scholarly journals Therapeutic Approach to Neurodegenerative Diseases by Medical Gases: Focusing on Redox Signaling and Related Antioxidant Enzymes

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Kyota Fujita ◽  
Megumi Yamafuji ◽  
Yusaku Nakabeppu ◽  
Mami Noda
Keyword(s):  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Neurodegenerative Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Heme Oxygenase 1 ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Therapeutic Uses

Oxidative stress in the central nervous system is strongly associated with neuronal cell death in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In order to overcome the oxidative damage, there are some protective signaling pathways related to transcriptional upregulation of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD)-1/-2. Their expression is regulated by several transcription factors and/or cofactors like nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α). These antioxidant enzymes are associated with, and in some cases, prevent neuronal death in animal models of neurodegenerative diseases. They are activated by endogenous mediators and phytochemicals, and also by several gases such as carbon monoxide (CO), hydrogen sulphide (H2S), and hydrogen (H2). These might thereby protect the brain from severe oxidative damage and resultant neurodegenerative diseases. In this paper, we discuss how the expression levels of these antioxidant enzymes are regulated. We also introduce recent advances in the therapeutic uses of medical gases against neurodegenerative diseases.

Highlighting the protective or degenerative role of AMPK activators in dementia experimental models

2021 ◽  
Vol 20 ◽  
Author(s):  
Marjan Nikbakhtzadeh ◽  
Fatemeh Shaerzadeh ◽  
Ghorbangol Ashabi
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Atp Synthesis ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Energy Balancing ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR). Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

2020 ◽  
Vol 21 (19) ◽  
pp. 7247
Author(s):  
Jyun-Bin Huang ◽  
Shih-Pin Hsu ◽  
Hsiu-Yung Pan ◽  
Shang-Der Chen ◽  
Shu-Fang Chen ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Protein Kinase ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitogen Activated Protein ◽  
Hippocampal Ca3

Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.

scholarly journals Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1

2011 ◽  
Vol 300 (5) ◽  
pp. F1180-F1192 ◽  
Author(s):  
Qing Qing Wu ◽  
Yanxia Wang ◽  
Martin Senitko ◽  
Colin Meyer ◽  
W. Christian Wigley ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Therapeutic Benefit ◽  
Heme Oxygenase 1 ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peritubular Capillaries ◽  
Protective Genes ◽  
Nrf2 Protein

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.

scholarly journals Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D-Galactose-Induced Aging Mice by Increasing Nrf2 and PGC-1α through the cAMP-CREB Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Yu Wang ◽  
Tianyun Zhang ◽  
Hui Zhao ◽  
Chunxiao Qi ◽  
Xiaoming Ji ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Mitochondrial Biogenesis ◽  
Phosphodiesterase Inhibitor ◽  
Adenosine Monophosphate ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Mitochondrial Ultrastructure ◽  
Peroxisome Proliferator Activated Receptor ◽  
Antioxidant Genes ◽  
Creb Pathway

Aging is a complex phenomenon associated with oxidative stress and mitochondrial dysfunction. The objective of this study was to investigate the potential ameliorative effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on the aging process and its underlying mechanisms. We treated D-galactose- (D-gal-) induced aging mice with PTX and measured the changes in behavior, degree of oxidative damage, and mitochondrial ultrastructure and content as well as the expression of nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant genes and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha- (PGC-1α-) dependent mitochondrial biogenesis genes. The results demonstrated that PTX improved cognitive deficits, reduced oxidative damage, ameliorated abnormal mitochondrial ultrastructure, increased mitochondrial content and Nrf2 activation, and upregulated antioxidant and mitochondrial biogenesis gene expression in the hippocampus of wild-type aging mice. However, the above antiaging effects of PTX were obviously decreased in the brains of Nrf2-deficient D-gal-induced aging mice. Moreover, in hydrogen peroxide-treated SH-SY5Y cells, we found that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and Nrf2/PGC-1α act in a linear way by CREB siRNA transfection. Thus, PTX administration improved the aging-related decline in brain function by enhancing antioxidative capability and promoting mitochondrial biogenesis, which might depend on increasing Nrf2 and PGC-1α by activating the cAMP-CREB pathway.

