Inflammatory and oxidative mechanisms potentiate bifenthrin-induced neurological alterations and anxiety-like behavior in adult rats
Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations. Thirty-six Wistar rats were thus randomly divided into three groups and were orally administered with BF (0.6 and 2.1 mg/kg body weight, respectively) or the vehicle (corn oil), on a daily basis for 60 days. Results revealed that BF exposure in rats enhanced anxiety-like behavior after 60 days of treatment, as assessed with the elevated plus-maze test by decreases in the percentage of time spent in open arms and frequency of entries into these arms. BF-treated rats also exhibited increased oxidation of lipids and carbonylated proteins in the frontal cortex and striatum, and decreased glutathione levels and antioxidant enzyme activities including superoxide dismutase, catalase and glutathione peroxidase. Treatment with BF also increased protein synthesis and mRNA expression of the inflammatory mediators cyclooxygenase-2 (COX-2), microsomal prostaglandin synthase-1 (mPGES-1) and nuclear factor-kappaBp65 (NF-kBp65), as well as the production of tumor necrosis factor-α (TNF-α) and ROS. Moreover, BF exposure significantly decreased protein synthesis and mRNA expression of nuclear factor erythroid-2 (Nrf2) and acetylcholinesterase (AChE), as well as gene expression of muscarinic-cholinergic receptors (mAchR) and choline acetyltransferase (ChAT) in the frontal cortex and striatum. These data suggest that BF induced neurological alterations in the frontal cortex and striatum of rats, and that this may be associated with neuroinflammation and oxidative stress via the activation of Nrf2/NF-kBp65 pathways, which might promote anxiety-like behavior.
Hydrogen-rich water attenuates oxidative stress in rats with traumatic brain injury via Nrf2 pathway
Several studies have recently found that oxidative stress plays a pivotal role in the pathogenesis of traumatic brain injury (TBI) and may represent a target in TBI treatment. Hydrogen-rich water was recently shown to exert neuroprotective effects in various neurological diseases through its antioxidant properties. However, the mechanisms underlying its effects in TBI are not clearly understood. The purpose of our study was to evaluate the neuroprotective role of hydrogen-rich water in rats with TBI and to elucidate the possible mechanisms underlying its effects.
Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation.
Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs
A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.
Anti-inflammatory Activity of 8-Hydroxydaidzein in LPS-Stimulated BV2 Microglial Cells via Activation of Nrf2-Antioxidant and Attenuation of Akt/NF-κB-Inflammatory Signaling Pathways, as Well As Inhibition of COX-2 Activity
It was demonstrated that isoflavones can cross the blood-brain barrier, making them desirable candidate agents for the prevention of neurological symptoms. 8-Hydroxydaidzein (8-OHD, 4',7,8-trihydoxyisoflavone) is an isoflavone found only in fermented soy food. Current results showed that 8-OHD inhibited LPS-stimulated production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, by inhibiting gene expression in BV2 microglial cells. Moreover, 8-OHD markedly quenched reactive oxygen species (ROS) and activated NF-E2-related factor 2 (Nrf2) so as to upregulate expression of Phase II enzymes, including heme oxygenase (HO)-1, NAD(P)H quinone dehydrogenase 1 (NQO1), and the modifier subunit of glutamate cysteine ligase (GCLM). 8-OHD also suppressed LPS-stimulated phosphorylation of Akt and NF-κB-p65. The anti-inflammatory activity of 8-OHD was attenuated by the HO-1 inhibitor zinc protoporphyrin (Znpp) but augmented by the PI3K/Akt inhibitor LY294002. 8-OHD also diminished LPS-induced prostaglandin E (PGE) production without affecting cyclooxygenase (COX)-2 expression. In vitro assay shows that 8-OHD displayed mixed-type inhibition of COX-2 with an IC of 8.9 ± 1.2 μM. These data suggest that the anti-inflammatory activity of 8-OHD may be associated with the activation of Nrf2/HO-1 and attenuation of Akt/NF-κB signaling pathways as well as inhibition of COX-2 enzyme activity. In conclusion, 8-OHD, a potent Nrf2 activator, Akt/NF-κB activation suppressor, and COX-2 enzyme inhibitor, may have health-promoting effects for mitigating microglia activation and preventing neuroinflammation.
