scholarly journals Cholecystokinin and Panic Disorder: Reflections on the History and Some Unsolved Questions

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5657
Author(s):  
Jens F. Rehfeld
Keyword(s):  
Panic Disorder ◽  
Panic Attacks ◽  
Normal Brain ◽  
Brain Functions ◽  
Gut Hormone ◽  
Neuropsychiatric Diseases ◽  
The Common ◽  
Almost All ◽  
The Brain ◽  
Cck2 Receptor

The classic gut hormone cholecystokinin (CCK) and its CCK2-receptor are expressed in almost all regions of the brain. This widespread expression makes CCK by far the most abundant peptidergic transmitter system in the brain. This CNS-ubiquity has, however, complicated the delineation of the roles of CCK peptides in normal brain functions and neuropsychiatric diseases. Nevertheless, the common panic disorder disease is apparently associated with CCK in the brain. Thus, the C-terminal tetrapeptide fragment of CCK (CCK-4) induces, by intravenous administration in a dose-related manner, panic attacks that are similar to the endogenous attacks in panic disorder patients. This review describes the history behind the discovery of the panicogenic effect of CCK-4. Subsequently, the review discusses three unsettled questions about the involvement of cerebral CCK in the pathogenesis of anxiety and panic disorder, including therapeutic attempts with CCK2-receptor antagonists.

scholarly journals Dynamic N6-methyladenosine RNA methylation in brain and diseases

Epigenomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 371-380 ◽  
Author(s):  
Andrew M Shafik ◽  
Emily G Allen ◽  
Peng Jin
Keyword(s):  
Brain Development ◽  
Rna Modification ◽  
Normal Brain ◽  
Biological Processes ◽  
Future Directions ◽  
Body Of Knowledge ◽  
Neuropsychiatric Diseases ◽  
The Brain ◽  
Normal Brain Development

N6-methyladenosine (m6A) is a dynamic RNA modification that regulates various aspects of RNA metabolism and has been implicated in many biological processes and transitions. m6A is highly abundant in the brain; however, only recently has the role of m6A in brain development been a focus. The machinery that controls m6A is critically important for proper neurodevelopment, and the precise mechanisms by which m6A regulates these processes are starting to emerge. However, the role of m6A in neurodegenerative and neuropsychiatric diseases still requires much elucidation. This review discusses and summarizes the current body of knowledge surrounding the function of the m6A modification in regulating normal brain development, neurodegenerative diseases and outlines possible future directions.

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

BMC Medicine ◽  
2019 ◽  
Vol 17 (1) ◽  
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.

scholarly journals Cholesterol: Its Regulation and Role in Central Nervous System Disorders

Cholesterol ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Matthias Orth ◽  
Stefano Bellosta
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Metabolic Pathways ◽  
Cholesterol Metabolism ◽  
Major Constituent ◽  
Normal Brain ◽  
Lipoprotein Receptors ◽  
Brain Cholesterol ◽  
Brain Functions ◽  
The Brain

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

scholarly journals Characterization of Brain Iron Deposition Pattern and Its Association With Genetic Risk Factor in Alzheimer’s Disease Using Susceptibility-Weighted Imaging

2021 ◽  
Vol 15 ◽  
Author(s):  
Peiting You ◽  
Xiang Li ◽  
Zhijiang Wang ◽  
Huali Wang ◽  
Bin Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Iron Deposition ◽  
Susceptibility Weighted Imaging ◽  
Normal Brain ◽  
Brain Iron ◽  
Brain Functions ◽  
The Brain ◽  
Brain Iron Deposition

The presence of iron is an important factor for normal brain functions, whereas excessive deposition of iron may impair normal cognitive function in the brain and lead to Alzheimer’s disease (AD). MRI has been widely applied to characterize brain structural and functional changes caused by AD. However, the effectiveness of using susceptibility-weighted imaging (SWI) for the analysis of brain iron deposition is still unclear, especially within the context of early AD diagnosis. Thus, in this study, we aim to explore the relationship between brain iron deposition measured by SWI with the progression of AD using various feature selection and classification methods. The proposed model was evaluated on a 69-subject SWI imaging dataset consisting of 24 AD patients, 21 mild cognitive impairment patients, and 24 normal controls. The identified AD progression-related regions were then compared with the regions reported from previous genetic association studies, and we observed considerable overlap between these two. Further, we have identified a new potential AD-related gene (MEF2C) closely related to the interaction between iron deposition and AD progression in the brain.

scholarly journals Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yvonne Cashinn Chia ◽  
Clarice Evey Anjum ◽  
Hui Rong Yee ◽  
Yenny Kenisi ◽  
Mike K. S. Chan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Blood Brain Barrier ◽  
Cellular Therapy ◽  
Immune Cell ◽  
Brain Barrier ◽  
Normal Brain ◽  
Brain Functions ◽  
Blood Brain ◽  
The Brain

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

scholarly journals Glycogen Synthase Kinase-3β: A Mediator of Inflammation in Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jari Koistinaho ◽  
Tarja Malm ◽  
Gundars Goldsteins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Immune Defense ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Normal Brain ◽  
Brain Functions ◽  
The Brain

