Protective effect of edaravone on blood-brain barrier (BBB) in experimental cerebral infarction rats was investigated. SD rats were prepared as the permanent middle cerebral artery occlusion model and randomly divided into 4 groups: cerebral infarction model group, edaravone low, medium and high dose groups. Healthy rats only for operation and no filament were selected as the sham operation control group. Rats in the cerebral infarction model group and the control group were given normal saline, and those in the edaravone low, medium and high dose groups were given edaravone 10, 15 and 20 mg/kg, respectively. The survival status, the body weight and neurological function score before and after treatment, the brain water content and the permeability of the blood-brain barrier after treatment were measured. The expression levels of NFE2-related factor 2 (NRF2) and hemeoxygenase 1 (HO-1) in rat brain tissue were detected by western blotting. Levels of peripheral blood malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were detected by ELISA. The state of the rats in three edaravone groups was improved compared with that of the cerebral infarction group. Compared with the cerebral infarction model group, the body weight was significantly increased after treatment and the neurological function score, brain tissue water content and BBB permeability were significantly decreased in three edaravone groups (P<0.05). Compared with the model group of cerebral infarction, the expression of NRF-2 and HO-1 in the brain of the three edaravone groups was significantly higher (P<0.05). Compared with the model group of cerebral infarction, the expression of MDA and GSH in the three edaravone groups was significantly decreased, GSH and SOD was increased (P<0.05), in a dose-dependent manner. Edaravone might play a protective role in the BBB by activating the NRF-2/HO-1 signaling pathway.

Our previous study showed that propofol, one of the widely used anesthetic agents, can attenuate subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) via inhibiting inflammatory and oxidative reaction. However, it is perplexing whether propofol attenuates inflammatory and oxidative reaction through modulating PI3K/Akt pathway. The present study investigated whether PI3K/Akt pathway is involved in propofol's anti-inflammation, antioxidation, and neuroprotection against SAH-induced EBI.

Theaflavin has been proven to own strong antioxidative capacity; however, the molecular mechanism underlying its protective effect against cerebral ischemia‑reperfusion (I/R) injury remains unclear. Therefore, the present study was designed to elucidate the neuroprotective effects of theaflavin on cerebral I/R injury and its underlying molecular mechanisms. To investigate the effects of theaflavin on neurological function, neurogenesis, and oxidative stress, experiments were performed using a cerebral I/R injury rat model, and neural stem cells (NSCs) were subjected to oxygen‑glucose deprivation and reoxygenation (OGD/R). Further, the expression profiles of miRNA‑128‑3p and the regulatory function of nuclear factor (erythroid‑derived 2)‑related factor 2 (Nrf2) were evaluated in these models. We found that theaflavin treatment significantly reduced infarct volume and neuronal injury, and thus improved the impaired memory and learning ability. Furthermore, theaflavin treatment significantly enhanced the increase in NSC proliferation, reduction in the apoptotic rate and inhibition of oxidative stress. Mechanistically, theaflavin targeted miRNA‑128‑3p and further activated the Nrf2 pathway to reduce oxidative stress. In summary, theaflavin has a strong ability to attenuate cerebral I/R injury through miRNA‑128‑3p‑mediated recovery of the impaired antioxidant defense system, which suggests that it could be a potential drug candidate for ischemic stroke.

Oxidative stress is considered to play an important role in the cerebral ischemia-reperfusion injury. The nuclear transcription factor erythroid-2-related factor 2 (Nrf2)/NAD(P)H dehydrogenase [quinone] 1 (NQO1) pathway has been considered as a potential target for neuroprotection in cerebral ischemia-reperfusion injury. Nomilin (NOM) is a limonoid compound obtained from the extracts of citrus fruits. The purpose of our study was to determine whether NOM could exert beneficial effects in cerebral ischemia-reperfusion rats. Firstly, NOM treatment significantly mitigated cell death and decreased lactate dehydrogenase (LDH) release and ROS production in SH-SY5Y cells induced by oxygen-glucose deprivation (OGD), which was almost abolished by Nrf2 knockdown. Secondly, NOM improved infarct area, brain edema and neurological deficits in an experimental stroke rat model via middle cerebral artery occlusion (MCAO). Furthermore, NOM attenuated blood-brain barrier (BBB) disruption in MCAO rats, which might be associated with alleviating the loss of tight junction proteins, including ZO-1 and occludin-5. Further results revealed that NOM treatment effectively mitigated oxidative stress and facilitated the expressions of Nrf2 and NQO1, which might confirm that the loss of tight junction proteins in the microvasculature was likely mediated by oxidative stress. In conclusion, our study provided evidence that the protective effects of NOM in cerebral ischemia-reperfusion rats were related to the Nrf2/NQO1 pathway.

Maltol, a maillard reaction product from ginseng ( C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.

