The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways

Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects.

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Metformin Protects against Oxidative Stress Injury Induced by Ischemia/Reperfusion via Regulation of the lncRNA-H19/miR-148a-3p/Rock2 Axis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8768327 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 5

Author(s):

Jing Zeng ◽

Long Zhu ◽

Jing Liu ◽

Tao Zhu ◽

Zhaohui Xie ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Luciferase Reporter ◽

Neuroprotective Effects ◽

Stress Injury ◽

Oxidative Stress Injury

Previous studies have shown that metformin not only is a hypoglycemic agent but also has neuroprotective effects. However, the mechanism of action of metformin in ischemic stroke is unclear. Oxidative stress is an important factor in the pathogenesis of cerebral ischemia-reperfusion injury. It has been reported that metformin is associated with stroke risk in the clinical population. This study is aimed at investigating the effect and mechanism of metformin in an experimental model of oxidative stress induced by ischemia/reperfusion (I/R) in vivo and oxygen glucose deprivation/reperfusion (OGD/R) in vitro. Metformin (100, 200, and 300 mg/kg) was administered intraperitoneally immediately after induction of cerebral ischemia. The indicators of oxidative stress selected were antioxidant enzyme activities of catalase, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione peroxidation enzyme (GSHPx). First, we demonstrated that metformin can significantly alleviate acute and chronic cerebral I/R injury and it has a strong regulatory effect on stroke-induced oxidative stress. It can reduce the elevated activities of MDA and NO and increase the levels of GSHPx and SOD in the cerebrum of mice and N2a cells exposed to I/R. Furthermore, real-time PCR and western blot were used to detect the expression of long noncoding RNA H19 (lncRNA-H19), microRNA-148a-3p (miR-148a-3p), and Rho-associated protein kinase 2 (Rock2). The direct interaction of lncRNA-H19, miR-148a-3p, and Rock2 was tested using a dual luciferase reporter assay. lncRNA-H19 altered OGD/R-induced oxidative stress by modulating miR-148a-3p to increase Rock2 expression. The expression of lncRNA-H19 and Rock2 could be downregulated with metformin in vivo and in vitro. In conclusion, our study confirmed that metformin exerts neuroprotective effects by regulating ischemic stroke-induced oxidative stress injury via the lncRNA-H19/miR-148a-3p/Rock2 axis. These results provide new evidence that metformin may represent a potential treatment for stroke-related brain injury.

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A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases

Antioxidants ◽

10.3390/antiox9101019 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1019 ◽

Cited By ~ 1

Author(s):

Nur Zuliani Ramli ◽

Mohamad Fairuz Yahaya ◽

Ikuo Tooyama ◽

Hanafi Ahmad Damanhuri

Keyword(s):

Oxidative Stress ◽

Natural Antioxidants ◽

Green Tea Polyphenols ◽

Food Sources ◽

Gene Expressions ◽

Neuroprotective Effects ◽

Antioxidative Effects

Nutraceuticals have been extensively studied worldwide due to its neuroprotective effects in in vivo and in vitro studies, attributed by the antioxidative properties. Alzheimer (AD) and Parkinson disease (PD) are the two main neurodegenerative disorders that are discussed in this review. Both AD and PD share the similar involvement of oxidative stress in their pathophysiology. Nutraceuticals exert their antioxidative effects via direct scavenging of free radicals, prevent damage to biomolecules, indirectly stimulate the endogenous antioxidative enzymes and gene expressions, inhibit activation of pro-oxidant enzymes, and chelate metals. In addition, nutraceuticals can act as modulators of pro-survival, pro-apoptotic, and inflammatory signaling pathways. They have been shown to be effective particularly in preclinical stages, due to their multiple mechanisms of action in attenuating oxidative stress underlying AD and PD. Natural antioxidants from food sources and natural products such as resveratrol, curcumin, green tea polyphenols, and vitamin E are promising therapeutic agents in oxidative stress-mediated neurodegenerative disease as they have fewer adverse effects, more tolerable, cheaper, and sustainable for long term consumption.

