Di-(2-ethylhexyl) phthalate (DEHP) in the environment and food chain may impact cerebrum development and neurobehavioral in humans and wildlife. However, it is unclear that DEHP exposure caused cerebral toxicity. This experiment used gavage to expose female quail to 0, 250, 500, and 1000 mg/kg BW/day for 45 days to assess the potential neurotoxicity of DEHP to the cerebrum. It can be observed that there will be obvious neurological abnormalities in the experiment. Cerebrum histological lesions can be observed with HE-staining. Detecting oxidative stress indices, Nrf2 pathway, and mitochondrial dynamics factor, by analyzing the results, these results were observed that DEHP exposure can cause damage to the cerebrum by causing oxidative stress and affecting the balance of mitochondrial dynamics. Nrf2-mediated defense is not activated by exposure to 250 mg/kg DEHP. Nrf2-mediated defense is activated but is not resistant to exposure to medium and high doses of DEHP (500 mg/kg; 1000 mg/kg). DEHP triggers cerebral mitochondrial dysfunction via modulating mitochondrial dynamics.

Autism is a neurodevelopmental disease which is characterized by its core behavioral symptoms such as impairment in social interaction and stereotyped repetitive behavior. Th17 immune responses and oxidative stress are reported to be elevated in both human autistic subjects and BTBR T + Itpr3tf/J (BTBR) mice. On the other hand, activation of nuclear factor erythroid 2 related factor (Nrf2), a master transcription factor is essential for the management of anti-inflammatory and antioxidant genes. Sulforaphane activates Nrf2 and thus is considered a potential approach to treat several neurological disorders including autism. In the current work, we used sulforaphane in asocial BTBR mice and its social counterpart C57/BL6 (C57) mice to assess its therapeutic potential and molecular mechanisms (Th17 immune responses, and oxidant-antioxidant balance) through which it acts. Our results demonstrate that BTBR treated with sulforaphane had reduced self-grooming/marble burying behavior, and increased social interaction in three chambered sociability test as compared to untreated BTBR mice. Further, sulforaphane-treated BTBR mice had reduced Th17 immune responses (STAT3, RORC, IL-17 A and IL-23R expression in CD4 + T cells), oxidative stress parameters in neutrophils/cerebellum (NFkB, iNOS, and lipid peroxides). Furthermore, sulforaphane-treated BTBR and C57 mice had upregulated enzymatic antioxidant defenses in neutrophils/cerebellum (SOD, GPx and GR expression and activity). We reason that activation of Nrf2 by sulforaphane corrected Th17 immune dysfunction and oxidant-antioxidant imbalance in periphery and brain in BTBR mice. These mechanisms lead to improvement in autism-like symptoms in BTBR mice.

Cobalt nanoparticles (CoNPs) have been widely used in industry given their physical, chemical and magnetic properties; however, CoNPs may cause neurological symptoms and diseases in human, yet their mechanisms of toxicity remain unknown. Here, we used male Wistar rats to investigate differences in the toxic effects associated with CoNPs and CoCl. Upon exposure to CoCl, and 96 nm or 123 nm CoNPs at the same concentration, the Co content in CoCl group was significantly higher than that in either the CoNPs groups in brain tissues and blood, but lower in liver. Significant neural damage was observed in both hippocampus and cortex of the temporal lobe. Increase malondialdehyde (MDA) content and CASPASE 9 protein level were associated both with CoCl and CoNPs treatments, consistent with lipid perioxidation and apoptosis. Heme oxygenase-1 and (NF-E2) p45-related factor-2 protein levels were elevated in response to 96 nm CoNPs exposure. In PC12 cells, NRF2 downregulation led to reduced cell viability and increased apoptotic rate. In conclusion, both CoNPs and CoCl cause adverse neural effects, with nanoparticles showing greater neurotoxic potency. In addition, NRF2 protects neural cells from damage induced by CoCl and CoNPs by activating downstream antioxidant responses.

