The aim of our study was to investigate the effects of a new synthetic compound (E) -1- (E) -1- (2- hydroxy -5- chlorophenyl) -3- (3, 5, 6- three methyl pyrazine -2- based) -2- propylene -1 ketone, Z-11, a tetramethylpyrazine analogue, on cerebral ischemia reperfusion injury and the underlying mechanism. 240-260 g adult male Wistar rats were subjected to middle cerebral artery occlusion for 2 h, followed by 22 h of reperfusion. Z-11 (1.7, 3.4 and 6.8 mg/kg, i.p.), Edaravone (3 mg/kg, i.p.) and DMSO (1‰, i.p.) was administered at 2 h after the onset of ischemia. The rats' neurological score, infarct volume, and body weight change were tested, and some oxidative stress markers such as superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents were evaluated after 22 h of reperfusion. Results showed that neurologic deficit, infarct volume and body weight change were ameliorated after cerebral ischemia reperfusion, and that Z-11 exhibits an excellent effect at a dosage of 6.8 mg/kg. This dose also reduced the content of MDA, and upregulated SOD activity and GSH content. Similarly, 6.8 mg/kg Z-11 treatment inhibited the reactive oxygen species content and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, with the protein levels of Ras-related C3 botulinum toxin substrate1(Rac-1) and mitogenic oxidase (Nox2) downregulated even further. Moreover, the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase-1 (HO-1) were upregulated. This indicates that Z-11 could play a protective role in cerebral ischemia-reperfusion injury, and that the protective effect of Z-11 may be related to improvements in the antioxidant capacity of brain tissue. The mechanisms are associated with enhancing oxidant defence systems via the activation of Nrf2/HO-1 and Rac-1/NADPH oxidase pathways.

Luteoloside, a flavonoid compound, has been reported to have anti-inflammatory, anti-oxidative, antibacterial, antiviral, anticancer, and cardioprotective effects, among others, but its neuroprotective effects have rarely been studied. The purpose of this study was to investigate the protective effect of luteoloside on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of luteoloside on cerebral ischemia-reperfusion (I/R). Male Sprague-Dawley rats were randomly divided into six groups: sham, MCAO, luteoloside (20 mg/kg, 40 mg/kg, 80 mg/kg) and nimodipine (4 mg/kg). The results showed that luteoloside alleviated neurologic deficits and cerebral edema as well as improved cerebral infarction and histopathological changes in MCAO rats. Luteoloside significantly inhibited I/R-induced neuroinflammation, as demonstrated by reduced levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the brain tissues of MCAO rats. Furthermore, our results demonstrated that luteoloside significantly suppressed the activation of nuclear factor-kappa B (NF-κB) signaling, upregulated the protein expression of peroxisome proliferator activated receptor gamma (PPARγ) and increased NF-E2-related factor (Nrf2) nuclear accumulation in MCAO rats. Collectively, our findings suggested that luteoloside played a crucial neuroprotective role by inhibiting NF-κB signaling in focal cerebral ischemia in rats. Furthermore, PPARγ and Nrf2 were also important for the anti-inflammatory effect of luteoloside. In addition, our data suggested that luteoloside might be an effective treatment for cerebral ischemia and other neurological disorders.

Traumatic spinal cord injury (SCI) is a devastating condition with few efficacious drugs. Sinomenine, a bioactive alkaloid extracted from medicinal herb, has been used as a treatment of rheumatoid diseases. This present study explored the therapeutic effects of sinomenine on locomotor dysfunction and neuropathology in SCI. Our findings revealed that sinomenine mitigated neurological deficits and enhanced neuronal preservation, paralleled with a reduction of apoptosis. Also, sinomenine significantly reduced inflammatory cytokines and oxidative stress factors. We further examined erythroid-2-related factor 2 (Nrf2) nuclear translocation, which mainly controls the coordinated expression of important antioxidant and detoxification genes. An increase in Nrf2 translocation from cytoplasm to nucleus and Nrf2-mediated transactivation was observed after sinomenine administration. Knocking down Nrf2 by siRNA could counteract sinomenine-mediated anti-oxidant stress and anti-inflammation following HO-stimulated and LPS-stimulated PC12 cells. Together, our findings indicated that sinomenine has the potential to be an effective therapeutic agent for SCI by inhibiting inflammation and oxidative stress via Nrf2 activation.

Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. Understanding the mechanism of ischemia/reperfusion (I/R)-induced oxidative stress injury may provide new treatment for ischemic stroke. Kelch-like ECH-associated protein 1 (Keap1)/ NF-E2-related factor 2 (Nrf2)/ antioxidant response elements (ARE) signaling pathway has been considered to be the major cellular defense against oxidative stress. In the present study, our objective is to evaluate the molecular mechanism of miR-34b/Keap1 in modulating focal cerebral I/R induced oxidative injury. miR-34b was predicted to target the 3'-UTR of the rat Keap1. After focal cerebral I/R, miR-34b expression was downregulated in a time-dependent manner; miR-34b overexpression ameliorated I/R-induced oxidative stress injury in middle cerebral artery occlusion (MCAO) rats by reducing the infarction volume, the neurological severity scores, the levels of nitric oxide (NO) and (3-nitrotyrosine) 3-NT while increasing total (superoxide dismutases) SOD and manganese SOD (MnSOD). Through direct targeting, miR-34b could suppress the protein levels of Keap1 and increase the protein levels of Nrf2 and heme oxygenase (HO-1). Regarding the molecular mechanism, Keap1 overexpression exacerbated, while miR-34b improved H2O2-induced oxidative stress injury; the effect of miR-34b could be partially attenuated by Keap1 overexpression, suggesting that miR-34b modulated oxidative stress injury in vitro and in vivo through targeting Keap1. Taken together, we demonstrate that miR-34b protects against focal cerebral I/R-induced oxidative stress injury in MCAO rats and H2O2-induced oxidative stress injury in rat neuroblast B35 cells through targeting Keap1 and downstream Keap1/Nrf2 signaling pathway. We provided a novel mechanism of focal cerebral I/R injury from the perspective of miRNA regulation.

Acute liver failure (ALF) is a distinct clinical syndrome with high mortality and characterized by metabolic derangements, neurological complication, and multiple failures. Flavonoids exert great biological properties on anti-oxidation, anti-inflammation, and anti-apoptosis. After lipopolysaccharide (LPS)/d-galactosamine (d-GalN) administration, five flavonoids inhibited oxidative activities with reducing nitric oxide synthase (iNOS), malondialdehyde (MDA), and improving catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). They reduced the serum levels of alanine and aspartate aminotransferase (ALT, AST) and pro-inflammatory cytokines, prevented the phosphorylation of IKK, IκBα, and NF-κB/p65 in the NF-κB signaling pathway. Additionally five flavonoids inhibited hepatocyte apoptosis through increasing Bcl-2/Bax ratio and suppressing the Caspase family proteins. Chrysin, luteolin, apigenin, hesperetin and 3', 4'-dimethoxy hesperetin have apparently hepato-protective effects against ALF induced by LPS/d-GalN. The study found, the C2C3 double bond at A ring, and the hydroxyl group of C3' or C4' at B ring increased the protective activities, however, the effect of hydroxymethylation at C3' and C4' was reversed. In addition, apigenin has good hepatoprotective effects and potential as a promising therapeutic agent for ALF in clinical application.

Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).

To investigate the effect of tauroursodeoxycholic acid (TUDCA) on neurological impairment induced by acute cerebral infarction (ACI) and its relevant mechanism of action.

