MOLECULAR MECHANISMS OF ALCOHOL ADDICTION: THE ROLE OF GLUTAMATE RECEPTORS OF THE BRAIN

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

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Glymphatic System in the Central Nervous System, a Novel Therapeutic Direction Against Brain Edema After Stroke

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.698036 ◽

2021 ◽

Vol 13 ◽

Author(s):

Xiangyue Zhou ◽

Youwei Li ◽

Cameron Lenahan ◽

Yibo Ou ◽

Minghuan Wang ◽

...

Keyword(s):

Brain Edema ◽

Brain Tissue ◽

Molecular Mechanisms ◽

Glymphatic System ◽

System A ◽

Function Recovery ◽

The Central Nervous System ◽

The Stability ◽

The Brain

Stroke is the destruction of brain function and structure, and is caused by either cerebrovascular obstruction or rupture. It is a disease associated with high mortality and disability worldwide. Brain edema after stroke is an important factor affecting neurologic function recovery. The glymphatic system is a recently discovered cerebrospinal fluid (CSF) transport system. Through the perivascular space and aquaporin 4 (AQP4) on astrocytes, it promotes the exchange of CSF and interstitial fluid (ISF), clears brain metabolic waste, and maintains the stability of the internal environment within the brain. Excessive accumulation of fluid in the brain tissue causes cerebral edema, but the glymphatic system plays an important role in the process of both intake and removal of fluid within the brain. The changes in the glymphatic system after stroke may be an important contributor to brain edema. Understanding and targeting the molecular mechanisms and the role of the glymphatic system in the formation and regression of brain edema after stroke could promote the exclusion of fluids in the brain tissue and promote the recovery of neurological function in stroke patients. In this review, we will discuss the physiology of the glymphatic system, as well as the related mechanisms and therapeutic targets involved in the formation of brain edema after stroke, which could provide a new direction for research against brain edema after stroke.

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Сellular and Molecular Mechanisms of Proinflammatory Monocytes Participation in the Pathogenesis of Mental Disorders. Part 3

Psychiatry ◽

10.30629/2618-6667-2021-19-4-125-134 ◽

2021 ◽

Vol 19 (4) ◽

pp. 125-134

Author(s):

E. F. Vasilyeva ◽

O. S. Brusov

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mental Disorders ◽

Molecular Mechanisms ◽

Microglial Cells ◽

Inflammatory Reactions ◽

Mental Diseases ◽

The Central Nervous System ◽

The Brain

Background: at present, the important role of the monocyte-macrophage link of immunity in the pathogenesis of mental diseases has been determined. In the first and second parts of our review, the cellular and molecular mechanisms of activation of monocytes/macrophages, which secreting proinflammatory CD16 receptors, cytokines, chemokines and receptors to them, in the development of systemic immune inflammation in the pathogenesis of somatic diseases and mental disorders, including schizophrenia, bipolar affective disorder (BAD) and depression were analyzed. The association of high levels of proinflammatory activity of monocytes/macrophages in patients with mental disorders with somatic comorbidity, including immune system diseases, is shown. It is known that proinflammatory monocytes of peripheral blood, as a result of violation of the integrity of the hematoencephalic barrier can migrate to the central nervous system and activate the resident brain cells — microglia, causing its activation. Activation of microglia can lead to the development of neuroinammation and neurodegenerative processes in the brain and, as a result, to cognitive disorders. The aim of review: to analyze the results of the main scientific studies concerning the role of cellular and molecular mechanisms of peripheral blood monocytes interaction with microglial cells and platelets in the development of neuroinflammation in the pathogenesis of mental disorders, including Alzheimer’s disease (AD). Material and methods: keywords “mental disorders, AD, proinflammatory monocytes, microglia, neuroinflammation, cytokines, chemokines, cell adhesion molecules, platelets, microvesicles” were used to search for articles of domestic and foreign authors published over the past 30 years in the databases PubMed, eLibrary, Science Direct and EMBASE. Conclusion: this review analyzes the results of studies which show that monocytes/macrophages and microglia have similar gene expression profiles in schizophrenia, BAD, depression, and AD and also perform similar functions: phagocytosis and inflammatory responses. Monocytes recruited to the central nervous system stimulate the increased production of proinflammatory cytokines IL-1, IL-6, tumor necrosis factor alpha (TNF-α), chemokines, for example, MCP-1 (Monocyte chemotactic protein-1) by microglial cells. This promotes the recruitment of microglial cells to the sites of neuronal damage, and also enhances the formation of the brain protein beta-amyloid (Aβ). The results of modern studies are presented, indicating that platelets are involved in systemic inflammatory reactions, where they interact with monocytes to form monocyte-platelet aggregates (MTA), which induce the activation of monocytes with a pro inflammatory phenotype. In the last decade, it has been established that activated platelets and other cells of the immune system, including monocytes, detached microvesicles (MV) from the membrane. It has been shown that MV are involved as messengers in the transport of biologically active lipids, cytokines, complement, and other molecules that can cause exacerbation of systemic inflammatory reactions. The presented review allows us to expand our knowledge about the cellular and molecular aspects of the interaction of monocytes/macrophages with microglial cells and platelets in the development of neuroinflammation and cognitive decline in the pathogenesis of mental diseases and in AD, and also helps in the search for specific biomarkers of the clinical severity of mental disorder in patients and the prospects for their response to treatment.