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Brazilian Green Propolis Protects against Retinal Damage In Vitro and In Vivo

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nek005 ◽

2006 ◽

Vol 3 (1) ◽

pp. 71-77 ◽

Cited By ~ 41

Author(s):

Yuta Inokuchi ◽

Masamitsu Shimazawa ◽

Yoshimi Nakajima ◽

Shinsuke Suemori ◽

Satoshi Mishima ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Water Soluble ◽

Retinal Damage ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Brazilian Green Propolis

Propolis, a honeybee product, has gained popularity as a food and alternative medicine. Its constituents have been shown to exert pharmacological (anticancer, antimicrobial and anti-inflammatory) effects. We investigated whether Brazilian green propolis exerts neuroprotective effects in the retinain vitroand/orin vivo.In vitro, retinal damage was induced by 24 h hydrogen peroxide (H2O2) exposure, and cell viability was measured by Hoechst 33342 and YO-PRO-1 staining or by a resazurin–reduction assay. Propolis inhibited the neurotoxicity and apoptosis induced in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus) by 24 h H2O2 exposure. Propolis also inhibited the neurotoxicity induced in RGC-5 cultures by staurosporine. Regarding the possible underlying mechanism, in pig retina homogenates propolis protected against oxidative stress (lipid peroxidation), as also did trolox (water-soluble vitamin E). In micein vivo, propolis (100 mg kg−1; intraperitoneally administered four times) reduced the retinal damage (decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitrealin vivo N-methyl-d-aspartate injection. These findings indicate that Brazilian green propolis has neuroprotective effects against retinal damage bothin vitroandin vivo, and that a propolis-induced inhibition of oxidative stress may be partly responsible for these neuroprotective effects.

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Natural Glycoside Salidroside Ameliorates Orthopedic Surgery-Induced Cognitive Dysfunction Through Activating Adenosine 5‘-Monophosphate-Activated Protein Kinase Signaling in Mice

10.21203/rs.3.rs-745010/v1 ◽

2021 ◽

Author(s):

Cai-Long Pan ◽

Guo-Liang Dai ◽

Hui-Wen Zhang ◽

Chen-Yang Zhang ◽

Qing-Hai Meng ◽

...

Keyword(s):

Cognitive Dysfunction ◽

Orthopedic Surgery ◽

Neurological Diseases ◽

Docking Studies ◽

Morris Water Maze Test ◽

Ampk Pathway ◽

Inflammatory Phenotype ◽

Anti Inflammatory

Abstract Background: Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Salidroside, a plant-derived compound, has gained increased attention as treatment for various neurological diseases and particularly modifier of microglia-mediated neuroinflammation. However, the effect of salidroside on orthopedic surgery-induced cognitive dysfunction and the underlying mechanisms are largely unknown.Methods: The Morris water maze test was used to investigate potential effects of salidroside in the animal model of tibia fracturing with intramedullary fixation. Therapeutic mechanism and related signaling pathways of salidroside in PND were further investigated with animal tissues and microglial cultures in vitro by molecular biology tests.Results: Here we found that salidroside greatly attenuated cognitive impairment in mice after orthopedic surgery. Neuroinflammation in mouse hippocampus were also attenuated by salidroside. Meanwhile, salidroside treatment induced a switch in microglia polarization to the anti-inflammatory phenotype. In vitro, salidroside suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype to the anti-inflammatory phenotype. Mechanically, molecular docking studies revealed potential AMPK activation activity of salidroside. And salidroside did up-regulated the AMPK pathway proteins. Moreover, AMPK antagonist abolished the effects of salidroside in vivo and in vitro.Conclusions: Taken together, our results demonstrated that salidroside effectively suppressed PND by suppressing microglia-mediated neuroinflammation through activating AMPK pathway, and it might be a novel therapeutic approach for PND.

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Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.646729 ◽

2021 ◽

Vol 13 ◽

Author(s):

Jia Sun ◽

Jinzhong Cai ◽

Junhui Chen ◽

Siqiaozhi Li ◽

Xin Liao ◽

...

Keyword(s):

