Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in “Ischemia”—Stressed PC12 Pheochromocytoma Cells

Lahiani, Adi; Brand-Yavin, A.; Yavin, Ephraïm; Lazarovici, Philip

doi:10.3390/brainsci8020032

Cited by 33 publications

(23 citation statements)

References 233 publications

(266 reference statements)

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“…Therefore, further studies need to be conducted to comprehensively elucidate the involvement of Nrf2/ARE pathway by suitable approaches, such as overexpression of Keap1 or transient transfection of Nrf2–small interfering RNA (siRNA) [89]. Since HE-ETH and its constituents were found to induce NGF synthesis and upregulation of MAPK and Akt pathways [30] which were proven elsewhere to be neuroprotective [90,91,92,93], it is worthy to explore whether those pathways are also responsible for the activities of HE-ETH in this study.…”

Section: Discussionmentioning

confidence: 99%

Lion’s Mane Mushroom, Hericium erinaceus (Bull.: Fr.) Pers. Suppresses H2O2-Induced Oxidative Damage and LPS-Induced Inflammation in HT22 Hippocampal Neurons and BV2 Microglia

et al. 2019

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Oxidative stress and inflammation in neuron-glia system are key factors in the pathogenesis of neurodegenerative diseases. As synthetic drugs may cause side effects, natural products have gained recognition for the prevention or management of diseases. In this study, hot water (HE-HWA) and ethanolic (HE-ETH) extracts of the basidiocarps of Hericium erinaceus mushroom were investigated for their neuroprotective and anti-inflammatory activities against hydrogen peroxide (H2O2)-induced neurotoxicity in HT22 mouse hippocampal neurons and lipopolysaccharide (LPS)-induced BV2 microglial activation respectively. HE-ETH showed potent neuroprotective activity by significantly (p < 0.0001) increasing the viability of H2O2-treated neurons. This was accompanied by significant reduction in reactive oxygen species (ROS) (p < 0.05) and improvement of the antioxidant enzyme catalase (CAT) (p < 0.05) and glutathione (GSH) content (p < 0.01). Besides, HE-ETH significantly improved mitochondrial membrane potential (MMP) (p < 0.05) and ATP production (p < 0.0001) while reducing mitochondrial toxicity (p < 0.001), Bcl-2-associated X (Bax) gene expression (p < 0.05) and nuclear apoptosis (p < 0.0001). However, gene expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were unaffected (p > 0.05). HE-ETH also significantly (p < 0.0001) reduced nitric oxide (NO) level in LPS-treated BV2 indicating an anti-inflammatory activity in the microglia. These findings demonstrated HE-ETH maybe a potential neuroprotective and anti-inflammatory agent in neuron-glia environment.

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Section: Discussionmentioning

confidence: 99%

Lion’s Mane Mushroom, Hericium erinaceus (Bull.: Fr.) Pers. Suppresses H2O2-Induced Oxidative Damage and LPS-Induced Inflammation in HT22 Hippocampal Neurons and BV2 Microglia

et al. 2019

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“…Although mesenchymal stem cells are commonly believed to adjust with oxidative stress [4–6], the biggest obstacle to their therapeutic use is their poor survival in ischemic tissue targets after engraftment [7–9]. Therefore, studies focusing on how to protect transplanted BMSCs against oxidative stress-induced apoptosis become a key issue for the success of BMSC transplantation [10]. Pathological levels of ROS generated at the ischemic site of tissue injury have been hypothesized to lead to loss of transplanted BMSCs from this site [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Protective mechanism of artemisinin on rat bone marrow-derived mesenchymal stem cells against apoptosis induced by hydrogen peroxide via activation of c-Raf-Erk1/2-p90rsk-CREB pathway

