Desipramine Protects Neuronal Cell Death and Induces Heme Oxygenase-1 Expression in Mes23.5 Dopaminergic Neurons

(1) Background: A detailed understanding of the pathophysiology of hemorrhagic stroke is still missing. We hypothesized that expression of heme oxygenase-1 (HO-1) in microglia functions as a protective signaling pathway. (2) Methods: Hippocampal HT22 neuronal cells were exposed to heme-containing blood components and cell death was determined. We evaluated HO-1-induction and cytokine release by wildtype compared to tissue-specific HO-1-deficient (LyzM-Cre.Hmox1 fl/fl) primary microglia (PMG). In a study involving 46 patients with subarachnoid hemorrhage (SAH), relative HO-1 mRNA level in the cerebrospinal fluid were correlated with hematoma size and functional outcome. (3) Results: Neuronal cell death was induced by exposure to whole blood and hemoglobin. HO-1 was induced in microglia following blood exposure. Neuronal cells were protected from cell death by microglia cell medium conditioned with blood. This was associated with a HO-1-dependent increase in monocyte chemotactic protein-1 (MCP-1) production. HO-1 mRNA level in the cerebrospinal fluid of SAH-patients correlated positively with hematoma size. High HO-1 mRNA level in relation to hematoma size were associated with improved functional outcome at hospital discharge. (4) Conclusions: Microglial HO-1 induction with endogenous CO production functions as a crucial signaling pathway in blood-induced inflammation, determining microglial MCP-1 production and the extent of neuronal cell death. These results give further insight into the pathophysiology of neuronal damage after SAH and the function of HO-1 in humans.

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Berberine protects 6-hydroxydopamine-induced human dopaminergic neuronal cell death through the induction of heme oxygenase-1

Molecules and Cells ◽

10.1007/s10059-013-2298-5 ◽

2013 ◽

Vol 35 (2) ◽

pp. 151-157 ◽

Cited By ~ 39

Author(s):

Jinbum Bae ◽

Danbi Lee ◽

Yun Kyu Kim ◽

Minchan Gil ◽

Joo-Yong Lee ◽

...

Keyword(s):

Cell Death ◽

Heme Oxygenase ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Heme Oxygenase 1 ◽

Dopaminergic Neuronal Cell ◽

6 Hydroxydopamine

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Acerogenin A from Acer nikoense Maxim Prevents Oxidative Stress-Induced Neuronal Cell Death through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse Hippocampal HT22 Cell Line

Molecules ◽

10.3390/molecules200712545 ◽

2015 ◽

Vol 20 (7) ◽

pp. 12545-12557 ◽

Cited By ~ 14

Author(s):

Dong-Sung Lee ◽

Byung-Yoon Cha ◽

Je-Tae Woo ◽

Youn-Chul Kim ◽

Jun-Hyeog Jang

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cell Line ◽

Heme Oxygenase ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Heme Oxygenase 1 ◽

Ht22 Cell

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Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

Natural Product Communications ◽

10.1177/1934578x19896684 ◽

2019 ◽

Vol 14 (12) ◽

pp. 1934578X1989668 ◽

Cited By ~ 1

Author(s):

Phil Jun Lee ◽

Hye-Jin Park ◽

Hee Min Yoo ◽

Namki Cho

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Er Stress ◽

Heme Oxygenase ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ros Generation ◽

Heme Oxygenase 1 ◽

Ros Scavenging ◽

Neuroprotective Effects

A key pathologic event in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, is endoplasmic reticulum (ER) stress-induced neuronal cell death. ER stress-induced generation of reactive oxygen species (ROS) has been implicated in neurological disease processes. Betulin is one of the major triterpenoids found in Betula platyphylla that possesses several biological properties, including cytoprotective and antioxidative effects. Therefore, we investigated whether betulin could prevent ER stress-induced neurotoxicity in HT-22 hippocampal neuronal cells. We observed that betulin reduced the thapsigargin (TG, an ER stress inducer)-induced apoptosis of HT-22 cells. Moreover, the cytoprotective effects of betulin were comparable to those of tauroursodeoxycholic acid, a potent ER stress-reducing agent. In our study, we confirmed that the ER stress-induced accumulation of ROS plays an important role in HT-22 cell death. Betulin also displayed cytoprotective effects in TG-injured HT-22 cells by reducing ROS generation; these results were comparable to those for N-acetyl-L-cysteine, a known ROS inhibitor. In addition, SnPP, a heme oxygenase-1 (HO-1) inhibitor significantly blocked the cytoprotective effects and ROS scavenging activity of betulin. Based on these results, we believe that betulin-mediated induction of HO-1 may contribute to the neuroprotective effects against ER stress in HT-22 hippocampal cells. We also found that betulin significantly inhibited the TG-induced expression of CHOP and caspase-12. These results demonstrated that betulin could serve as a potential therapeutic agent against ER stress-induced neurodegenerative diseases.

