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Alpha7 nicotinic receptors as potential theranostic targets for experimental stroke

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Neural Regeneration Research 2024年第5期19卷 939-940页

作者： Maider Garbizu Laura Aguado Abraham Martín achucarro basque center for neuroscience LeioaSpain CIC biomaGUNE Basque Research and Technology AllianceSan SebastianSpain Ikerbasque basque Foundation for Science BilbaoSpain

Inflammatory reflex and cholinergic anti-inflammatory pathway:Innate immune system triggers a local inflammatory response following an injury or a pathogen ***,this inflammatory response is limited by rapid,localized,and adaptive anti-inflammatory responses which are crucial for maintaining ***,the loss of these responses converts a limited and protective inflammatory response into an excessive and harmful ***-inflammatory responses are integrated into the central nervous system,since the central nervous system accumulates information about harmful events,activates defenses,and builds memory for *** the same time,it has been demonstrated that hypothalamic neuronal signaling can be altered by inflammation in peripheral ***,immune cells release neuropeptides and neurotransmitters such as acetylcholine(ACh),the main neurotransmitter of the parasympathetic autonomic nervous system,evidencing the communication between the immune and nervous systems(Tracey,2002).

关键词： protective invasion Alpha

Astrocyte syncytium:from neonatal genesis to aging degeneration

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Neural Regeneration Research 2024年第2期19卷 395-396页

作者： Min Zhou Shiying Zhong Alexei Verkhratsky Department of neuroscience Ohio State University Wexner Medical CenterColumbusOHUSA Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achücarro basque center for neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain Department of neurosciences University of the Basque Country UPV/EHU and CIBERNEDLeioaSpain

Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal(the proponent of the neuronal doctrine)and Camillo Golgi(who advocated the syncytial reticular organization of neural networks)delivered their Noble prize lectures(Verkhratsky,2009).

关键词： degeneration neonatal aging

Glial decline and loss of homeostatic support rather than inflammation defines cognitive aging

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Neural Regeneration Research 2022年第3期17卷 565-566页

作者： Alexei Verkhratsky Natalia Lazareva Alexey Semyanov Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK achucarro center for neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoDepartment of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Sechenov First Moscow State Medical University MoscowRussia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of SciencesFaculty of BiologyMoscow State UniversityMoscowRussia

The preservation of cognitive longevity and arresting the pandemic of senile dementia engulfing the modern world is arguably the major challenge faced by biomedical research in the 21st *** is the leading risk factor for neurodegenerative diseases and vascular dementia,and yet there is a clear distinction between physiological and pathological brain aging.

关键词： inflammation senile aging

Mens sana in corpore sano: lifestyle changes modify astrocytes to contain Alzheimer's disease

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Neural Regeneration Research 2021年第8期16卷 1548-1549页

作者： Marcus Augusto-Oliveira Alexei Verkhratsky Laboratório de Farmacologia Molecular Instituto de Ciências BiológicasUniversidade Federal do Pará66075-110 BelémBrasil Faculty of Biology Medicine and HealthThe University of ManchesterManchesterM139PTUK achucarro center for neuroscience IKERBASQUEBasque Foundation for Science48011 BilbaoSpain&Department of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain

Alzheimer's disease(AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the *** by eliminating intelligence,diminishes a man to helpless body,places an unbearable strain on patients,families,and fuels socioeconomic healthcare crises around the *** main histopathological hallmarks of AD are the accumulation of extracellular amyloid depositions known as senile plaques and intracellular neurofibrillary to ngles,together with severe dysfunctional synaptic connectivity and neuronal death leading to brain atrophy.

关键词： Alzheimer senile eliminating

Alterations of protein homeostasis in Alzheimer's disease:beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response

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Neural Regeneration Research 2024年第8期19卷 1645-1646页

作者： Dmitry Lim Alexei Verkhratsky Department of Pharmaceutical Sciences Universitàdel Piemonte Orientale“Amedeo Avogadro”NovaraItaly Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK achucarro center for neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain&Department of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania Department of Forensic Analytical Toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina

Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and *** hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.