Background and Purpose- Mitoquinone has been reported as a mitochondria-targeting antioxidant to promote mitophagy in various chronic diseases. Here, our aim was to study the role of mitoquinone in mitophagy activation and oxidative stress-induced neuronal death reduction after subarachnoid hemorrhage (SAH) in rats. Methods- Endovascular perforation was used for SAH model of male Sprague-Dawley rats. Exogenous mitoquinone was injected intraperitoneally 1 hour after SAH. ML385, an inhibitor of Nrf2 (nuclear factor-E2-related factor 2), was given intracerebroventricularly 24 hours before SAH. Small interfering RNA for PHB2 (prohibitin 2) was injected intracerebroventricularly 48 hours before SAH. Nuclear, mitochondrial, and cytoplasmic fractions were gathered using nucleus and mitochondria isolation kits. SAH grade evaluation, short- and long- term neurological function tests, oxidative stress, and apoptosis measurements were performed. Pathway related proteins were investigated with Western blot and immunofluorescence staining. Results- Expression of Keap1 (Kelch-like epichlorohydrin-associated protein 1, 2.84× at 24 hours), Nrf2 (2.78× at 3 hours), and LC3II (light chain 3-II; 1.94× at 24 hours) increased, whereas PHB2 (0.46× at 24 hours) decreased after SAH compared with sham group. Mitoquinone treatment attenuated oxidative stress and neuronal death, both short-term and long-term. Administration of mitoquinone resulted in a decrease in expression of Keap1 (0.33×), Romo1 (reactive oxygen species modulator 1; 0.24×), Bax (B-cell lymphoma-2 associated X protein; 0.31×), Cleaved Caspase-3 (0.29×) and an increase in Nrf2 (2.13×), Bcl-xl (B-cell lymphoma-extra large; 1.67×), PINK1 (phosphatase and tensin-induced kinase 1; 1.67×), Parkin (1.49×), PHB2 (1.60×), and LC3II (1.67×) proteins compared with SAH+vehicle group. ML385 abolished the treatment effects of mitoquinone on behavior and protein levels. PHB2 small interfering RNA reversed the outcomes of mitoquinone administration through reduction in protein expressions downstream of PHB2. Conclusions- Mitoquinone inhibited oxidative stress-related neuronal death by activating mitophagy via Keap1/Nrf2/PHB2 pathway after SAH. Mitoquinone may serve as a potential treatment to relieve brain injury after SAH.

Alpha lipoic acid (ALA) is a powerful antioxidant which has been widely used in the treatment of different system diseases, such as cardiovascular and cerebrovascular diseases. But, there are few studies that refer to protective effects and potential mechanisms on traumatic brain injury (TBI). This study was carried out to investigate the neuroprotective effect following TBI and illuminate the underlying mechanism. Weight drop-injured model in rats was induced by weight-drop. ALA was administrated via intraperitoneal injection after TBI. Neurologic scores were examined following several tests. Neurological score was performed to measure behavioural outcomes. Nissl staining and TUNEL were performed to evaluate the neuronal apoptosis. Western blotting was engaged to analyse the protein content of the Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein factors, including hemeoxygenase-1 (HO-1) and quinine oxidoreductase-1 (NQO1). ALA treatment alleviated TBI-induced neuron cell apoptosis and improved neurobehavioural function by up-regulation of Nrf2 expression and its downstream protein factors after TBI. This study presents new perspective of the mechanisms responsible for the neuronal apoptosis of ALA, with possible involvement of Nrf2 pathway.

Epilepsy is a neurological disorder of the central nervous system characterized by hypersynchronized neuronal activity and has been associated with oxidative stress. Oxidative stress interferes with the expression of genes as well as transcriptional factors such as nuclear factor-erythroid 2-related factor 2 (Nrf2). We evaluated the expression of Nrf2 in the rat brain in treated with kainic acid (KA) and pentylenetetrazole (PTZ). Nrf2 immunoreactivity was observed in astrocytes of the hippocampal region in rats exposed at KA. Nrf2 expression was increased significantly in rats with KA and PTZ. These results provide evidence that the increased expression of Nrf2 is part of the mechanism against KA and PTZ toxicity.

Gintonin (GT), a ginseng-derived lysophosphatidic acid receptor ligand, regulates various cellular effects and represses inflammation. However, little is known about the potential value of GT regarding inflammation in the neurodegenerative diseases, such as Huntington's disease (HD). In this study, we investigated whether GT could ameliorate the neurological impairment and striatal toxicity in cellular or animal model of HD. Pre-, co-, and onset-treatment with GT (25, 50, or 100 mg/kg/day, p.o.) alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid (3-NPA). Pretreatment with GT also attenuated mitochondrial dysfunction i.e. succinate dehydrogenase and MitoSOX activities, apoptosis, microglial activation, and mRNA expression of inflammatory mediators i.e. IL-1β, IL-6, TNF-α, COX-2, and iNOS in the striatum after 3-NPA-intoxication. Its action mechanism was associated with lysophosphatidic acid receptors (LPARs) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activations and the inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. These beneficial effects of GT were neutralized by pre-inhibiting LPARs with Ki16425 (a LPAR1/3 antagonist). Interestingly, GT reduced cell death and mutant huntingtin (HTT) aggregates in STHdh cells. It also mitigated neurological impairment in mice with adeno-associated viral (AAV) vector serotype DJ-mediated overexpression of N171-82Q-mutant HTT in the striatum. Taken together, our findings firstly suggested that GT has beneficial effects with a wide therapeutic time-window in 3-NPA-induced striatal toxicity by antioxidant and anti-inflammatory activities through LPA. In addition, GT exerts neuroprotective effects in STHdh cells and AAV vector-infected model of HD. Thus GT might be an innovative therapeutic candidate to treat HD-like syndromes.

