scholarly journals Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection

2019 ◽  
Author(s):  
Fanny Matheis ◽  
Paul A. Muller ◽  
Christina Graves ◽  
Ilana Gabanyi ◽  
Zachary J. Kerner ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Gastrointestinal Symptoms ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Enteric Infection ◽  
Loss Of Function ◽  
Arginase 1 ◽  
Irritable Bowel

SummaryEnteric–associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinalmuscularismacrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational–profiling uncovered a caspase 11–dependent EAN cell–death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain– and loss–of-function experiments indicated that β2-adrenergic receptor (β2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post–infection and point to a role for tissue–resident MMs in limiting neuronal damage.

scholarly journals TNFα-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity?

2004 ◽  
Vol 1 (3) ◽  
pp. 263-273 ◽  
Author(s):  
DMITRI LEONOUDAKIS ◽  
STEVEN P. BRAITHWAITE ◽  
MICHAEL S. BEATTIE ◽  
ERIC C. BEATTIE
Keyword(s):  
Cell Death ◽  
Inflammatory Response ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Types ◽  
Synaptic Function ◽  
Ampar Trafficking ◽  
Novel Target

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

scholarly journals Neurotoxic Effect of Ethanolic Extract of Propolis in the Presence of Copper Ions is Mediated through Enhanced Production of ROS and Stimulation of Caspase-3/7 Activity

Toxins ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 273 ◽  
Author(s):  
Vedrana Radovanović ◽  
Josipa Vlainić ◽  
Nikolina Hanžić ◽  
Petra Ukić ◽  
Nada Oršolić ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ethanolic Extract ◽  
Mitogen Activated Protein Kinase ◽  
Enhanced Production ◽  
Toxicological Studies ◽  
Ethanolic Extract Of Propolis

Elevated amounts of copper are considered to be contributing factor in the progression of neurodegenerative diseases as they promote oxidative stress conditions. The aim of our study was to examine the effects of ethanolic extract of propolis (EEP) against copper-induced neuronal damage. In cultured P19 neuronal cells, EEP exacerbated copper-provoked neuronal cell death by increasing the generation of reactive oxygen species (ROS) and through the activation of caspase-3/7 activity. EEP augmented copper-induced up-regulation of p53 and Bax mRNA expressions. Neurotoxic effects of EEP were accompanied by a strong induction of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression and decrease in the expression of c-fos mRNA. SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK) prevented detrimental effects of EEP, whereas SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), exacerbated EEP-induced neuronal cell death. Quercetin, a polyphenolic nutraceutical, which is usually present in propolis, was also able to exacerbate copper-induced neuronal death. Our data indicates a pro-oxidative and apoptotic mode of EEP action in the presence of excess copper, wherein ROS/p53/p38 interactions play an important role in death cascades. Our study also pointed out that detailed pharmacological and toxicological studies must be carried out for propolis and other dietary supplements in order to fully recognize the potential adverse effects in specific conditions.

scholarly journals Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

2003 ◽  
Vol 23 (10) ◽  
pp. 1117-1128 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Protein Modification ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Animals ◽  
Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

scholarly journals Ischemia-Induced Neuronal Cell Death, Calcium Accumulation, and Glial Response in the Hippocampus of the Mongolian Gerbil and Protection by Propentofylline (HWA 285)

1987 ◽  
Vol 7 (6) ◽  
pp. 745-751 ◽  
Author(s):  
J. DeLeo ◽  
L. Toth ◽  
P. Schubert ◽  
K. Rudolphi ◽  
G. W. Kreutzberg
Keyword(s):  
Cell Death ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Strong Increase ◽  
Mongolian Gerbils ◽  
Nissl Staining ◽  
Calcium Accumulation ◽  
Calcium Loading ◽  
Bilateral Carotid

The localization and timing of cellular calcium loading and glial cell reaction in relation to selective death of hippocampal neurons was studied in Mongolian gerbils following transient forebrain ichemia. Two days after a 5-min period of ischemia, heavy calcium staining was histochemically demonstrated in circumscribed groups of nerve cells, located in the transition zone between the CA1 and CA3 areas. This preceded complete neuronal cell death that was quantitatively assessed by measuring the intensity of Nissl staining. After a 12-min period of ischemia, extensive calcium loading was observed in conjunction with severe neuronal damage throughout the CA1 region as well in the dorsal nuclei of the thalamus. The extent of calcium staining decreased with time and was not seen at stages later than 7 days. Already at 2 days after a 5-min period of ischemia, a strong increase of glial fibrillary acidic protein immunoreactivity was seen. This indicates a marked and early hypertrophy of astrocytes that was not accompanied by an obvious proliferation. Neither the astrocytic response nor the neuronal calcium accumulation were observed in gerbils pretreated with propentofylline, HWA 285 (10 mg/kg, i.p.) 15 min before bilateral carotid artery occlusion. Also, the decrease of Nissl staining in the CA1 area after 5 and 12 min of ischemia was considerably less pronounced and did not significantly differ from sham-operated controls.

scholarly journals The Drosophila Amyloid Precursor Protein homologue mediates neuronal survival and neuro-glial interactions