Cerebral ischemia-reperfusion is a complicated pathological process. The injury and cascade reactions caused by cerebral ischemia and reperfusion are characterized by high mortality, high recurrence, and high disability. However, only a limited number of antithrombotic drugs, such as recombinant tissue plasminogen activator (r-TPA), aspirin, and heparin, are currently available for ischemic stroke, and its safety concerns is inevitable which associated with reperfusion injury and hemorrhage. Therefore, it is necessary to further explore and examine some potential neuroprotective agents with treatment for cerebral ischemia and reperfusion injury to reduce safety concerns caused by antithrombotic drugs in ischemic stroke. Ginseng Rg1 (G-Rg1) is a saponin composed of natural active ingredients and derived from the roots or stems of and ginseng in traditional Chinese medicine. Its pharmacological effects exert remarkable neurotrophic and neuroprotective effects in the central nervous system. To explore and summarize the protective effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury, we conducted this review, in which we searched the PubMed database to obtain and organize studies concerning the pharmacological effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury. This study provides a valuable reference and clues for the development of new agents to combat ischemic stroke. Our summarized review and analysis show that the pharmacological effects of and mechanisms underlying ginsenoside Rg1 activity against cerebral ischemia and reperfusion injury mainly involve 4 sets of mechanisms: anti-oxidant activity and associated apoptosis via the Akt, Nrf2/HO-1, PPARγ/HO-1, extracellular regulated protein kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) pathways (or mitochondrial apoptosis pathway) and the caspase-3/ROCK1/MLC pathway; anti-inflammatory and immune stimulatory-related activities that involve apoptosis or necrosis via MAPK pathways (the JNK1/2 + ERK1/2 and PPARγ/HO-1 pathways), endoplasmic reticulum stress (ERS), high mobility group protein1 (HMGB1)-induced TLR2/4/9 and receptor for advanced glycation end products (RAGE) pathways, and the activation of NF-κB; neurological cell cycle, proliferation, differentiation, and regeneration via the MAPK pathways (JNK1/2 + ERK1/2, PI3K-Akt/mTOR, PKB/Akt and HIF-1α/VEGF pathways); and energy metabolism and the regulation of cellular ATP levels, the blood-brain barrier and other effects via N-methyl-D-aspartic acid (NMDA) receptors, ERS, and AMP/AMPK-GLUT pathways. Collectively, these mechanisms result in significant neuroprotective effects against cerebral ischemic injury. These findings will be valuable in that they should further promote the development of candidate drugs and provide more information to support the application of previous findings in stroke clinical trials.

BACKGROUND Status epilepticus (SE) is a refractory neurological disease with high mortality and morbidity rates. SE can be induced by numerous factors, including oxidative stress. Catalpol has several biological activities, including regulating the oxidative stress response. However, the role of catapol in SE has not been fully elucidated. MATERIAL AND METHODS Thirty Wistar rats were randomly and equally divided into 3 groups: a control group, an SE group established by LiCl-pilocarpine intraperitoneal injection, and an SE+catalpol group established administering catalpol to SE rats. Epileptic seizure level and after-discharge duration (ADD) were analyzed. Cognitive function was assessed by Morris water maze. Myeloperoxidase (MPO) and superoxide dismutase (SOD) activities were tested. Keap1 and ARE mRNA expressions were detected by real-time PCR. Nrf2 protein expression was determined by Western blot. RESULTS Catalpol significantly decreased epileptic seizure level, extended ADD, and improved cognitive function compared with the SE group (P<0.05). MPO was increased, SOD was reduced, Keap1 mRNA was upregulated, and Nrf2 protein and ARE mRNA were reduced in the SE group compared with the control group (P<0.05). Catalpol markedly decreased MPO, enhanced SOD activity, decreased Keap1 mRNA level, and elevated Nrf2 protein and ARE mRNA expressions compared with the SE group (P<0.05). CONCLUSIONS Catalpol plays an anti-epileptic role and improves cognitive function by regulating the Nrf2-Keap1-ARE signaling pathway to inhibit oxidative stress response.