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PEP-1-GLRX1 Reduces Dopaminergic Neuronal Cell Loss by Modulating MAPK and Apoptosis Signaling in Parkinson’s Disease

Molecules ◽

10.3390/molecules26113329 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3329

Author(s):

Yeon Joo Choi ◽

Dae Won Kim ◽

Min Jea Shin ◽

Hyeon Ji Yeo ◽

Eun Ji Yeo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Dopaminergic Neurons ◽

Therapeutic Agent ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cell Loss ◽

Dopaminergic Neuronal Cell ◽

Apoptosis Related Protein

Parkinson’s disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP+-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood–brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP+- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.

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p21 inhibitor UC2288 ameliorates MPTP induced Parkinson’s disease progression through inhibition of oxidative stress and neuroinflammation

10.21203/rs.3.rs-19130/v1 ◽

2020 ◽

Author(s):

Jun Hyung Im ◽

In Jun Yeo ◽

Seong Hee Jeon ◽

Dong Hun Lee ◽

Hyeon Joo Ham ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurodegenerative Disease ◽

Dopaminergic Neurons ◽

Kinase Inhibitor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cultured Neurons ◽

Dopamine Depletion ◽

Erk Kinase

Abstract BackgroundParkinson's disease (PD) is a neurodegenerative disease characterized by the early prominent death of dopaminergic neurons and a decrease of dopamine levels. Dopamine depletion leads to several motor dysfunctions, including resting tremor, muscular rigidity, bradykinesia and postural instability. Our previous study determined that knockout of parkin, a gene of PD degrade p21, suppresses neurogenesis which is critical for a neurodegenerative disease. MethodsThus, we investigated the effect of UC2288, an inhibitor of p21, for its therapeutic effect on PD. We found that UC2288 attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in Rota-rod and Pole test as well as dopamine depletion.ResultsMoreover, UC2288 recovered the number of TH positive cells, but decreased the number of GFAP and Iba-1 positive cells accompanied the decrease of BAX and cleaved caspase3 as well as iNOS and COX-2 expression. In cultured neurons, UC2288 recovered MPP+-induced neuronal cell death in a concentration dependent manner. We also found that UC2288 decreased the p21 reactive cell number, oxidative neuronal damages, cytokines product in vivo and cultured neurons. In a mechanism study, we found that UC2288 significantly decreased the activation of ERK and p38 kinase pathway in the mitogen-activated protein kinase (MAPK) pathway. In addition, 1-10 μM concentration of ERK kinase inhibitor U0126 recovered MPP+-induced neuronal cell death. However, ERK kinase inhibitor U0126 further decreased cell viability with the increase of H2O2.ConclusionThese results indicated that the administration of UC2288 exerted neuroprotective effects on the death of dopaminergic neurons through the suppression of oxidative stress and neuroinflammation via ERK pathway inhibition.

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Hemoglobin and Iron Handling in Brain after Subarachnoid Hemorrhage and the Effect of Deferoxamine on Early Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.137 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1793-1803 ◽

Cited By ~ 95

Author(s):

Jin-Yul Lee ◽

Richard F Keep ◽

Yangdong He ◽

Oren Sagher ◽

Ya Hua ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Subarachnoid Hemorrhage ◽

