Rosmarinic acid elicits neuroprotection in ischemic stroke Nrf2 and heme oxygenase 1 signaling
Cui HY, Zhang XJ, Yang Y, Zhang C, Zhu CH, Miao JY and Chen R
Rosmarinic acid (RA) can elicit a neuroprotective effect against ischemic stroke, but the precise molecular mechanism remains poorly understood. In this study, an experimental ischemic stroke model was established in CD-1 mice (Beijing Vital River Laboratory Animal Technology, Beijing, China) by occluding the right middle cerebral artery for 1 hour and allowing reperfusion for 24 hours. After intraperitoneally injecting model mice with 10, 20, or 40 mg/kg RA, functional neurological deficits were evaluated using modified Longa scores. Subsequently, cerebral infarct volume was measured using TTC staining and ischemic brain tissue was examined for cell apoptosis with TUNEL staining. Superoxide dismutase activity and malondialdehyde levels were measured by spectrophometry. Expression of heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), Bcl-2, Bax, Akt, and phospho-Ser473 Akt proteins in ischemic brain tissue was detected by western blot, while mRNA levels of Nrf2, HO-1, Bcl-2, and Bax were analyzed using real time quantitative PCR. In addition, HO-1 enzyme activity was measured spectrophotometrically. RA (20 and 40 mg/kg) greatly improved neurological function, reduced infarct volume, decreased cell apoptosis, upregulated Bcl-2 protein and mRNA expression, downregulated Bax protein and mRNA expression, increased HO-1 and Nrf2 protein and mRNA expression, increased superoxide dismutase activity, and decreased malondialdehyde levels in ischemic brain tissue of model mice. However, intraperitoneal injection of a HO-1 inhibitor (10 mg/kg zinc protoporphyrin IX) reversed the neuroprotective effects of RA on HO-1 enzyme activity and Bcl-2 and Bax protein expression. The PI3K/Akt signaling pathway inhibitor LY294002 (10 mM) inhibited Akt phosphorylation, as well as Nrf2 and HO-1 expression. Our findings suggest that RA has anti-oxidative and anti-apoptotic properties that protect against ischemic stroke by a mechanism involving upregulation of Nrf2 and HO-1 expression via the PI3K/Akt signaling pathway.
Molecular Mechanisms of Neurotoxicity Induced by Polymyxins and Chemoprevention
Dai C, Xiao X, Li J, Ciccotosto GD, Cappai R, Tang S, Schneider-Futschik EK, Hoyer D, Velkov T and Shen J
Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt, and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.
Corrigendum to "Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway" [Redox Biol. 18 (2018) 158-172]
Xu P, Liu Q, Xie Y, Shi X, Li Y, Peng M, Guo H, Sun R, Li J, Hong Y, Liu X and Xu G
Mitochondrial protective effect of neferine through the modulation of Nrf2 signalling in ischemic stroke
Wu C, Chen J, Yang R, Duan F, Li S and Chen X
Ischemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome the clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limited their clinical effectiveness. Due to the brain particular energy requirements, the energy microenvironment, centred in the mitochondria, is a new research hotspot in the complex pathology of ischemic stroke. Here, we studied the effects of neferine (Nef), a bis-benzylisoquinoline alkaloid extracted from the seed embryo of Nelumbo Nucifera Gaertn, on ischemic stroke and its underlying mitochondrial protective mechanisms.
Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway
Fetoni AR, Zorzi V, Paciello F, Ziraldo G, Peres C, Raspa M, Scavizzi F, Salvatore AM, Crispino G, Tognola G, Gentile G, Spampinato AG, Cuccaro D, Guarnaccia M, Morello G, Van Camp G, Fransen E, Brumat M, Girotto G, Paludetti G, Gasparini P, Cavallaro S and Mammano F
Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2 mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2 mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2 mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.