The neurological disorders and neural pathology brought about by chronic alcoholism are difficult to be reversed. Increasing evidence highlights the protective roles of erythropoietin (EPO) in neurodegenerative diseases and injuries of the central nervous system. In the present study, we investigated the therapeutic effects of EPO on the neurological function deficits and neural pathology caused by chronic alcoholism and the regulatory mechanisms. Using the canonical mouse model of chronic alcohol exposure designed to mimic the repeated cycles of heavy abuse typical of chronic alcoholism, it was found that EPO delivered via intranasal route effectively restored the alcohol‑impaired motor cooperation in rotarod and beam walk tests, reversed alcoholic cognitive and emotional alterations in the novel location recognition task and open‑filed test, and rescued alcohol‑disrupted nervous conduction in the somatosensory‑evoked potential (SSEP) test. Consistently, the intranasally administered EPO promoted the remyelination and synapse formation in chronic alcohol‑affected neocortex and hippocampus as evidenced by immunofluorescence staining and transmission electron microscopy. Additionally, we discovered that the exogenous rhEPO, which entered the cerebrum through intranasal route, activated the erythropoietin receptor (EPOR) and the downstream ERKs and PI3K/AKT signaling, and suppressed autophagy‑related degradation of nuclear factor, erythroid 2‑like 2 (Nrf2). Furthermore, the intranasal EPO‑exerted neuroprotection was almost abolished when the specific Nrf2 antagonist ATRA was administered intraperitoneally prior to intranasal EPO treatment. Collectively, our data demonstrated the repairing potential of EPO for the neurological disorders and neural pathology caused by chronic alcoholism, and identified the Nrf2 activity as the key mechanism mediating the protective effects of EPO.

The present investigation evaluates the protective effect of vorinostat on neuronal cells in the traumatic brain injury (TBI) and also postulates the possible mechanism of its action. Marmarou's weight-drop model was used to induce the TBI. Further, animals were treated with vorinostat 100 mg/kg intraperitoneally 30 min before the TBI induction. Neurological score and brain water content were determined in all the groups and thereafter oxidative stress parameters and adenosine triphosphate (ATP) content were determined in the neuronal tissues of TBI mice. Western blot assay and reverse transcription polymerase chain reaction (RT-PCR) was performed for the determination of the expression of several proteins in the neuronal tissues. Moreover, immunohistochemical staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was also done on the neuronal tissues of TBI mice. Data of the study reveal that treatment with vorinostat significantly reduces the altered level of grip test scores and water content in the brain of traumatic injured mice. Moreover, the altered level of oxidative stress parameters, translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and ATP content was attenuated by treating TBI mice with vorinostat. Also treatment with vorinostat ameliorates the altered expression of p-Akt, NF-B, iNOS and caspase by the western blot assay in the neuronal tissue of TBI mice and mRNA level of HO-1 and NQO-1 significantly enhanced in vorinostat compared to the negative control group. Furthermore, the TUNEL assay also reveals that the apoptosis of neuronal cells was significantly (p < 0.01) reduced in the vorinostat-treated group compared to the negative control group. The present study concludes that vorinostat protects the neuronal injury in TBI mice by reducing the altered level of oxidative stress and inflammatory response.

Many clinical studies have demonstrated that statins, especially simvastatin, can decrease the incidence of Parkinson's disease (PD). However, the specific underlying mechanism remains unclear. This study aimed to investigate how simvastatin affects experimental parkinsonian models via the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated activation of the anti-oxidant system.