Oxidative Stress ◽

Intracerebral Hemorrhage ◽

Signaling Pathway ◽

Hippocampal Neurons ◽

Neuronal Apoptosis ◽

Neurological Dysfunction ◽

Heme Oxygenase 1 ◽

And Oxidative Stress

As a severe neurological deficit, intracerebral hemorrhage (ICH) is associated with overwhelming mortality. Subsequent oxidative stress and neurological dysfunction are likely to cause secondary brain injury. Therefore, this study sought to define the role of Krüppel-like factor 6 (KLF6) and underlying mechanism in oxidative stress and neurological dysfunction following ICH. An in vivo model of ICH was established in rats by injection of autologous blood, and an in vitro ICH cell model was developed in hippocampal neurons by oxyhemoglobin (OxyHb) exposure. Next, gain- and loss-of-function assays were performed in vivo and in vitro to clarify the effect of KLF6 on neurological dysfunction and oxidative stress in ICH rats and neuronal apoptosis and mitochondrial reactive oxygen species in OxyHb-induced hippocampal neurons. KLF6, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were highly expressed in hippocampal tissues of ICH rats, whereas sirtuin 5 (SIRT5) presented a poor expression. Mechanistically, KLF6 bound to the SIRT5 promoter and transcriptionally repressed SIRT5 to activate the Nrf2/HO-1 signaling pathway. KLF6 silencing alleviated neurological dysfunction and oxidative stress in ICH rats and diminished oxidative stress and neuronal apoptosis in OxyHb-induced neurons, whereas SIRT5 overexpression negated its effect. To sum up, KLF6 silencing elevated SIRT5 expression to inactivate the Nrf2/HO-1 signaling pathway, thus attenuating oxidative stress and neurological dysfunction after ICH.

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Antioxidant Activity In vivo and Ex Vivo of Tautomeric Pair of Polyprenylated Benzophenone - Garcinielliptone FC (Platonia insignis Mart Seeds)

Current Bioactive Compounds ◽

10.2174/1573407214666180914120726 ◽

2020 ◽

Vol 16 (3) ◽

pp. 284-293

Author(s):

George Laylson da Silva Oliveira ◽

Maria das Dores Alves de Oliveira ◽

Maria da Conceição Oliveira Prado ◽

Alexandre de Barros Falcão Ferraz ◽

José Carlos Correia Lima da Silva ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Antioxidant Activity ◽

Oxidative Damage ◽

Ex Vivo ◽

Redox Balance ◽

Oxidative Stress Biomarkers ◽

Iron Citrate

Background: Garcinielliptone FC corresponds to a polyprenylated acylphloroglucinol having a benzophenonic core (diphenylmethanone) substituted with isoprenyl(s) group(s) (3-methyl-2-butenyl) and 2-isopropenyl-hex-5-enyl. Objective: The present work evaluated the antioxidant activity of garcinielliptone FC (GFC) in vitro against non-biological radicals [2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS•+)] and ex vivo against oxidative damage induced by AAPH (2,2'-azobis-2-methylpropionamidine dihydrochloride) and iron/citrate ion in erythrocytes and mitochondria, respectively. Methods: In addition to the protective effect, the main biochemical indexes of oxidative stress, such as lipid peroxidation through the formation of Thiobarbituric Acid Reactive Substances (TBARS), Superoxide Dismutase (SOD), Catalase (CAT) activity and reduced glutathione (GSH) levels. Results: According to the results obtained in erythrocytes, the antioxidant results at concentrations of 0.1, 0.3, 0.7, 1.5 and 3.0 mM were 26.34 ± 0.68, 43.39 ± 2.17, 62.27 ± 2.17, 86.69 ± 0.47 and 92.89 ± 0.45%, respectively, where GFC reduced the rate of oxidative hemolysis when compared to AAPH (p<0.05). The antioxidant activity observed in erythrocytes was also seen in mitochondria in which GFC reduced mitochondrial swelling by increasing the absorbance when compared to iron/citrate ion complex (p<0.05). In both biological models, GFC had an antioxidant effect on erythrocyte and mitochondrial redox balance when analyzing oxidative stress biomarkers, such as reduction of lipid peroxidation and inhibition of depletion in the activity of SOD, CAT and GSH levels. Conclusion: In conclusion, GFC had in vitro and ex vivo antioxidant activity against oxidative damage induced in erythrocytes and mitochondria acting on the erythrocytic and mitochondrial redox balance.