Diallyl Trisulfide Protects Motor Neurons from the Neurotoxic Protein TDP-43 via Activating Lysosomal Degradation and the Antioxidant Response
Liu C, Leng B, Li Y, Jiang H, Duan W, Guo Y, Li C and Hong K
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease for which only limited effective therapeutics are available. Currently, TAR DNA-binding protein 43 (TDP-43) is recognized as a pathological and biochemical marker for ALS. Increases in the levels of aggregated or mislocalized forms of TDP-43 might result in ALS pathology. Therefore, clearance pathways for intracellular protein aggregates have been suggested as potential therapeutic targets for the treatment of ALS. Here we report that treatment of motor neuron-like NSC34 cells overexpressing TDP-43 with diallyl trisulfide (DATS) induced neuronal autophagy and lysosomal clearance of TDP-43 and C-terminal TDP-43 fragments. We also observed that the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) was accumulated in the nucleus and the expression of the antioxidant enzymes heme oxygenase1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO1) was increased. Consequently, DATS suppressed the increase in the levels of reactive oxygen species induced by TDP-43 expression. This study extends the findings of prior reports indicating that lower doses of DATS mediate cell survival in part by inducing autophagy and activating the Nrf2/antioxidant response element pathway.
East Indian sandalwood ( L.) oil confers neuroprotection and geroprotection in activating SKN-1/Nrf2 signaling pathway
Mohankumar A, Shanmugam G, Kalaiselvi D, Levenson C, Nivitha S, Thiruppathi G and Sundararaj P
East Indian Sandalwood Oil (EISO) has diverse beneficial effects and has been used for thousands of years in traditional folk-medicine for treatment of different human ailments. However, there has been no in-depth scientific investigation to decipher the neuroprotective and geroprotective mechanism of EISO and its principle components, α- and β-santalol. Hence the current study was undertaken to assess the protective effects of EISO, and α- and β-santalol against neurotoxic (6-OHDA/6-hydroxydopamine) and proteotoxic (α-synuclein) stresses in a model. Initially, we found that EISO and its principle components exerted an excellent antioxidant and antiapoptotic activity as it was able to extend the lifespan, and inhibit the ROS generation, and germline cell apoptosis in 6-OHDA-intoxicated . Further, we showed that supplementation of EISO, and α- and β-santalol reduced the 6-OHDA and α-synuclein-induced Parkinson's disease associated pathologies and improved the physiological functions. The genetic and reporter gene expression analysis revealed that an EISO, or α- and β-santalol-mediated protective effect does not appear to rely on DAF-2/DAF-16, but selectively regulates SKN-1 and its downstream targets involved in antioxidant defense and geroprotective processes. Together, our findings indicated that EISO and its principle components are worth exploring further as a candidate redox-based neuroprotectant for the prevention and management of age-related neurological disorders.
Photoreceptor Survival Is Regulated by GSTO1-1 in the Degenerating Retina
Fernando N, Wooff Y, Aggio-Bruce R, Chu-Tan JA, Jiao H, Dietrich C, Rutar M, Rooke M, Menon D, Eells JT, Valter K, Board PG, Provis J and Natoli R
Glutathione-S-transferase omega 1-1 (GSTO1-1) is a cytosolic glutathione transferase enzyme, involved in glutathionylation, toll-like receptor signaling, and calcium channel regulation. GSTO1-1 dysregulation has been implicated in oxidative stress and inflammation, and contributes to the pathogenesis of several diseases and neurological disorders; however, its role in retinal degenerations is unknown. The aim of this study was to investigate the role of GSTO1-1 in modulating oxidative stress and consequent inflammation in the normal and degenerating retina.
Edaravone Reduces Iron-Mediated Hydrocephalus and Behavioral Disorder in Rat by Activating the Nrf2/HO-1 Pathway
Zhang J, Shi X, Chen Z, Geng J, Wang Y, Feng H, Zhu G and Chen Q
Our previous studies have demonstrated that hemorrhage-derived iron has a key role in causing brain injury after intraventricular hemorrhage (IVH). Based on this finding, we hypothesized that edaravone, a free-radical scavenger, has the potential to alleviate hydrocephalus and neurological deficits post-IVH by suppressing iron-induced oxidative stress. Thus, this study aimed to investigate the efficacy of edaravone for rats with FeCl injection, as well as to explore the related molecular mechanism. An experimental model was established in adult male Sprague-Dawley rats via FeCl injection into the right lateral ventricle. Edaravone or vehicle was administered immediately, 1 day and 2 days after intraventricular injection. Brain water content, magnetic resonance imaging, neurological score, oxidative stress assays, Western blot analysis, and electron microscopy were employed to evaluate brain injury in these rats. Intraventricular injection of FeCl induced brain edema, ventricular dilation, and neurobehavioral disorder in rats. Edaravone treatment significantly attenuated the above symptoms, reduced ependymal cilia and neuron damage, and inhibited oxidative stress (elevated levels of an antioxidant, superoxide dismutase; decreased levels of an oxidant, malondialdehyde). Moreover, edaravone administration effectively activated the Nrf2/HO-1 signaling pathway in rat brain following FeCl injection. These results showed that edaravone treatment alleviated brain edema, ventricular expansion, and neurological disorder after FeCl injection. The possible mechanism is by protecting ependymal cilia and neurons from oxidative stress injury and activating the Nrf2/HO-1 signaling pathway. These results provide further experimental evidence for edaravone application in the treatment of IVH.