6"-O-succinylapigenin [apigenin-7-O-(6''-O-succinyl)-glucoside], a novel compound, is identified in chamomile. Although it is highly produced by Bacillus amyloliquefaciens FJ18, its bioactivity remains unknown. The neuroprotective effects and antioxidative mechanism of 6''-O-succcinylapigenin in the middle cerebral artery occlusion model in male rats was investigated in this study. The structure of this compound was determined by spectroscopic data analysis. After 2h of occlusion and 24h of reperfusion, magnetic resonance imaging and assessed neurological scores following middle cerebral artery occlusion (MCAO) in male rats to determine the infarction size and neurological deficits, respectively. In addition, we tested protein levels of the nuclear factor E2-related factor 2 (Nrf2), Kelch-like ECH-associated protein1 (Keap1), heme oxygenase-1 (HO-1), and extracellular-signal-regulated kinase (ERK), to investigate the mechanism of antioxidative action of 6''-O-succcinylapigenin. Finally, we employed immunofluorescence to determine the location of Nrf2 and Keap1 in HT22 cells cultured in vitro. Our results revealed that administration of 6''-O-succcinylapigenin induced a decrease in both infarct volume and neurological scores following MCAO, and significantly increased the activity of HO-1 and nuclear Nrf2 in vivo. Similarly, immunofluorescence assays indicated that Nrf2 is highly expressed in the nucleus following treatment with 6''-O-succcinylapigenin in vitro. Our study suggests that 6''-O-succcinylapigenin exerts an anti-ischemic effect by activating the ERK/Nrf2/HO-1 pathway.

Hesperetin is a bioactive flavonoid in the body, produced from hesperidin. No comprehensive studies have shown its protective effects in neurodegenerative disorders. Here, we hypothesized that hesperetin may protect the mice brain against Aβ-induced neurodegeneration. Twenty-four hours after intracerebroventricular injection of Aβ1-42, the treated group was injected hesperetin. For in vitro experiments, HT22 and BV-2 cells were used. Immunoblot, immunofluorescence, and behavioral analyses were used to evaluate the different parameters. Our results indicated that hesperetin significantly attenuated oxidative stress, as assessed by the expression of Nrf2/HO-1 and LPO and ROS assays, in the hippocampus, cortex, and in vitro HT22 cells. Similarly, activated glial cells were regulated by hesperetin, as assessed by the expression of GFAP and Iba-1. Moreover, the expression of TLR4, p-NF-κB, and downstream targets was analyzed; the results showed that hesperetin reinstated the expression of these markers. The effects of hesperetin were further confirmed by using specific TLR4 and p-NF-κB inhibitors in BV-2 cells. Next, we evaluated Aβ pathology in the cortex, hippocampus, and HT22 cells, showing that hesperetin significantly reduced the Aβ pathology. Furthermore, the antiapoptotic effects of hesperetin were assessed, which showed strong antiapoptotic effects. Overall, the neuroprotective effect of hesperetin was found to be a multipotent effect, involving the inhibition of oxidative stress, neuroinflammation, apoptotic cell death, and cognitive consolidation. Given antioxidant, anti-inflammatory, and antiapoptotic potentials against Aβ-induced neurodegeneration and memory impairment, hesperetin may be a promising therapeutic agent for Alzheimer's disease-like neurological disorders.

Mitochondrial dysfunction is involved in the mechanism of early brain injury (EBI) following subarachnoid hemorrhage (SAH). Blood-brain barrier disruption is a devastating outcome in the early stage of SAH. In this study, we aimed to investigate the role of a mitochondria-related drug Mitoquinone (MitoQ) in blood-brain barrier disruption after SAH in rats.