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

2019 ◽  
Vol 14 (12) ◽  
pp. 1934578X1989668 ◽  
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.

scholarly journals Neuroprotective Effects of Taraxacum officinale Wigg. Extract on Glutamate-Induced Oxidative Stress in HT22 Cells via HO-1/Nrf2 Pathways

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 926 ◽  
Author(s):  
Shan Huang ◽  
Ning Meng ◽  
Zhiming Liu ◽  
Li Guo ◽  
Linsha Dong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Taraxacum Officinale ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Ht22 Cells

Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Taraxacum officinale has been reported to possess antioxidant activities. However, whether it can protect neurons against oxidative damage and the underlying molecular mechanisms have not been fully determined. In the present study, we examined the neuroprotective effects of ethanol extracts of this plant (ETOW) on glutamate-induced oxidative stress in HT22 cells. Both cell viability and reactive oxygen species (ROS) assays showed that ETOW effectively attenuated glutamate-induced cytotoxicity and ROS generation. Furthermore, our results revealed that ETOW increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor-2 (Nrf2). The inhibitory effects of ETOW on glutamate-stimulated cell toxicity and ROS production were partially reversed by tin protoporphyrin (SnPP), an HO activity inhibitor. Taken together, these results demonstrate that ETOW can protect HT22 cells against glutamate-induced oxidative damage by inducing the Nrf2/HO-1 pathways. Our study supports the idea that Taraxacum officinale Wigg. is a promising agent for preventing neurodegenerative diseases.

scholarly journals Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression

2020 ◽  
Author(s):  
Naoki Fujita ◽  
Kana Sase ◽  
Chihiro Tsukahara ◽  
Ibuki Arizono ◽  
Hitoshi Takagi ◽  
...  
Keyword(s):  
Cell Death ◽  
Diabetic Retinopathy ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Oral Intake ◽  
Peroxisome Proliferator ◽  
Retinal Ganglion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apoptotic Effect ◽  
Male Wistar Rats

AbstractExcitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.

scholarly journals Collaborative Power of Nrf2 and PPARγ Activators against Metabolic and Drug-Induced Oxidative Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Choongho Lee
Keyword(s):  
Oxidative Damage ◽  
Mammalian Cells ◽  
Metabolic Disorders ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Oxygen Species ◽  
Defense System ◽  
Drug Induced ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidative Protection

Mammalian cells have evolved a unique strategy to protect themselves against oxidative damage induced by reactive oxygen species (ROS). Especially, two transcription factors, nuclear factor erythroid 2p45-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor γ (PPARγ), have been shown to play key roles in establishing this cellular antioxidative defense system. Recently, several researchers reported ameliorating effects of pharmacological activators for these Nrf2 and PPARγ pathways on the progression of various metabolic disorders and drug-induced organ injuries by oxidative stress. In this review, general features of Nrf2 and PPARγ pathways in the context of oxidative protection will be summarized first. Then, a number of successful applications of natural and synthetic Nrf2 and PPARγ activators to the alleviation of pathological and drug-related oxidative damage will be discussed later.

scholarly journals Methyl lucidone exhibits neuroprotective effects on glutamate-induced oxidative stress in HT-22 cells via Nrf-2/HO-1 signaling

2019 ◽  
Vol 62 (1) ◽  
Author(s):  
Jee-Yun Park ◽  
Khulan Amarsanaa ◽  
Yanji Cui ◽  
Ji-Hyung Lee ◽  
Jinji Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Radical Scavenging Activity ◽  
Neuronal Cell Death ◽  
Radical Scavenging ◽  
Neuronal Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Akt Phosphorylation

Abstract Oxidative stress causes neuronal cell death in various neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease. Therefore, reducing intracellular reactive oxygen species (ROS) has been evaluated as an effective treatment strategy for neurodegenerative disorders. Methyl lucidone (MLC) extracted from Lindera erythrocarpa Makino (Lauraceae) has been previously reported to exhibit microglial-mediated neuroprotective effects via inhibiting neuroinflammation. However, the antioxidant effects of MLC are still unclear. The aim of this study was to determine the neuroprotective mechanism of MLC in HT-22 neurons against oxidative stress induced by glutamate. In results, the pretreatment of MLC significantly enhanced the viability of HT-22 cells under glutamate-induced oxidative conditions, suggesting that MLC has a neuronal mechanism to protect neurons without microglial regulation. Also, the glutamate effect to increase ROS production was effectively blocked by MLC without any free radical scavenging activity. To induce this antioxidant effect, MLC upregulated the expression of heme oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2), known as an intracellular antioxidant enzyme, and its transcription factor. Additionally, Akt phosphorylation regulating Nrf-2 was confirmed to be involved in the neuroprotective signaling activated by MLC. These results indicate that MLC may play a role as an antioxidant agent to inhibit neurodegenerative processes via activating antioxidant signaling pathways that include Nrf-2 and phosphatidylinositol 3-kinase (PI3K).

scholarly journals The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 934
Author(s):  
Woon-Man Kung ◽  
Muh-Shi Lin
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Management Strategies ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Proinflammatory Response ◽  
Pharmacological Management ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iron Sulfur ◽  
Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

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