Hispidulin Protects Against Focal Cerebral Ischemia Reperfusion Injury in Rats
Focal cerebral ischemia is associated with ischemia/reperfusion (I/R) injury. Hispidulin is a flavonoid compound with a variety of pharmacological properties. The neuroprotective effects of hispidulin have not been fully elucidated. Herein, we demonstrated that pretreatment of animals with hispidulin improved the neurological outcomes and decreased the infarct size and brain edema in the cerebral focal I/R model. Mechanistically, we showed in vivo and in vitro that hispidulin exerted a protective effect against I/R injury by inducing the Nrf2 antioxidant pathway through modulation of AMPK/GSK3β signaling. Taken together, our results suggest that hispidulin may be a useful neuroprotective agent against ischemia/reperfusion (I/R) injury.
Berberine: Pathways to protect neurons
Berberine, an isoquinoline alkaloid, is demonstrated to have a variety of pharmacologic effects. Widely used as nonprescription drug for diarrhea, berberine has also broadened its applications in therapies of cardiovascular diseases, diabetes mellitus, tumor, and so forth. However, researches about berberine's protective effects on nervous system are still so insufficient that clinical uses cannot popularize and underlying molecules mechanisms are confused and incomplete. Well-known pathways such as Pl3K/Akt/Bcl-2 pathway, Nrf2/HO-1 pathway, and MAPK signaling pathway help berberine to protect neurons through antiapoptotic, antioxidative, and anti-inflammatory activities. New hypotheses have been raised consistently to explore more possible ways of berberine preventing nerves from injuries as attention on its neuroprotective properties is increasing. Therefore, this review is trying to analyze these mechanisms, which actually play roles in neuronal disease models such as brain ischemia, Alzheimer's disease, and experimental autoimmune encephalomyelitis. Much more understanding about how berberine mediates these pathways provides novel insights into the clinical treatment of neurological disorders.
Ulinastatin alleviates neurological deficiencies evoked by transient cerebral ischemia via improving autophagy, Nrf-2-ARE and apoptosis signals in hippocampus
Ulinastatin [or called as urinary trypsin inhibitor (UTI)] plays a role in regulating neurological deficits evoked by transient cerebral ischemia. However, the underlying mechanisms still need to be determined. The present study was to examine the effects of UTI on autophagy, Nrf2-ARE and apoptosis signal pathway in the hippocampus in the process of neurological functions after cerebral ischemia using a rat model of cardiac arrest (CA). CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Western Blot analysis was employed to determine the expression of representative autophagy (namely, Atg5, LC3, Beclin 1), p62 protein (a maker of autophagic flux), and Nrf2-ARE pathways. Neuronal apoptosis was assessed by determining expression levels of Caspase-3 and Caspase-9, and by examining terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL). The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. Our results show that CA amplified autophagy and apoptotic Caspase-3/Caspase-9, and downregulated Nrf2-ARE pathway in the hippocampus CA1 region. Systemic administration of UTI attenuated autophagy and apoptosis, and largely restored Nrf2-ARE signal pathway following cerebral ischemia and thereby alleviated neurological deficits with increasing survival of CA rats. Our data suggest that UTI improves the worsened protein expression of autophagy and apoptosis, and restores Nrf2-ARE signals in the hippocampus and this is linked to inhibition of neurological deficiencies in transient cerebral ischemia. UTI plays a beneficial role in modulating neurological deficits induced by transient cerebral ischemia via central autophagy, apoptosis and Nrf2-ARE mechanisms.
Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway
Fisetin, a natural flavonoid, has neuroprotection properties in many brain injury models. However, its role in traumatic brain injury (TBI) has not been fully explained. In the present study, we aimed to explore the neuroprotective effects of fisetin in a mouse model of TBI. We found that fisetin improved neurological function, reduced cerebral edema, attenuated brain lesion and ameliorated blood-brain barrier (BBB) disruption after TBI. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fisetin treatment. Furthermore, administration of fisetin suppressed neuron cell death and apoptosis, increased the expression of B-cell lymphoma 2 (Bcl-2), while decreased the expression of Bcl-2-associated X protein (Bax) and caspase-3 after TBI. In addition, fisetin activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway following TBI. However, fisetin only failed to suppress oxidative stress in Nrf2 mice. In conclusion, our data provided the first evidence that fisetin played a critical role in neuroprotection after TBI partly through the activation of the Nrf2-ARE pathway.
Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of Nrf2 expression in ovariectomized rats
Postmenopausal women possess higher incidence of stroke and worse prognosis. Although estrogen replacement therapy has obvious neuroprotective effects against stroke, it is always accompanied with several adverse effects and undesired outcomes. Genistein, a natural phytoestrogen, has been indicated to be a potential neuroprotective alternative for postmenopausal women against stroke. However, the role and mechanism of genistein's neuroprotective effects against stroke in ovariectomized rats have rarely been explored.
Ketamine ameliorates oxidative stress-induced apoptosis in experimental traumatic brain injury via the Nrf2 pathway
Ketamine can act as a multifunctional neuroprotective agent by inhibiting oxidative stress, cellular dysfunction, and apoptosis. Although it has been proven to be effective in various neurologic disorders, the mechanism of the treatment of traumatic brain injury (TBI) is not fully understood. The aim of this study was to investigate the neuroprotective function of ketamine in models of TBI and the potential role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in this putative protective effect.
Valproic Acid Attenuates Traumatic Brain Injury-Induced Inflammation : Involvement of Autophagy and the Nrf2/ARE Signaling Pathway
Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element (ARE). ARE is known to associate with the transcription factor NF-E2-related factor 2 (Nrf2), a transcription factor that is associated with histone deacetylases (HDACs). This pathway, known as the Nrf2/ARE pathway, is a critical antioxidative factor pathway that regulates the balance of oxygen free radicals and the inflammatory response, and is also related to autophagic activities. Although valproic acid (VPA) is known to inhibit HDACs, it is unclear whether VPA plays a role in the microglia-mediated neuroinflammatory response after TBI via regulating oxidative stress and autophagy induced by the Nrf2/ARE signaling pathway. In this study, we demonstrate that microglial activation, oxidative stress, autophagy, and the Nrf2/ARE signaling pathway play essential roles in secondary injury following TBI. Treatment with VPA alleviated TBI-induced secondary brain injury, including neurological deficits, cerebral edema, and neuronal apoptosis. Moreover, VPA treatment upregulated the occurrence of autophagy and Nrf2/ARE pathway activity after TBI, and there was an increase in H3, H4 histone acetylation levels, accompanied by decreased transcriptional activity of the HDAC3 promoter in cortical lesions. These results suggest that VPA-mediated up-regulation of autophagy and antioxidative responses are likely due to increased activation of Nrf2/ARE pathway, through direct inhibition of HDAC3. This inhibition further reduces TBI-induced microglial activation and the subsequent inflammatory response, ultimately leading to neuroprotection.
