Sensory Information ◽

Intrinsic Activity ◽

Systems Neuroscience ◽

Brain Functions ◽

Molecular Neuroscience ◽

Constant State ◽

Health And Disease ◽

The Brain

Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease.

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NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis

BMC Medicine ◽

10.1186/s12916-019-1439-x ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Shu-zhen Zhang ◽

Qin-qin Wang ◽

Qiao-qiao Yang ◽

Huan-yu Gu ◽

Yan-qing Yin ◽

...

Keyword(s):

Innate Immunity ◽

Diphtheria Toxin ◽

Transforming Growth Factor ◽

Critical Role ◽

Normal Brain ◽

Sequencing Analysis ◽

Brain Functions ◽

Lps Challenge ◽

The Impact ◽

The Brain

Abstract Background Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. Methods Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. Results We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. Conclusions These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

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Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph12020093 ◽

2019 ◽

Vol 12 (2) ◽

pp. 93 ◽

Cited By ~ 12

Author(s):

Shashank Masaldan ◽

Abdel Ali Belaidi ◽

Scott Ayton ◽

Ashley I. Bush

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hydroxyl Radicals ◽

Iron Accumulation ◽

Brain Iron ◽

Dependent Cell ◽

Cellular Dysfunction ◽

The Impact ◽

The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

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Regulatory Roles of Bone in Neurodegenerative Diseases

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.610581 ◽

2020 ◽

Vol 12 ◽

Author(s):

Zhengran Yu ◽

Zemin Ling ◽

Lin Lu ◽

Jin Zhao ◽

Xiang Chen ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

The Elderly ◽

Lymphoid Organ ◽

The Body ◽

Hematopoietic Stem ◽

Brain Functions ◽

And Function ◽

The Impact ◽

The Brain

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

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Neural Control of Immunity in Hypertension: Council on Hypertension Mid Career Award for Research Excellence, 2019

Hypertension ◽

10.1161/hypertensionaha.120.14637 ◽

2020 ◽

Vol 76 (3) ◽

pp. 622-628

Author(s):

Daniela Carnevale

Keyword(s):

Immune Response ◽

Nervous System ◽

Neural Control ◽

Neural Signals ◽

The Past ◽

Target Organs ◽

Long Time ◽

The Common ◽

The Brain

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these 2 evolutionarily highly conserved systems has been recognized for long time, the investigation into the pathophysiological mechanisms underlying their crosstalk has been tackled only in recent decades. Recent work of the past years elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. This review will focus on the neural mechanisms regulating the immune response and the role of this neuroimmune crosstalk in hypertension. In this context, the review highlights the components of the brain-spleen axis with a focus on the neuroimmune interface established in the spleen, where neural signals shape the immune response recruited to target organs of high blood pressure.

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The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

Nutrients ◽

10.3390/nu12020435 ◽

2020 ◽

Vol 12 (2) ◽

pp. 435 ◽

Cited By ~ 4

Author(s):

Anna Winiarska-Mieczan ◽

Ewa Baranowska-Wójcik ◽

Małgorzata Kwiecień ◽

Eugeniusz R. Grela ◽

Dominik Szwajgier ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Negative Impact ◽

Functional Disorders ◽

Brain Functions ◽

Diet Supplements ◽

The Impact ◽

The Brain ◽

All Diseases

Neurodegenerative diseases are progressive diseases of the nervous system that lead to neuron loss or functional disorders. Neurodegenerative diseases require long-term, sometimes life-long pharmacological treatment, which increases the risk of adverse effects and a negative impact of pharmaceuticals on the patients’ general condition. One of the main problems related to the treatment of this type of condition is the limited ability to deliver drugs to the brain due to their poor solubility, low bioavailability, and the effects of the blood-brain barrier. Given the above, one of the main objectives of contemporary scientific research focuses on the prevention of neurodegenerative diseases. As disorders related to the competence of the antioxidative system are a marker in all diseases of this type, the primary prophylactics should entail the use of exogenous antioxidants, particularly ones that can be used over extended periods, regardless of the patient’s age, and that are easily available, e.g., as part of a diet or as diet supplements. The paper analyzes the significance of the oxidoreductive balance in the pathogenesis of neurodegenerative diseases. Based on information published globally in the last 10 years, an analysis is also provided with regard to the impact of exogenous antioxidants on brain functions with respect to the prevention of this type of diseases.