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Kynurenic acid and cancer: facts and controversies

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03332-w ◽

2019 ◽

Vol 77 (8) ◽

pp. 1531-1550 ◽

Cited By ~ 7

Author(s):

Katarzyna Walczak ◽

Artur Wnorowski ◽

Waldemar A. Turski ◽

Tomasz Plech

Keyword(s):

Kynurenic Acid ◽

Molecular Mechanisms ◽

Potential Role ◽

Cancer Cell Proliferation ◽

Gastrointestinal Microbiota ◽

Tryptophan Metabolite ◽

Peripheral Cells ◽

The Relationship ◽

The Brain

Abstract Kynurenic acid (KYNA) is an endogenous tryptophan metabolite exerting neuroprotective and anticonvulsant properties in the brain. However, its importance on the periphery is still not fully elucidated. KYNA is produced endogenously in various types of peripheral cells, tissues and by gastrointestinal microbiota. Furthermore, it was found in several products of daily human diet and its absorption in the digestive tract was evidenced. More recent studies were focused on the potential role of KYNA in carcinogenesis and cancer therapy; however, the results were ambiguous and the biological activity of KYNA in these processes has not been unequivocally established. This review aims to summarize the current views on the relationship between KYNA and cancer. The differences in KYNA concentration between physiological conditions and cancer, as well as KYNA production by both normal and cancer cells, will be discussed. The review also describes the effect of KYNA on cancer cell proliferation and the known potential molecular mechanisms of this activity.

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Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport

Physiology ◽

10.1152/physiol.00015.2009 ◽

2009 ◽

Vol 24 (4) ◽

pp. 257-265 ◽

Cited By ~ 119

Author(s):

Kristopher T. Kahle ◽

J. Marc Simard ◽

Kevin J. Staley ◽

Brian V. Nahed ◽

Pamela S. Jones ◽

...

Keyword(s):

Cerebral Edema ◽

Molecular Mechanisms ◽

Cell Volume Regulation ◽

Cell Swelling ◽

Ischemic Brain Injury ◽

Edema Formation ◽

Ischemic Brain ◽

The Brain ◽

Permeability Alterations

The brain achieves homeostasis of its intracellular and extracellular fluids by precisely regulating the transport of solute and water across its major cellular barriers: endothelia of the blood-brain barrier (BBB), choroid plexus epithelia, and neuroglial cell membranes. Cerebral edema, the pathological accumulation of fluid in the brain’s intracellular and extracellular spaces, is a major cause of morbidity and mortality following stroke and other forms of ischemic brain injury. Until recently, mechanisms of cerebral edema formation have been obscure; consequently, its treatment has been empiric and suboptimal. Here, we provide a paradigm for understanding ischemic cerebral edema, showing that its molecular pathogenesis is a complex yet step-wise process that results largely from impaired astrocytic cell volume regulation and permeability alterations in the cerebral microvasculature, both of which arise from pathological changes in the activities of specific ion channels and transporters. Recent data has implicated the bumetanide-sensitive NKCC1, an electroneutral cotransporter expressed in astrocytes and the BBB, in cerebral edema formation in several different rodent models of stroke. Pharmacological inhibition or genetic deficiency of NKCC1 decreases ischemia-induced cell swelling, BBB breakdown, cerebral edema, and neurotoxicity. Combination pharmacological strategies that include NKCC1 as a target might thus prove beneficial for the treatment of ischemic, and potentially other types of, cerebral edema.