Neuronal Cell Death ◽

Iron Concentration ◽

Neuronal Cell ◽

Nonheme Iron ◽

Terminal Deoxynucleotidyl Transferase ◽

Tunel Staining ◽

Heme Oxygenase 1

The purpose of this study was to investigate hemoglobin and iron handling after subarachnoid hemorrhage (SAH), examine the relationship between iron and neuroglial cell changes, and determine whether deferoxamine (DFX) can reduce SAH-induced injury. The SAH was induced in Sprague-Dawley rats ( n=110) using an endovascular perforation technique. Animals were treated with DFX (100 mg/kg) or vehicle 2 and 6 hours after SAH induction followed by every 12 hours for 3 days. Rats were killed at 6 hours, Days 1 and 3 to determine nonheme iron and examine iron-handling proteins using Western blot and immunohistochemistry. 8-Hydroxyl-2′-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining were performed to assess oxidative DNA damage and neuronal cell death. After SAH, marked heme-oxygenase-1 (HO-1) upregulation at Day 3 ( P<0.01) was accompanied by elevated nonheme iron ( P<0.01), transferrin (Tf) ( P<0.01), Tf receptor ( P<0.05), and ferritin levels ( P<0.01). Deferoxamine treatment reduced SAH-induced mortality (12% versus 29%, P<0.05), brain nonheme iron concentration, iron-handling protein expression, oxidative stress, and neuronal cell death at Day 3 ( P<0.01) after SAH. These results suggest that iron overload in the acute phase of SAH causes oxidative injury leading to neuronal cell death. Deferoxamine effectively reduced oxidative stress and neuronal cell death, and may be a potential therapeutic agent for SAH.

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The antioxidant Rutin counteracts the pathological impact of α-synuclein on the enteric nervous system in vitro

Biological Chemistry ◽

10.1515/hsz-2021-0259 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Anne Christmann ◽

Manuela Gries ◽

Patrik Scholz ◽

Pascal L. Stahr ◽

Jessica Ka Yan Law ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Dopaminergic Neurons ◽

Synaptic Vesicles ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuroprotective Effects ◽

The Brain ◽

And Oxidative Stress

Abstract Motoric disturbances in Parkinson’s disease (PD) derive from the loss of dopaminergic neurons in the substantia nigra. Intestinal dysfunctions often appear long before manifestation of neuronal symptoms, suggesting a strong correlation between gut and brain in PD. Oxidative stress is a key player in neurodegeneration causing neuronal cell death. Using natural antioxidative flavonoids like Rutin, might provide intervening strategies to improve PD pathogenesis. To explore the potential effects of micro (mRutin) compared to nano Rutin (nRutin) upon the brain and the gut during PD, its neuroprotective effects were assessed using an in vitro PD model. Our results demonstrated that Rutin inhibited the neurotoxicity induced by A53T α-synuclein (Syn) administration by decreasing oxidized lipids and increasing cell viability in both, mesencephalic and enteric cells. For enteric cells, neurite outgrowth, number of synaptic vesicles, and tyrosine hydroxylase positive cells were significantly reduced when treated with Syn. This could be reversed by the addition of Rutin. nRutin revealed a more pronounced result in all experiments. In conclusion, our study shows that Rutin, especially the nanocrystals, are promising natural compounds to protect neurons from cell death and oxidative stress during PD. Early intake of Rutin may provide a realizable option to prevent or slow PD pathogenesis.

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Mechanism of acute endosulfan intoxication-induced neurotoxicity in Sprague-Dawley rats / Mehanizam akutne neurotoksičnosti u Sprague-Dawley štakora izazvane trovanjem endosulfanom

Archives of Industrial Hygiene and Toxicology ◽

10.1515/aiht-2016-67-2702 ◽

2016 ◽

Vol 67 (1) ◽

pp. 9-17 ◽

Cited By ~ 7

Author(s):

Tae-chang Jang ◽

Jung-hee Jang ◽

Kyung-won Lee

Keyword(s):

Cell Death ◽

Molecular Mechanism ◽

Inflammatory Responses ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Heme Oxygenase 1 ◽

Sprague Dawley ◽

Oxidative Damages ◽

Sprague Dawley Rats ◽

Factor Α

Abstract The purpose of this study was to investigate the molecular mechanism underlying oxidative and inflammatory neuronal cell death induced by endosulfan, a pesticide belonging to the chemical family of organochlorines. The cortical and hippocampal tissues derived from Sprague-Dawley (SD) rats treated with endosulfan exhibited increased intracellular accumulation of reactive oxygen species and oxidative damages to cellular macromolecules such as depletion of glutathione, lipid peroxidation, and protein carbonylation. Conversely, the expression of antioxidant enzymes including γ-glutamylcysteine ligase (GCL), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) was markedly reduced in the brain tissues exposed to endosulfan. Moreover, during endosulfan-induced neuronal cell death, mRNA expression of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was elevated, which seemed to be mediated by the activation of nuclear factor-kappa B (NF-κB) by phosphorylation of p65 subunit. These results suggest a new molecular mechanism underlying the endosulfan-induced acute neurotoxicity via induction of oxidative stress and pro-inflammatory responses.

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