Melatonin Upregulates Nuclear Factor Erythroid-2 Related Factor 2 (Nrf2) and Mediates Mitophagy to Protect Against Early Brain Injury After Subarachnoid Hemorrhage
Sun B, Yang S, Li S and Hang C
BACKGROUND The aim of this study was to investigate whether melatonin is involved in brain injury following subarachnoid hemorrhage (SAH). MATERIAL AND METHODS An SAH model was established and TUNEL assays were utilized to detect the effect of melatonin on cell apoptosis. Western blot analysis was used to detect the effect of melatonin on expression of autophagic markers and apoptotic factors. Real-time PCR, Western blot analysis, and luciferase assay were performed to study the effect of melatonin on nuclear factor erythroid-2 related factor 2 (NRF2) expression. RESULTS The SAH group displayed a lower neurological score and a higher brain water content, while melatonin treatment increased the neurological score and decreased the brain water content. The administration of melatonin also inhibited the apoptosis of neurons in the brain. In addition, higher Beclin-1 expression and higher conversion ratio from LC3- II to LC3-I were observed in the SAH group. The activation of Beclin-1 and the conversion from LC3-II to LC3-I was further enhanced by melatonin treatment. Furthermore, in the SAH group, the level of Bcl-2 was decreased while the level of Bax and cleaved caspase-3 were increased. However, following melatonin treatment in the SAH group, the level of Bcl-2 was increased while the levels of Bax and cleaved caspase-3 were decreased. CONCLUSIONS Our study indicated that, by increasing the expression of NRF2, the mitophagy induced by melatonin provided protection against brain injury post-SAH.
Hepatic Encephalopathy and Astrocyte Senescence
Görg B, Karababa A and Häussinger D
Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45α. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.
A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase
Sugiyama T, Imai T, Nakamura S, Yamauchi K, Sawada S, Shimazawa M and Hara H
The poor prognosis of intracranial hemorrhage (ICH) is attributed to secondary brain injury (SBI), which is caused by oxidative stress. Blood components induce reactive oxygen species (ROS) over-production and cause cytotoxicity. We focused on the antioxidant system and investigated nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a transcription factor that controls several antioxidant enzymes. We examined the effects of a novel Nrf2 activator, RS9, on SBI after ICH. ICH was induced by injecting autologous blood collected from the jugular vein (25 µL) into the striatum of mice. RS9 was administrated 0, 24, and 48 h after the induction of ICH. Using the ICH model, we measured brain edema, neurological function, and antioxidant proteins expression. We then investigated the mechanisms responsible for the effects of RS9 in vitro using the SH-SY5Y cell line. We used zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, to elucidate the relationship between HO-1 expression and cell death in vitro in a hemin injury model. RS9 decreased brain edema, improved neurological deficits, decreased neuronal damage area and up-regulated HO-1 and superoxide dismutase 1(SOD) expressions in the ICH mouse model. RS9 also suppressed neuronal cell death and ROS over-production in vitro. These protective effects were cancelled by the ZnPP co-treatment. Our results suggest that the activation of Nrf2 by RS9 exerts neuroprotective effects that are mediated by the attenuation of oxidative stress, and also that RS9 is an effective therapeutic candidate for the treatment for SBI after ICH.
Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models
Kerr F, Bjedov I and Sofola-Adesakin O
Lithium has long been used for the treatment of psychiatric disorders, due to its robust beneficial effect as a mood stabilizing drug. Lithium's effectiveness for improving neurological function is therefore well-described, stimulating the investigation of its potential use in several neurodegenerative conditions including Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases. A narrow therapeutic window for these effects, however, has led to concerted efforts to understand the molecular mechanisms of lithium action in the brain, in order to develop more selective treatments that harness its neuroprotective potential whilst limiting contraindications. Animal models have proven pivotal in these studies, with lithium displaying advantageous effects on behavior across species, including worms (), zebrafish (), fruit flies () and rodents. Due to their susceptibility to genetic manipulation, functional genomic analyses in these model organisms have provided evidence for the main molecular determinants of lithium action, including inhibition of inositol monophosphatase (IMPA) and glycogen synthase kinase-3 (GSK-3). Accumulating pre-clinical evidence has indeed provided a basis for research into the therapeutic use of lithium for the treatment of dementia, an area of medical priority due to its increasing global impact and lack of disease-modifying drugs. Although lithium has been extensively described to prevent AD-associated amyloid and tau pathologies, this review article will focus on generic mechanisms by which lithium preserves neuronal function and improves memory in animal models of dementia. Of these, evidence from worms, flies and mice points to GSK-3 as the most robust mediator of lithium's neuro-protective effect, but it's interaction with downstream pathways, including Wnt/β-catenin, CREB/brain-derived neurotrophic factor (BDNF), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and toll-like receptor 4 (TLR4)/nuclear factor-κB (NFκB), have identified multiple targets for development of drugs which harness lithium's neurogenic, cytoprotective, synaptic maintenance, anti-oxidant, anti-inflammatory and protein homeostasis properties, in addition to more potent and selective GSK-3 inhibitors. Lithium, therefore, has advantages as a multi-functional therapy to combat the complex molecular pathology of dementia. Animal studies will be vital, however, for comparative analyses to determine which of these defense mechanisms are most required to slow-down cognitive decline in dementia, and whether combination therapies can synergize systems to exploit lithium's neuro-protective power while avoiding deleterious toxicity.
Xuebijing enhances neuroprotective effects of ulinastatin on transient cerebral ischemia via Nrf2-are signal pathways in the hippocampus
Hu HX, Zhu MQ, Sun YC, Ma C, Wang X and Liu XL
Prior studies have demonstrated that ulinastatin (UTI) plays a beneficial role in regulating cerebral ischemic injury evoked by cardiac arrest (CA). It is noteworthy to find interventions that can enhance effects of this drug and thereby increase its clinical application. Xuebijing (XBJ) is comprised of extracts from Chinese herbs and has been widely used in China as an anti-endotoxicity drug for the treatment of sepsis and ischemic disorders associated with multiple organ dysfunction syndrome. Thus, in this study we examined the effects of a combination of UTI and XBJ to improve neural injury in the process of neurological functions after transient cerebral ischemia. Our results show that CA impaired Nrf2- antioxidant response element (Nrf2-ARE) and superoxide dismutase (SOD) in the hippocampus CA1 region. This process further amplified products of oxidative stress, namely 8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). A lower dose of UTI failed to restore Nrf2-ARE and attenuate 8-iso PGF2α and 8-OHdG SOD following CA; however, systemic administration of XBJ amplified the effects of this dose of UTI on antioxidative signal pathway of the hippocampus. Overall, the results of this study have implications for the enhanced neuroprotective role played by a combination of XBJ and UTI in improving neural injury observed in transient cerebral ischemia; and Nrf2-ARE signal is a part of key mechanisms that are involved in neuroprotective effects of XBJ and UTI.
Olfactory ensheathing cells transplantation attenuates chronic cerebral hypoperfusion induced cognitive dysfunction and brain damages by activating Nrf2/HO-1 signaling pathway
Yu A, Mao L, Zhao F and Sun B
Chronic cerebral hypoperfusion (CCH) has become a crucial factor contributing to neurological disorders and cognitive deficits. Olfactory ensheathing cells (OECs) transplantation has been widely used to repair central nerve systems (CNS) injury, however, whether this intervention has therapeutic effects on CCH-induced cognitive dysfunction and brain damages is still unknown. In this study, we sought to determine the potential therapeutic effects of OECs transplantation on CCH. Two days after the establishment of 2VO rat model, OECs or its medium transplantation were performed via intrastriatal injection. In our study, OECs treatment significantly improved learning and memory in 2VO rats. Transplantation of OECs also significantly reduced brain cell death, neuroinflammation and oxidative stress. Mechanistically, transplantation of OECs increased the expression of nuclear factor-like 2 (Nrf2) and hemeoxygenase 1 (HO-1). Finally, treatment with Brusatol, a Nrf2 inhibitor, markedly abolished the neuroprotective effects of OECs on cognitive decline, oxidative stress, Nrf2 and HO-1 expression. These results demonstrated that OECs transplantation protected CCH-induced cognitive impairment and brain injury by suppressing neuroinflammation and oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of OECs transplantation in CCH.

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