Fang¹,

Zhao²,

Li³

et al. 2019

Stem Cell Res Ther

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BackgroundBone marrow-derived mesenchymal stem cell (BMSC) transplantation is one of the new therapeutic strategies for treating ischemic brain and heart tissues. However, the poor survival rate of transplanted BMSCs in ischemic tissue, due to high levels of reactive oxygen species (ROS), limits the therapeutic efficacy of this approach. Considering that BMSC survival may greatly enhance the effectiveness of transplantation therapy, development of effective therapeutics capable of mitigating oxidative stress-induced BMSC apoptosis is an important unmet clinical need.MethodsBMSCs were isolated from the 4-week-old male Sprague Dawley rats by whole bone marrow adherent culturing, and the characteristics were verified by morphology, immunophenotype, adipogenic, and osteogenic differentiation potential. BMSCs were pretreated with artemisinin, and H2O2 was used to induce apoptosis. Cell viability was detected by MTT, FACS, LDH, and Hoechst 33342 staining assays. Mitochondrial membrane potential (ΔΨm) was measured by JC-1 assay. The apoptosis was analyzed by Annexin V-FITC/PI and Caspase 3 Activity Assay kits. ROS level was evaluated by using CellROX® Deep Red Reagent. SOD, CAT, and GPx enzymatic activities were assessed separately using Cu/Zn-SOD and Mn-SOD Assay Kit with WST-8, Catalase Assay Kit, and Total Glutathione Peroxidase Assay Kit. The effects of artemisinin on protein expression of BMSCs including p-Erk1/2, t-Erk1/2, p-c-Raf, p-p90rsk, p-CREB, BCL-2, Bax, p-Akt, t-Akt, β-actin, and GAPDH were measured by western blotting.ResultsWe characterized for the first time the protective effect of artemisinin, an anti-malaria drug, using oxidative stress-induced apoptosis in vitro, in rat BMSC cultures. We found that artemisinin, at clinically relevant concentrations, improved BMSC survival by reduction of ROS production, increase of antioxidant enzyme activities including SOD, CAT, and GPx, in correlation with decreased Caspase 3 activation, lactate dehydrogenase (LDH) release and apoptosis, all induced by H2O2. Artemisinin significantly increased extracellular-signal-regulated kinase 1/2 (Erk1/2) phosphorylation, in a concentration- and time-dependent manner. PD98059, the specific inhibitor of the Erk1/2 pathway, blocked Erk1/2 phosphorylation and artemisinin protection. Similarly, decreased expression of Erk1/2 by siRNA attenuated the protective effect of artemisinin. Additionally, when the upstream activator KRAS was knocked down by siRNA, the protective effect of artemisinin was also blocked. These data strongly indicated the involvement of the Erk1/2 pathway. Consistent with this hypothesis, artemisinin increased the phosphorylation of Erk1/2 upstream kinases proto-oncogene c-RAF serine/threonine-protein kinase (c-Raf) and of Erk1/2 downstream targets p90 ribosomal s6 kinase (p90rsk) and cAMP response element binding protein (CREB). In addition, we found that the expression of anti-apoptotic protein B cell lymphoma 2 protein (BcL-2) was also upregulated by artemisinin.ConclusionThese studies demonstrate the proof...

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“…Multiple signaling kinases related to cell survival and proliferation reportedly regulate the nuclear translocation of HO-1. Mitogen-activated protein kinases (MAPKs) are some of the most common signaling pathways, which serve to coordinate the cellular response to a variety of extracellular stimuli [20]. These are well characterized in mammals and include c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK) [21,22].…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

Wang

Zhao

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.

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Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in “Ischemia”—Stressed PC12 Pheochromocytoma Cells

Cited by 33 publications

References 233 publications

Lion’s Mane Mushroom, Hericium erinaceus (Bull.: Fr.) Pers. Suppresses H2O2-Induced Oxidative Damage and LPS-Induced Inflammation in HT22 Hippocampal Neurons and BV2 Microglia

Lion’s Mane Mushroom, Hericium erinaceus (Bull.: Fr.) Pers. Suppresses H2O2-Induced Oxidative Damage and LPS-Induced Inflammation in HT22 Hippocampal Neurons and BV2 Microglia

Protective mechanism of artemisinin on rat bone marrow-derived mesenchymal stem cells against apoptosis induced by hydrogen peroxide via activation of c-Raf-Erk1/2-p90rsk-CREB pathway

Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats

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