The Phenolic Components of improve Prognosis in Rats after Cerebral Ischemia/Reperfusion by Enhancing the Endogenous Antioxidant Mechanisms
Pharmacological or spontaneous thrombolysis in ischemic stroke triggers an outbreak of reactive oxygen species and results in neuron death. Nrf2-mediated antioxidation in cells has been proved as a pivotal target for neuroprotection. This research reports that phenolic components of Blume (PCGE), a traditional Chinese medicine, can alleviate the pathological lesions in the penumbra and hippocampus by increasing the survival of neurons and astrocytes and improve neurofunction and cognition after reperfusion in a rat model of middle cerebral artery occlusion. LDH assay indicated that pretreatment of cells with PCGE (25 g/ml) for 24 h significantly reduced HO-induced cell death in astrocytes and SH-SY5Y cells. Western blot showed that the nucleus accumulation of Nrf2 and the expression of cellular HO-1 and NQO-1, two of Nrf2 downstream proteins, were increased in both cells. BDNF, an Nrf2-dependent neurotrophic factor, was also upregulated by PCGE in astrocytes. These results illustrated that PCGE can reduce the cerebral ischemia/reperfusion injury and improve prognosis by remedying the cell damage within affected tissues. The protective effects of PCGE seem to be via activation of a Nrf2-mediated cellular defense system. Therefore, PCGE could be a therapeutic candidate for ischemic stroke and other oxidative stress associated neurological disorders.
6'--Galloylpaeoniflorin Attenuates Cerebral Ischemia Reperfusion-Induced Neuroinflammation and Oxidative Stress via PI3K/Akt/Nrf2 Activation
6'--galloylpaeoniflorin (GPF), a galloylated derivative of paeoniflorin isolated from peony root, has been proven to possess antioxidant potential. In this present study, we revealed that GPF treatment exerted significant neuroprotection of PC12 cells following OGD, as evidenced by a reduction of oxidative stress, inflammatory response, cellular injury, and apoptosis in vitro. Furthermore, treatment with GPF increased the levels of phosphorylated Akt (p-Akt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as promoted Nrf2 translocation in PC12 cells, which could be inhibited by Ly294002, an inhibitor of phosphoinositide 3-kinase (PI3K). In addition, Nrf2 knockdown or Ly294002 treatment significantly attenuated the antioxidant, anti-inflammatory, and antiapoptotic activities of GPF . studies indicated that GPF treatment significantly reduced infarct volume and improved neurological deficits in rats subjected to CIRI, as well as decreased oxidative stress, inflammation, and apoptosis, which could be inhibited by administration of Ly294002. In conclusion, these results revealed that GPF possesses neuroprotective effects against oxidative stress, inflammation, and apoptosis after ischemia-reperfusion insult via activation of the PI3K/Akt/Nrf2 pathway.
Apolipoprotein E Deficiency Exacerbates Spinal Cord Injury in Mice: Inflammatory Response and Oxidative Stress Mediated by NF-κB Signaling Pathway
Spinal cord injury (SCI) is a severe neurological trauma that involves complex pathological processes. Inflammatory response and oxidative stress are prevalent during the second injury and can influence the functional recovery of SCI. Specially, Apolipoprotein E (APOE) induces neuronal repair and nerve regeneration, and the deficiency of impairs spinal cord-blood-barrier and reduces functional recovery after SCI. However, the mechanism by which mediates signaling pathways of inflammatory response and oxidative stress in SCI remains largely elusive. This study was designed to investigate the signaling pathways that regulate deficiency-dependent inflammatory response and oxidative stress in the acute stage of SCI. In the present study, mice retarded functional recovery and had a larger lesion size when compared to wild-type mice after SCI. Moreover, deficiency of induced an exaggerated inflammatory response by increasing expression of interleukin-6 (IL-6) and interleukin-1β (IL-1β), and increased oxidative stress by reducing expression of Nrf2 and HO-1. Furthermore, lack of promoted neuronal apoptosis and decreased neuronal numbers in the anterior horn of the spinal cord after SCI. Mechanistically, we found that the absence of increased inflammation and oxidative stress through activation of NF-κB after SCI. In contrast, an inhibitor of nuclear factor-κB (NF-κB; Pyrrolidine dithiocarbamate) alleviates these changes. Collectively, these results indicate that a critical role for activation of NF-κB in regulating -deficiency dependent inflammation and oxidative stress is detrimental to recovery after SCI.