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Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: a theoretical review

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0046 ◽

2014 ◽

Vol 25 (6) ◽

Cited By ~ 47

Author(s):

Lauren E. Salminen ◽

Robert H. Paul

Keyword(s):

Oxidative Stress ◽

Antioxidant Defense ◽

Future Research ◽

Aging Brain ◽

Older Individuals ◽

Glutathione S Transferase ◽

Antioxidant Defense Enzymes ◽

Repair Mechanisms ◽

The Impact ◽

The Brain

AbstractNormal aging involves a gradual breakdown of physiological processes that leads to a decline in cognitive functions and brain integrity, yet the onset and progression of decline are variable among older individuals. While many biological changes may contribute to this degree of variability, oxidative stress is a key mechanism of the aging process that can cause direct damage to cellular architecture within the brain. Oligodendrocytes are at a high risk for oxidative damage due to their role in myelin maintenance and production and limited repair mechanisms, suggesting that white matter may be particularly vulnerable to oxidative activity. Antioxidant defense enzymes within the brain, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), are crucial for breaking down the harmful end products of oxidative phosphorylation. Previous studies have revealed that allele variations of polymorphisms that encode these antioxidants are associated with abnormalities in SOD, CAT, GPx, and GST activity in the central nervous system. This review will focus on the role of oxidative stress in the aging brain and the impact of decreased antioxidant defense on brain integrity and cognitive function. Directions for future research investigations of antioxidant defense genes will also be discussed.

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Brain Physiology and Pathophysiology in Mental Stress

ISRN Physiology ◽

10.1155/2013/806104 ◽

2013 ◽

Vol 2013 ◽

pp. 1-23 ◽

Cited By ~ 14

Author(s):

Karim Alkadhi

Keyword(s):

Signal Transduction ◽

Learning And Memory ◽

Mental Stress ◽

Negative Effects ◽

Functional Changes ◽

Brain Physiology ◽

Brain Functions ◽

Brain Structure And Function ◽

The Impact ◽

The Brain

Exposure to various forms of stress is a common daily occurrence in the lives of most individuals, with both positive and negative effects on brain function. The impact of stress is strongly influenced by the type and duration of the stressor. In its acute form, stress may be a necessary adaptive mechanism for survival and with only transient changes within the brain. However, severe and/or prolonged stress causes overactivation and dysregulation of the hypothalamic pituitary adrenal (HPA) axis thus inflicting detrimental changes in the brain structure and function. Therefore, chronic stress is often considered a negative modulator of the cognitive functions including the learning and memory processes. Exposure to long-lasting stress diminishes health and increases vulnerability to mental disorders. In addition, stress exacerbates functional changes associated with various brain disorders including Alzheimer’s disease and Parkinson’s disease. The primary purpose of this paper is to provide an overview for neuroscientists who are seeking a concise account of the effects of stress on learning and memory and associated signal transduction mechanisms. This review discusses chronic mental stress and its detrimental effects on various aspects of brain functions including learning and memory, synaptic plasticity, and cognition-related signaling enabled via key signal transduction molecules.

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Neurocircuitry of the nicotinic cholinergic system

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2010.12.4/dbertrand ◽

2010 ◽

Vol 12 (4) ◽

pp. 463-470 ◽

Cited By ~ 1

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Functional Organization ◽

Brain Anatomy ◽

Brain Organization ◽

Neuronal Communication ◽

Brain Functions ◽

Static View ◽

Natural Alkaloid ◽

The Brain

Continuing to discover how the brain works is one of the great challenges ahead of us. Although understanding the brain anatomy and its functional organization provided a first and indispensable foundation, it became clear that a static view was insufficient. To understand the complexity of neuronal communication, it is necessary to examine the chemical nature of the neurotransmission and, using the example of the acetylcholine receptors, follow the different layers of networks that can be distinguished. The natural alkaloid nicotine contained in tobacco leaves acts as an agonist with a subclass of acetylcholine receptors, and provides an interesting tool to approach brain functions. Analysis of the nicotinic acetylcholine receptors, which are ligand gated channels, revealed that these receptors are expressed at different critical locations on the neurons including the synaptic boutons, neurites, cell bodies, and even on the axons. These receptors can modulate the activity at the microcircuit synaptic level, in the cell processing of information, and, by acting on the velocity of action potential, the synchrony of communication between brain areas. These actions at multiple levels of brain organization provide an example of the complexity of brain neurocircuitry and an illustration of the relevance of this knowledge for psychiatry.

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Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disorders

EMJ Neurology ◽

10.33590/emjneurol/20-00068 ◽

2020 ◽

pp. 68-79

Author(s):

Varruchi Sharma ◽

Atul Sankhyan ◽

Anshika Varshney ◽

Renuka Choudhary ◽

Anil K. Sharma

Keyword(s):

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Intervention Strategy ◽

Neurological Complications ◽

Communication Link ◽

Brain Functions ◽

Current Review ◽

The Impact ◽

The Brain

It has been suggested that an intricate communication link exists between the gut microbiota and the brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity of the microbiota is considered to be relatively constant in healthy individuals, despite differences in the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic balance is often perturbed as a result of neurological complications. Therefore, it is of paramount importance to explore the link between gut microbiota and brain function and behaviour through neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and synbiotics might prove beneficial in the prevention and/or treatment of neurological disorders. It is important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use the gut microbiota as a therapeutic intervention strategy for neurological disorders.

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