Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling DOI
Prajwal Raghunatha, Amir R. Vosoughi, Tiina M. Kauppinen

и другие.

Glia, Год журнала: 2020, Номер 68(7), С. 1421 - 1434

Опубликована: Фев. 8, 2020

Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist recovery and repair, prolonged microglial pro-inflammatory responses are known to exacerbate processes. Yet, detrimental outcomes of extended activation counterbalanced beneficial including phagocytosis release trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) key signaling hub driving responses, but pathway maintaining PARP-1 remains elusive. best understood for its role in DNA our group activity be stimulated via Ca2+ influx-dependent ERK1/2-mediated phosphorylation. However, date, route entry responsible stimulating not been identified. A likely candidate -permeable transient receptor potential melastatin 2 (TRPM2) channels activated downstream cascade involves ADP-ribose (ADPR) production glycohydrolase (PARG). Here we demonstrate NMDA (NMDAR) stimulation primary cultured induces their proliferation, morphological mediators. These were contingent on recruitment PARP-1, PARG permeable TRPM2 channels. Furthermore, show influx necessary activate PARP-1/TRPM2 signaling, an ERK1/2-dependent, damage independent, manner. findings, showing mediate effects NMDAR stimulation, provides unifying mechanism linking elevated glutamate levels chronic neuroinflammation.

Язык: Английский

Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert DOI Creative Commons
Andreas Reiner, Joshua Levitz

Neuron, Год журнала: 2018, Номер 98(6), С. 1080 - 1098

Опубликована: Июнь 1, 2018

Язык: Английский

Процитировано

500
Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions DOI Creative Commons
Chuan Qin, Sheng Yang,

Yun‐Hui Chu

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 6, 2022

Abstract Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and one of the leading causes death disability worldwide. Thus, it great necessity to further detailly elucidate mechanisms ischemic find out new therapies against disease. In recent years, efforts have been made understand pathophysiology stroke, including cellular excitotoxicity, oxidative stress, cell processes, neuroinflammation. meantime, a plethora signaling pathways, either detrimental or neuroprotective, are also highly involved forementioned pathophysiology. These pathways closely intertwined form complex network. Also, these reveal therapeutic potential, as targeting could possibly serve approaches stroke. this review, we describe categorize them based on pathophysiological processes they participate in. Therapeutic associated with mentioned above, discussed. Meanwhile, clinical trials regarding potentially target involved, summarized details. Conclusively, review elucidated potential molecular related underlying summarize targeted various pathophysiology, particular reference future prospects for treating

Язык: Английский

Процитировано

442
Synaptic proximity enables NMDAR signalling to promote brain metastasis DOI
Qiqun Zeng, Iacovos P. Michael, Peng Zhang

и другие.

Nature, Год журнала: 2019, Номер 573(7775), С. 526 - 531

Опубликована: Сен. 18, 2019

Язык: Английский

Процитировано

415
Targeting NMDA receptors in stroke: new hope in neuroprotection DOI Creative Commons

Qiu Jing Wu,

Michael Tymianski

Molecular Brain, Год журнала: 2018, Номер 11(1)

Опубликована: Март 13, 2018

NMDA (N-methyl-d-aspartate) receptors (NMDARs) play a central role in excitotoxic neuronal death caused by ischemic stroke, but NMDAR channel blockers have failed to be translated into clinical stroke treatments. However, recent research on NMDAR-associated signaling complexes has identified important death-signaling pathways linked NMDARs. This led the generation of inhibitors that inhibit these downstream from receptor without necessarily blocking therapeutic approach may fewer side effects and/or provide wider window for as compared antagonists. In this review, we highlight key findings cascades NMDARs and novel promising therapeutics stroke.

Язык: Английский

Процитировано

280
Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications DOI Open Access
Luc Leybaert, Paul D. Lampe, Stefan Dhein

и другие.