Traumatic Brain Injury (TBI) affects more than 1.7 million Americans each year and about 30% of TBI-patients having visual impairments. The loss of retinal ganglion cells (RGC) in the retina and axonal degeneration in the optic nerve have been attributed to vision impairment following TBI; however, the molecular mechanism has not been elucidated. Here we have shown that an increase in histone di-methylation at lysine 9 residue (H3K9Me2), synthesized by the catalytic activity of a histone methyltransferase, G9a is responsible for RGC loss and axonal degeneration in the optic nerve following TBI. To elucidate the molecular mechanism, we found that an increase in H3K9Me2 results in the induction of oxidative stress both in the RGC and optic nerve by decreasing the mRNA level of antioxidants such as Superoxide dismutase (sod) and catalase through impairing the transcriptional activity of Nuclear factor E2-related factor 2 (Nrf2) via direct interaction. The induction of oxidative stress is associated with death in RGC and oligodendrocyte precursor cells (OPCs). The death in OPCs is correlated with a reduction in myelination, and the expression of myelin binding protein (MBP) in association with degeneration of neurofilaments in the optic nerve. This event allied to an impairment of the retrograde transport of axons and loss of nerve fiber layer in the optic nerve following TBI. An administration of G9a inhibitor, UNC0638 attenuates the induction of H3K9Me2 both in RGC and optic nerve and subsequently activates Nrf2 to reduce oxidative stress. This event was concomitant with the rescue in the loss of retinal thickness, attenuation in optic nerve degeneration and improvement in the retrograde transport of axons following TBI.

To investigate the effects of icariside II on brain tissue oxidative stress and Nrf2/HO-1 expression in rats with cerebral ischemia-reperfusion injury (CIRI).

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.

Inflammation and oxidative stress are considered major factors in the pathogenesis of ischemic stroke. Increasing evidence has demonstrated that Schizandrin A (Sch A), a lignin compound isolated from , exhibits prominent anti-inflammatory and antioxidant activities. In this study, we investigated the anti-inflammatory and antioxidant effects of Sch A against cerebral ischemia/reperfusion (I/R) injury as well as the underlying molecular mechanisms. Sch A treatment significantly improved the neurological score and reduced infarct volume 24 h after reperfusion. It dose-dependently inhibited the expression of cyclooxygenase-2 and inducible nitric oxide synthase, reduced the release of pro-inflammatory cytokines (tumor necrosis factor-α interleukin [IL]-1β and IL-6), and increased anti-inflammatory cytokines (transforming growth factor-β and interleukin-10). Furthermore, it increased the activity of superoxide dismutase and catalase, decreased reactive oxygen species production and 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine levels. Transcription of nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream genes (heme oxygenase-1 and NAD[P]H: quinone oxidoreductase 1) increased. Knockdown of Nrf2 by siRNA inhibited the neuroprotective effects of Sch A. In addition, Sch A increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) both and . Activation of the Nrf2 pathway as well as the protective effects of Sch A in an oxygen and glucose deprivation-induced injury model was abolished by AMPK knockdown. Our study indicates that Sch A protects against cerebral I/R injury by suppressing inflammation and oxidative stress, and that this effect is regulated by the AMPK/Nrf2 pathway.

Pentraxin 3 (PTX3) and nuclear factor-like 2 (Nrf2) are known to induce tumor progression in certain malignancies but act as tumor suppressors in other human neoplasms. In this study, we not only tested the association between PTX3 expression and the World Health Organization (WHO) tumor grading system but also evaluated overall patient survival under variable expression of PTX3 and Nrf2 in primary brain tumors (PBTs). Immunohistochemistry (IHC) was performed for PTX3 and Nrf2 in 10 nonneoplastic brain tissues and 197 PBTs. IHC scores were calculated as the degree of cytoplasmic and nuclear PTX3 and Nrf2 staining intensity multiplied by the percentage of positively stained tissue area. The correlation between PTX3 and Nrf2 IHC scores and tumor grades as well as overall survival time was analyzed by Pearson product-moment correlation and Kaplan-Meier estimate. According to our results, PTX3 IHC scores showed a positive correlation with the WHO grades of gliomas and meningiomas. In addition, we also observed that higher PTX3 expression was associated with poor prognosis in gliomas but not in meningiomas. The concordance between PTX3 and Nrf2 immunohistochemistry (IHC) scores was analyzed using linear regression analysis. When compared to groups with high IHC scores for either one or both biomarkers, gliomas with low expression of both PTX3 and Nrf2 showed significantly better prognosis. In conclusion, we demonstrated that high PTX3 expression implied aggressive tumor behavior and shorter survival time in glioma patients. In addition, our results also showed that gliomas with low PTX3 and Nrf2 immunohistochemical expression could imply a longer overall survival time. Therefore, the combination of lower PTX3 and Nrf2 immunohistochemical expression may be important in offering a better prognosis in gliomas, although the detailed mechanism is yet to be elucidated.