2020 ◽  
Author(s):  
Irini A. Kessissoglou ◽  
Dominique Langui ◽  
Amr Hasan ◽  
Maral Maral ◽  
Suchetana Bias Dutta ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Transmembrane Protein ◽  
Neuronal Cell Death ◽  
Wnt Signaling Pathway ◽  
Physiological Role ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Precursor Protein ◽  
Loss Of Function

AbstractThe amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease, most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function results in the dysregulation of endolysosomal function, in both neurons and glia, with a notable enlargement of early endosomal compartment in neurons followed by neuronal cell death, the accumulation of dead neurons in the brain during a critical period at a young age and subsequent reduction in lifespan. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL is taken up by glia, regulates their endosomal morphology and this is necessary and sufficient for the clearance of neuronal debris in an axotomy model. We propose that the APP proteins represent a novel family of neuro-glial signaling proteins required for adult brain homeostasis.

Argon treatment alters microglial activation and neuronal cell death after experimental subarachnoid hemorrhage – a randomized controlled animal trial

2019 ◽  
Author(s):  
Benedikt Kremer ◽  
Mark Coburn ◽  
Agnieszka Weinandy ◽  
Kay Nolte ◽  
Hans Clusmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Subarachnoid Hemorrhage ◽  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Control Group ◽  
Cortical Region ◽  
Significant Difference ◽  
Experimental Subarachnoid Hemorrhage

Abstract Background Here, we demonstrate argon´s neuroprotective and immunomodulatory properties after experimental subarachnoid hemorrhage (SAH) examining various localizations (hippocampal and cortical regions) with respect to neuronal damage and microglial activation 6, 24 and 72h after SAH. Methods One hour after SAH (endovascular perforation rat model) or sham surgery, a gas mixture containing 50 vol% argon (argon group) or 50 vol% nitrogen (control group) was applied for 1h. Cerebral coronal sections (H&E; Iba-1 stained) were analyzed for neuronal cell death and microglial activation in predefined anatomical regions. Results Comparing the hippocampal regions 6h after SAH reduced neuronal damage was seen in the argon group (p<0.0001) as well as in the cortical region (p=0.014). Over time the effect diminished: A substantial difference 24h after SAH was only seen for the cortical region (p=0.004). No significant difference was observed 72h after SAH. The hippocampal and overall microglial activation 24h after SAH were significantly reduced in the argon group (p=0.013; p<0.0001), whereas 72h after SAH significance was only detected in the cortical area (p=0.014). Conclusion Argon treatment ameliorated early neuronal damage after SAH. However, inhibition of microglial activation might indicate a beneficial effect with regard to secondary inflammatory.

scholarly journals Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1518
Author(s):  
Danuta Jantas ◽  
Władysław Lasoń
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Antioxidant Systems ◽  
Published Data ◽  
Therapeutic Implications ◽  
Cellular Models

Neurodegenerative diseases are the most frequent chronic, age-associated neurological pathologies having a major impact on the patient’s quality of life. Despite a heavy medical, social and economic burden they pose, no causative treatment is available for these diseases. Among the important pathogenic factors contributing to neuronal loss during neurodegeneration is elevated oxidative stress resulting from a disturbed balance between endogenous prooxidant and antioxidant systems. For many years, it was thought that increased oxidative stress was a cause of neuronal cell death executed via an apoptotic mechanism. However, in recent years it has been postulated that rather programmed necrosis (necroptosis) is the key form of neuronal death in the course of neurodegenerative diseases. Such assumption was supported by biochemical and morphological features of the dying cells as well as by the fact that various necroptosis inhibitors were neuroprotective in cellular and animal models of neurodegenerative diseases. In this review, we discuss the relationship between oxidative stress and RIP1-dependent necroptosis and apoptosis in the context of the pathomechanism of neurodegenerative disorders. Based on the published data mainly from cellular models of neurodegeneration linking oxidative stress and necroptosis, we postulate that administration of multipotential neuroprotectants with antioxidant and antinecroptotic properties may constitute an efficient pharmacotherapeutic strategy for the treatment of neurodegenerative diseases.

scholarly journals The Drosophila amyloid precursor protein homologue mediates neuronal survival and neuroglial interactions

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3000703 ◽  
Author(s):  
Irini A. Kessissoglou ◽  
Dominique Langui ◽  
Amr Hasan ◽  
Maral Maral ◽  
Suchetana B. Dutta ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Transmembrane Protein ◽  
Neuronal Cell Death ◽  
Wnt Signaling Pathway ◽  
Physiological Role ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Precursor Protein ◽  
Loss Of Function

The amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease (fAD), most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway during development. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function (LOF) results in the dysregulation of endolysosomal function in neurons, with a notable enlargement of early endosomal compartments followed by neuronal cell death and the accumulation of dead neurons in the brain during a critical period at a young age. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL interacts with glia and regulates the size of their endosomes, the expression of the Draper engulfment receptor, and the clearance of neuronal debris in an axotomy model. We propose that APP proteins represent a novel family of neuroglial signaling factors required for adult brain homeostasis.

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