Pharmacological Reviews, Год журнала: 2017, Номер 69(4), С. 396 - 478

Опубликована: Сен. 20, 2017

Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and intercellular gap junction channels directly connect cells. In the heart, electrically myocytes specialized conductive tissues to coordinate atrial ventricular contraction/relaxation cycles pump function. blood vessels, these facilitate long-distance endothelial cell communication, synchronize smooth muscle contraction, support endothelial-smooth communication. central nervous system they form cellular syncytia neural Gap normally open closed, but pathologic conditions may restrict communication promote hemichannel opening, thereby disturbing a delicate balance. Until recently, most connexin-targeting agents exhibited little specificity several off-target effects. Recent work with peptide-based approaches has demonstrated improved opened avenues for more rational approach toward independently modulating function of junctions hemichannels. We here review role connexins their in cardiovascular neurovascular health disease, focusing on crucial regulatory aspects identification potential targets modify conclude investigations have raised new opportunities interfering soon allow preservation inhibition mitigation inflammatory signaling.

Язык: Английский

Процитировано

229
ATP Release Channels DOI Open Access
Akiyuki Taruno

International Journal of Molecular Sciences, Год журнала: 2018, Номер 19(3), С. 808 - 808

Опубликована: Март 11, 2018

Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms cellular ATP release have demonstrated in many cell types. Although large negatively charged molecules cannot diffuse across lipid bilayer plasma membrane, conductive from cytosol into space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for permeation: anion permeability a ion-conducting pore. Currently, five groups are acknowledged ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated (VRACs, also known volume-sensitive outwardly rectifying (VSOR) channels), maxi-anion (MACs). Recently, major breakthroughs made field by molecular identification CALHM1 action potential-dependent channel taste bud cells, LRRC8s components VRACs, SLCO2A1 core subunit MACs. Here, function roles these summarized, along discussion on future implications understanding

Язык: Английский

Процитировано

175
Excitotoxicity: Still Hammering the Ischemic Brain in 2020 DOI Creative Commons
Dennis W. Choi

Frontiers in Neuroscience, Год журнала: 2020, Номер 14

Опубликована: Окт. 26, 2020

Interest in excitotoxicity expanded following its implication the pathogenesis of ischemic brain injury 1980s, but waned subsequent to failure N-methyl-D-aspartate (NMDA) antagonists high profile clinical stroke trials. Nonetheless there has been steady progress elucidating underlying mechanism. This review will outline historical path current understandings brain, and suggest that this knowledge should be leveraged now develop neuroprotective treatments for stroke.

Язык: Английский

Процитировано

156
Structures of human pannexin 1 reveal ion pathways and mechanism of gating DOI
Zheng Ruan,

Ian J. Orozco,

Juan Du

и другие.

Nature, Год журнала: 2020, Номер 584(7822), С. 646 - 651

Опубликована: Июнь 3, 2020

Язык: Английский

Процитировано

153
Molecular mechanisms of ischemia and glutamate excitotoxicity DOI Creative Commons
Diogo Neves, Ivan L. Salazar, Ramiro D. Almeida

и другие.

Life Sciences, Год журнала: 2023, Номер 328, С. 121814 - 121814

Опубликована: Май 25, 2023

Excitotoxicity is classically defined as the neuronal damage caused by excessive release of glutamate, and subsequent activation excitatory plasma membrane receptors. In mammalian brain, this phenomenon mainly driven glutamate receptors (GRs). common to several chronic disorders Central Nervous System (CNS) considered primary mechanism loss function cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms pathways lead excitotoxic including pro-death signaling cascade events downstream receptors, calcium (Ca2+) overload, oxidative stress, mitochondrial impairment, synaptic cleft well altered energy metabolism. Here, we review current knowledge on molecular that underlie excitotoxicity, emphasizing role Nicotinamide Adenine Dinucleotide (NAD) We also discuss novel promising therapeutic strategies treat highlighting recent clinical trials. Finally, will shed light ongoing search for stroke biomarkers, an exciting field research, which may improve diagnosis, prognosis allow better treatment options.

Язык: Английский

Процитировано

82
Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets DOI Creative Commons
Yan Zhang, Suliman Khan, Yang Liu

и другие.

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Март 9, 2022

Intracerebral hemorrhage (ICH) is a highly fatal disease with mortality rate of approximately 50%. Oxidative stress (OS) prominent cause brain injury in ICH. Important sources reactive oxygen species after are mitochondria dysfunction, degradated products erythrocytes, excitotoxic glutamate, activated microglia and infiltrated neutrophils. OS harms the central nervous system ICH mainly through impacting inflammation, killing cells exacerbating damage blood barrier. This review discusses possible molecular mechanisms producing ICH, anti-OS strategies to ameliorate devastation

Язык: Английский

Процитировано

80