Proliferation and activation of microglial cells is a neuropathological characteristic of brain injury and neurodegeneration, including Alzheimer's disease. Microglia act as the first and main form of immune defense in the nervous system. While the primary function of microglia is to survey and maintain the cellular environment optimal for neurons in the brain parenchyma by actively scavenging the brain for damaged brain cells and foreign proteins or particles, sustained activation of microglia may result in high production of proinflammatory mediators that disturb normal brain functions and even cause neuronal injury. Glycogen synthase kinase-3βhas been recently identified as a major regulator of immune system and mediates inflammatory responses in microglia. Glycogen synthase kinase-3βhas been extensively investigated in connection to tau and amyloidβtoxicity, whereas reports on the role of this enzyme in neuroinflammation in Alzheimer's disease are negligible. Here we review and discuss the role of glycogen synthase-3βin immune cells in the context of Alzheimer's disease pathology.

scholarly journals In-vivo histology of iron and myelin in the brain using magnetic susceptibility source separation in MRI

2020 ◽  
Author(s):  
Hyeong-Geol Shin ◽  
Jingu Lee ◽  
Young Hyun Yun ◽  
Seong Ho Yoo ◽  
Jinhee Jang ◽  
...  
Keyword(s):  
Magnetic Susceptibility ◽  
Ex Vivo ◽  
Biophysical Model ◽  
Normal Brain ◽  
Brain Functions ◽  
Magnetic Resonance Imaging Mri ◽  
The Individual ◽  
Multiple Sclerosis Patients ◽  
The Brain

ABSTRACTObtaining a histological fingerprint from the in-vivo brain has been a long-standing target of magnetic resonance imaging (MRI). In particular, non-invasive imaging of iron and myelin, which are involved in normal brain functions and are histopathological hallmarks in a few neurodegenerative diseases, has practical utilities in neuroscience and medicine. Here, we propose a biophysical model that describes the individual contribution of iron and myelin to MRI signals via their difference in magnetic susceptibility (i.e., paramagnetic iron vs. diamagnetic myelin). Using this model, we develop a method, χ-separation, that generates the voxel-wise distributions of iron and myelin. The method is validated using computer simulation and phantom experiments, and applied to ex-vivo and in-vivo brains. The results delineate the well-known histological features of iron and myelin in the specimen (e.g., co-localization of iron and myelin in Gennari line), healthy volunteers (e.g., myelin-lacking and iron-rich pulvinar), and multiple sclerosis patients (e.g., demyelinated iron-rim lesion). This new in-vivo histology technology, taking less than 20 min, may serve as a practical tool for exploring the microstructural information of the brain.

Chemotherapy of brain tumors

1972 ◽  
Vol 37 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Charles H. Tator
Keyword(s):  
Brain Tumors ◽  
Chemotherapeutic Agent ◽  
Normal Brain ◽  
Neoplastic Cells ◽  
Central Mass ◽  
Content Type ◽  
Intracerebral Tumor ◽  
Almost All ◽  
The Brain ◽  
Adjacent Brain

✓ The uptake and distribution in brain tumors of a parenterally administered chemotherapeutic agent were studied in mice bearing intracerebral implants of a transplantable ependymoblastoma. Tritiated methotrexate (3H-MTX) was injected intravenously, and autoradiographs of the tumors and adjacent brain were prepared at 2, 10, and 60 min after injection using a technique suitable for soluble compounds. In the tumors at 2 min the drug was mainly intravascular and interstitial while at 60 min the drug was mainly intracellular. This is the first demonstration of cellular uptake of a chemotherapeutic agent by neoplastic cells within the brain. At 60 min, almost all the cells in the central mass of the intracerebral tumors were heavily labeled. However, cells at the periphery of the mass and those infiltrating into adjacent brain showed scanty labeling. Uptake in normal brain was very low, while uptake in edematous brain adjacent to the tumors was much higher although not as high as in the tumors. The study shows that this chemotherapeutic agent is capable of penetrating into the neoplastic cells of an intracerebral tumor following parenteral administration, but that the degree of penetration varies considerably depending on the location of the cells within the brain.

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

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1035
Author(s):  
Natalia Cichon ◽  
Joanna Saluk-Bijak ◽  
Leslaw Gorniak ◽  
Lukasz Przyslo ◽  
Michal Bijak
Keyword(s):  
Oxidative Stress ◽  
Standard Treatment ◽  
Functional Organization ◽  
Nerve Tissue ◽  
Neuroprotective Activity ◽  
Brain Functions ◽  
Long Time ◽  
The Common ◽  
The Impact ◽  
The Brain

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.

scholarly journals Cholecystokinin-mediated Neuromodulation of Anxiety and Schizophrenia: A “Dimmer-Switch” Hypothesis

2020 ◽  
Vol 18 ◽  
Author(s):  
Santiago J. Ballaz ◽  
Michel Bourin
Keyword(s):  
Neural Activity ◽  
Panic Attacks ◽  
Inhibitory Interneurons ◽  
Cortical Dynamics ◽  
Reward Circuitry ◽  
Cognitive Component ◽  
Dopaminergic Systems ◽  
The Brain ◽  
Cck2 Receptor ◽  
Cck Release

: Cholecystokin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor have CCK agonists consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.

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