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Overexpression of miR-506-3p Aggravates DBP-Induced Testicular Oxidative Stress in Rats by Downregulating ANXA5 via Nrf2/HO-1 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4640605 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Min Tang ◽

Lei Zhang ◽

Zheng Zhu ◽

Ran Li ◽

Shangqian Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Male Rats ◽

Adolescent Male ◽

Seminiferous Tubules ◽

Stress Injury ◽

Oxidative Stress Injury ◽

Testicular Injury

Background. Di-N-butylphthalate (DBP) is a kind of unique endocrine toxicity linked to hormonal disruptions that affects the male reproductive system and has given rise to more and more attention. However, the mechanism of DBP-induced testicular injury remains unclear. Here, the objective of this study was to investigate the potential molecular mechanism of miR-506-3p in DBP-induced rat testicular oxidative stress injury via ANXA5 (Annexin A5)/Nrf2/HO-1 signaling pathway. Methods. In vivo, a total of 40 adolescent male rats were treated from 2 weeks with 800 mg/kg/day of DBP in 1 mL/kg corn oil administered daily by oral gavage. Among them, some rats were also injected subcutaneously with 2 nmol agomir-506-3p and/or 10 nmol recombinant rat ANXA5. The pathomorphological changes of testicular tissue were assessed by histological examination, and the antioxidant factors were evaluated. Subsequently, ANXA5, Nrf2, and its dependent antioxidant enzymes, such as HO-1, NQO1, and GST, were detected by Western blotting or immunohistochemical staining. In vitro, TM3 cells (Leydig cells) were used to detect the cell activity by CCK-8 and the transfection in the DBP-treated group. Results. Differentially expressed miRNAs between the DBP-treated and normal rats were analyzed, and qRT-PCR showed miR-506-3p was highly expressed in testicular tissues of the DBP-treated rats. DBP-treated rats presented severe inflammatory infiltration, increased abnormal germ cells, and missed cell layers frequently existed in seminiferous tubules, resulted in oxidative stress and decreased testicular function. Meanwhile, upregulation of miR-506-3p aggravated the above changes. In addition, miR-506-3p directly bound to ANXA5, and overexpression of miR-506-3p could reduce the ANXA5 expression and also decrease the protein levels of Nrf2/HO-1 signaling pathway. Additionally, we found that recombinant rat ANXA5 reversed the DBP-treated testicular oxidative stress promoting injury of miR-506-3p in rats. In vivo results were reproduced in in vitro experiments. Conclusions. This study provided evidence that miR-506-3p could aggravate the DBP-treated testicular oxidative stress injury in vivo and in vitro by inhibiting ANXA5 expression and downregulating Nrf2/HO-1 signaling pathway, which might provide novel understanding in DBP-induced testicular injury therapy.

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TRPV1 Antagonist Prevents Neonatal Sevoflurane-Induced Synaptic Abnormality and Cognitive Impairment in Mice Through Regulating the Src/Cofilin Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.684516 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuqiang Liu ◽

Han Yang ◽

Yifei Fu ◽

Zhenglong Pan ◽

Fang Qiu ◽

...

Keyword(s):

Cognitive Dysfunction ◽

Hippocampal Neurons ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Newborn Mice ◽

Trpv1 Channels ◽

Trpv1 Antagonist

Long-term neurodevelopmental disorders following neonatal anesthesia have been reported both in young animals and in children. The activation of transient receptor potential vanilloid 1 (TRPV1) channels in hippocampus adversely affects neurodevelopment. The current study explored the underlying mechanism of TRPV1 channels on long-lasting cognitive dysfunction induced by anesthetic exposure to the developing brain. we demonstrated that TRPV1 expression was increased after sevoflurane exposure both in vitro and in vivo. Sevoflurane exposure to hippocampal neurons decreased the synaptic density and the surface GluA1 expression, as well as increased co-localization of internalized AMPAR in early and recycling endosomes. Sevoflurane exposure to newborn mice impaired learning and memory in adulthood, and reduced AMPAR subunit GluA1, 2 and 3 expressions in the crude synaptosomal fractions from mouse hippocampus. The inhibition of TRPV1 reversed the phenotypic changes induced by sevoflurane. Moreover, sevoflurane exposure increased Src phosphorylation at tyrosine 416 site thereby reducing cofilin phosphorylation. TRPV1 blockade reversed these suppressive effects of sevoflurane. Our data suggested that TRPV1 antagonist may protect against synaptic damage and cognitive dysfunction induced by sevoflurane exposure during the brain developing stage.

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The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy

Science Translational Medicine ◽

10.1126/scitranslmed.abc0555 ◽

2021 ◽

Vol 13 (596) ◽

pp. eabc0555

Author(s):

Laura Rodríguez-Pascau ◽

Anna Vilalta ◽

Marc Cerrada ◽

Estefania Traver ◽

Sonja Forss-Petter ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Molecular Mechanisms ◽

Phase 1 ◽

Clinical Manifestations ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Pparγ Agonist

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5′-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid–induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte–derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.

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