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Glutamatergic pathways as a target for the treatment of dyskinesias in Parkinson's disease

Biochemical Society Transactions ◽

10.1042/bst20140006 ◽

2014 ◽

Vol 42 (2) ◽

pp. 600-604 ◽

Cited By ~ 9

Author(s):

M. Angela Cenci

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Glutamate Receptors ◽

Clinical Results ◽

Dopamine Depletion ◽

Pathophysiological Role ◽

Striatal Dopamine Depletion ◽

Glutamatergic Pathways ◽

The Brain

PD (Parkinson's disease) is characterized by some typical motor features that are caused by striatal dopamine depletion and respond well to dopamine-replacement therapy with L-dopa. Unfortunately, the majority of PD patients treated with L-dopa develop abnormal involuntary movements (dyskinesias) within a few years. The mechanisms underlying the development of LIDs (L-dopa-induced dyskinesias) involve, on one hand, a presynaptic dysregulation of dopamine release and clearance and, on the other hand, an abnormal postsynaptic response to dopamine in the brain. There is a large amount of evidence that these dopamine-dependent mechanisms are modulated by glutamatergic pathways and glutamate receptors. The present article summarizes the pathophysiological role of glutamatergic pathways in LID and reviews pre-clinical and clinical results obtained using pharmacological modulators of different classes and subtypes of glutamate receptors to treat parkinsonian dyskinesias.

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Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities

International Journal of Molecular Sciences ◽

10.3390/ijms222111313 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11313

Author(s):

Sana Javaid ◽

Talha Farooq ◽

Zohabia Rehman ◽

Ammara Afzal ◽

Waseem Ashraf ◽

...

Keyword(s):

Molecular Mechanisms ◽

Brain Injuries ◽

Structural Integrity ◽

Preclinical Studies ◽

Neuronal Transmission ◽

Expanding Population ◽

Motorized Vehicles ◽

The Brain ◽

And Oxidative Stress

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.

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The Neurobiology of Selenium: Looking Back and to the Future

Frontiers in Neuroscience ◽

10.3389/fnins.2021.652099 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ulrich Schweizer ◽

Simon Bohleber ◽

Wenchao Zhao ◽

Noelia Fradejas-Villar

Keyword(s):

Cell Biology ◽

Molecular Mechanisms ◽

Human Genetics ◽

Epileptic Seizures ◽

Cell Types ◽

Mammalian Brain ◽

The Individual ◽

The Brain ◽

Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

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ROLE OF INSULIN IN BRAIN: DELVE INTO THE MOLECULAR MECHANISMS

10.14293/s2199-1006.1.sor-.ppkjzat.v1 ◽

2021 ◽

Author(s):

Sofia Khanam

Keyword(s):

Molecular Mechanisms ◽

Insulin Signalling ◽

Diabetic Patients ◽

Functional Activities ◽

Mitochondrial Alterations ◽

Age Related ◽

The Brain ◽

And Oxidative Stress

We have learned over the last several decades that the brain is an important target for insulin action. In central nervous system (CNS) it mainly affects feeding behaviour and various aspects of memory and cognition. Insulin signalling in CNS has emerged as a novel field of research since decreases brain insulin levels and signalling were associated to impaired learning, memory and age-related neurodegenerative diseases. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). A close alliance between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients. There are links between T2DM and AD through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism and tau hyperphosphorylation. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: T2DM and AD, both in terms of intracellular signalling and potential therapeutic approach.

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Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

Cells ◽

10.3390/cells9112347 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2347

Author(s):

Anna Atlante ◽

Giuseppina Amadoro ◽

Antonella Bobba ◽

Valentina Latina

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Food Product ◽

Neuroprotective Effects ◽

The Road ◽

Beneficial Effects ◽

Β Amyloid ◽

The Brain

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.

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