关键词： Alzheimer homeostasis cortex

Clearing the corpses： regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

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Neural Regeneration Research 2016年第10期11卷 1533-1539页

作者： Irune Diaz-Aparicio Sol Beccari Oihane Abiega Amanda Sierra achucarro basque center for neuroscience Bizkaia Science and Technology Park Zamudio Spain University of the basque Country Leioa Spain Ikerbasque Foundation Bilbao Spain

Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

关键词： microglia phagocytosis apoptosis impairment epilepsy brain diseases neurodegeneration inflammation neuroinflammation

Store-operated calcium entry in neuroglia

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neuroscience Bulletin 2014年第1期30卷 125-133页

作者： Alexei Verkhratsky Vladimir Parpura Faculty of Life Sciences The University of Manchester achucarro center for neuroscience IKERBASQUE Basque Foundation for Science 48011 Bilbao Spain and Department of neurosciences University of the Basque Country UPV/EHU Department of Neurobiology Center for Glial Biology in Medicine Atomic Force Microscopy & Nanotechnology aboratories Civitan International Research Center Evelyn F. McKnight Brain Institute University of Alabama Department of Biotechnology University or Rijeka

Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca^2＋ signals that define the ＂Ca^2＋ excitability＂ of glia. In mammalian glial cells the major source of Ca^2＋ for this excitability is the lumen of the endoplasmic reticulum （ER）, which is ultimately （re）filled from the extracellular space. This occurs via store-operated Ca^2＋ entry （SOCE） which is supported by a specific signaling system connecting the ER with plasmalemmal Ca^2＋ entry. Here, emptying of the ER Ca^2＋ store is necessary and sufficient for the activation of SOCE, and without Ca^2＋ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca^2＋ sensors, such as stromal interaction molecule, and possibly ER Ca^2＋ pumps （of the SERCA type）. There are at least two sets of plasmalemmal channels mediating SOCE, the Ca2＊-release activated channels, Orai, and transient receptor potential （TRP） channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca^2＋ signal observed following stimulation of metabotropic receptors on glial cells.

关键词： calcium signaling astrocyte oligodendrocyte microglia store-operated calcium entry TRP STIM Orai

The anti-inflammatory astrocyte revealed:the role of the microbiome in shaping brain defences

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1404-1405页

作者： Alexei Verkhratsky Peter Illes Yong Tang Alexey Semyanov Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK achucarro center for neuroscience IKERBASQUEBasque Foundation for Science48011 BilbaoSpain&Department of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Sechenov First Moscow State Medical University MoscowRussia School of Acupuncture and Tuina and International Collaborative Centre on Big Science Plan for Purinergic Signalling Chengdu University of Traditional Chinese MedicineChengduChina Rudolf Boehm Institute for Pharmacology and Toxicology University of LeipzigLeipzigGermany Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of SciencesMoscow117997Russia Faculty of Biology Moscow State UniversityMoscowRussia

The paper,published recently in Nature by the group of Francisco Quintana,1 describes the anti-inflammatory astrocytes,activity of which is tuned by the microbiotome and meningeal natural killer(NK)*** are a sub-type of neuroglia responsible for homoeostasis and defence of the nervous *** reactions of neuroglial cells in various neurological disorders have been identified and characterised in the end of the 19th century;in particular hypertrophy of astrocytes was recognised as a frequent morbid change accompanying diseases of the central nervous system(CNS).

关键词： inflammatory stasis killer

Astrocyte chloride,excitatory-inhibitory balance and epilepsy

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Neural Regeneration Research 2024年第9期19卷 1887-1887页

作者： Verena Untiet Maiken Nedergaard Alexei Verkhratsky Division of Glial Disease and Therapeutics Center for Translational NeuromedicineUniversity of CopenhagenCopenhagenDenmark Division of Glial Disease and Therapeutics Center for Translational NeuromedicineDepartment of NeurosurgeryUniversity of Rochester Medical CenterRochesterNYUSA Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK achucarro Centre for neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain

Excitation and inhibition are at the core of brain function and *** sustain the activity of neuronal networks over time and space,glutamatergic excitation is balanced by GABAergic *** equipoise of excitation and inhibition,known as the excitation/inhibition(E/I)balance,is crucial for proper brain *** E/I balance is highly dynamic and shifts across different brain states:wakefulness primarily augments excitatory activity,while sleep promotes a decrease in excitation and an increase in inhibition(Bridi et al.,2020).Neuronal activity during various brain states is primarily regulated by neurotransmitters(Schiemann et al.,2015),alongside non-synaptic mechanisms that operate on a slower *** non-synaptic mechanisms are many,with the ionic composition of the extracellular space playing a significant role;altering extracellular ion concentrations affects sleep,arousal,electroencephalogram patterns,and behavioral states(Ding et al.,2016).

关键词： epilepsy excitatory excitation