Gastrodin (GAS) is a predominant bioactive constituent of the Chinese herbal medicine Tianma ( Blume). Many authors have reported GAS has the beneficial effect on diverse diseases of the CNS, including epilepsy, Alzheimer's disease, Parkinson's disease, and cerebral ischemia. Here, we report GAS exhibited a robust neuroprotective effect in an Sprague-Dawley rat model of stroke (transient middle cerebral artery occlusion, tMCAO), and show that the underlying molecular mechanism involves its protective effect against Zn-toxicity and its anti-oxidative effects in astrocytes. Intraperitoneal administration of GAS (40 mg/kg) after MCAO reduced mean infarct volume to 30.1 ± 5.9% of that of MCAO controls and this neuroprotective effect was accompanied by neurological function recoveries which was measured using modified neurological severity score (mNSS). Interestingly, GAS induced up-regulation and nuclear translocation of Nrf2, and subsequently increased the expressions of anti-oxidative genes, such as, HO-1 and GCLM, in astrocytes. Furthermore, GAS co- or pre-treatment markedly suppressed Zn-induced cell death caused by excessive ROS production and PARP-1 induction. We found that GAS suppressed p67 expression and PAR formation in astrocytes, which might underlie the anti- Zn-toxicity and anti-oxidative effects of GAS in astrocytes. These findings indicate GAS protects astrocytes from Zn-induced toxicity and oxidative stress and these effects contribute to its neuroprotective effects in the postischemic brain.

The aim of this study was to investigate whether uric acid (UA) might exert neuroprotection via activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and regulating neurotrophic factors in the cerebral cortices after transient focal cerebral ischemia/reperfusion (FCI/R) in rats. UA was intravenously injected through the tail vein (16 mg/kg) 30 min after the onset of reperfusion in rats subjected to middle cerebral artery occlusion for 2 h. Neurological deficit score was performed to analyze neurological function at 24 h after reperfusion. Terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling (TUNEL) staining and hematoxylin and eosin (HE) staining were used to detect histological injury of the cerebral cortex. Malondialdehyde (MDA), the carbonyl groups, and 8-hydroxyl-2'-deoxyguanosine (8-OHdG) levels were employed to evaluate oxidative stress. Nrf2 and its downstream antioxidant protein, heme oxygenase- (HO-) 1,were detected by western blot. Nrf2 DNA-binding activity was observed using an ELISA-based measurement. Expressions of BDNF and NGF were analyzed by immunohistochemistry. Our results showed that UA treatment significantly suppressed FCI/R-induced oxidative stress, accompanied by attenuating neuronal damage, which subsequently decreased the infarct volume and neurological deficit. Further, the treatment of UA activated Nrf2 signaling pathway and upregulated BDNF and NGF expression levels. Interestingly, the aforementioned effects of UA were markedly inhibited by administration of brusatol, an inhibitor of Nrf2. Taken together, the antioxidant and neuroprotective effects afforded by UA treatment involved the modulation of Nrf2-mediated oxidative stress and regulation of BDNF and NGF expression levels. Thus, UA treatment could be of interest to prevent FCI/R injury.

Kyung-Ok-Ko (KOK), a traditional multi-herbal medicine, has been widely used in Oriental medicine as a restorative that can enforce vitality of whole organs and as a medicine that can treat age-related symptoms including lack of vigor and weakened immunity. However, the beneficial effect of KOK on neurological diseases such as Parkinson's diseases (PD) is largely unknown. Thus, the objective of this study was to examine the protective effect of KOK on neurotoxicity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pre-treatment with KOK at 1 or 2 g/kg/day (p.o.) showed significant mitigating effects on neurological dysfunction (motor and welfare) based on pole, rotarod, and nest building tests. It also showed effects on survival rate. These positive effects of KOK were related to inhibition of loss of tyrosine hydroxylase-positive neurons, reduction of MitoSOX activity, increased apoptotic cells, microglia activation, and upregulation of inflammatory factors [interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide], and reduced blood-brain barrier (BBB) disruption in the substantia nigra pars compacta (SNpc) and/or striatum after MPTP intoxication. Interestingly, these effects of KOK against MPTP neurotoxicity were associated with inhibition of phosphorylation of mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways along with up-regulation of nuclear factor erythroid 2-related factor 2 pathways in SNpc and/or striatum. Collectively, our findings suggest that KOK might be able to mitigate neurotoxicity in MPTP-induced mouse model of PD via multi-effects, including anti-neuronal and anti-BBB disruption activities through its anti-inflammatory and anti-oxidative activities. Therefore, KOK might have potential for preventing and/or treating PD.