Dexmedetomidine (DEX) exhibits neuroprotective effects as a multifunctional neuroprotective agent in numerous neurological disorders. However, in traumatic brain injury (TBI), the molecular mechanisms of these neuroprotective effects remain unclear. The present study investigated whether DEX, which has been reported to exert protective effects against TBI, could attenuate neuroinflammatory-induced apoptosis and clarified the underlying mechanisms.

Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2 mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.

Stroke is a public health problem due to its high mortality and disability rates; despite these, the pharmacological treatments are limited. Oxidative stress plays an important role in cerebral damage in stroke and the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) confers protection against oxidative stress. Different compounds, such as diallyl trisulfide (DATS), have the ability to activate Nrf2. DATS protects against the damage induced in oxygen-glucose deprivation in neuronal cells; however, in in vivo models of cerebral ischemia, DATS has not been evaluated. Male Wistar rats were subjected to 1 h of ischemia and seven days of reperfusion and the protective effect of DATS was evaluated. DATS administration (IR + DATS) decreased the infarct area and brain damage in the striatum and cortex; improved neurological function; decreased malondialdehyde and metalloproteinase-9 levels; increased Nrf2 activation in the cortex and the expression of superoxide dismutase 1 (SOD1) in the nucleus, SOD2 and glutathione S-transferase (GST) in the striatum and cortex; and increased the activity of catalase (CAT) in the striatum and glutathione peroxidase (GPx) in the cortex. Our results demonstrate the protective effect of DATS in an in vivo model of cerebral ischemia that involves Nrf2 activation.

Levocarnitine plays a crucial role in the metabolism of organisms. The aim of this study was to explore the impact of Levocarnitine on cerebral ischemia-reperfusion (I/R) rats and the underlying mechanism.

Oxidative stress and neuroinflammation are central pathogenic mechanisms common to many neurological diseases. Isoliquiritigenin (ISL) is a flavonoid in licorice with multiple pharmacological properties, including anti-inflammatory activity, and has demonstrated protective efficacy against acute neural injury. However, potential actions against cognitive impairments have not been examined extensively. We established a rat model of cognitive impairment by intracerebroventricular injection of lipopolysaccharide (LPS), and examined the effects of ISL pretreatment on cognitive function, hippocampal injury, and hippocampal expression of various synaptic proteins, antioxidant enzymes, pro-inflammatory cytokines, and signaling factors controlling anti-oxidant and pro-inflammatory responses.

Epilepsy is a neurological disorder characterized by the prevalence of spontaneous and recurrent seizures. Oxidative stress has been recognized as an intrinsic mechanism for the initiation and progression of epilepsy. In the present study, we investigated the neuroprotective effect of dehydroepiandrosterone (DHEA) against iron-induced epilepsy in rats. Animals were made epileptic by intracortical injection of FeCl (5 μl of 100 mM), and DHEA (30 mg/kg b. wt., for 7, 14, and 21 days) was administered intraperitoneally. The results showed electrophysiological alterations, excessive oxidative damage, diminished antioxidant defence and induction of apoptosis in the cortex and hippocampus of epileptic rats. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1) was downregulated in both brain regions. While, DHEA treatment for 14 and 21 days has counteracted oxidative stress, reduced neuronal apoptosis and improved electrophysiological changes along with upregulation of Nrf2, HO-1, and NQO-1. In conclusion, our findings demonstrate that neuroprotective effect of DHEA against iron-induced epilepsy might be escorted by the alleviation of oxidative stress through Nrf2-mediated signal pathway.

Neonatal hypoxic/ischemic encephalopathy (NHIE) is a severe condition that leads to death or neurological disability in newborns. The underlying pathological mechanisms are unclear, and developing the target neuroprotective strategies are urgent. 2,7,2'-trihydroxy-4,4'7'-trimethoxy-1,1'-biphenanthrene (TTB) is a natural product isolated from (D. Don) Makino and (Thunb.) Lindl. TTB has demonstrated potent cytotoxic activity against stomach (HGC-27) and colon (HT-29) cancer cell lines. However, none of the studies have addressed the effects of TTB in NHIE. In the present study, an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocyte injury model was established to investigate the effect of TTB and its potential mechanisms. Our results showed that TTB alleviated the OGD/R-induced reactive oxygen species increase and the intracellular antioxidant capacity of superoxide dismutase activity decrease. Moreover, TTB potentially prolonged the activation state of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and maintained the protection against oxidative stress in OGD/R-induced astrocytes by inducing the nuclear translocation and up-regulation of Nrf2 along with the enhanced expression of the downstream target gene HO-1. Furthermore, TTB treatment diminished the accumulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression induced by OGD/R. We also found TTB-treated astrocytes reversed the inhibition of OGD/R on neurite growth of neurons by the astrocyte-neuron coculture system. In conclusion, TTB inhibited the OGD/R-induced astrocyte oxidative stress at least partially through the inhibition of HIF-1α and VEGF the Nrf2/HO-1 signaling pathway.

Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.

The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER's activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER's activity.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. : Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. : MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. : Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.