Abstract:Background/Aims: Ginsenoside Rb1 (Rb1) has been reported to have varieties of neuroprotective effects. This study aimed to evaluate the effects of Rb1 on pentylenetetrazol (PTZ)-induced rat brain injury and Mg2+ free-induced neuron injury and analyzed the detailed molecular mechanisms in vivo and in vitro. Methods: Seizure duration and latency were measured in epilepsy kindled rat. The cognitive impairment was assessed by Morris water maze (MWM) test. Oxidative stress parameters, malondialdehyde (MD… Show more
“…Activation of the PI3K/Akt signaling pathway can alter neuronal apoptosis and attenuates the severity of seizures in experimental epilepsy-induced rats [20][21][22]. On the other hand, activation of the antioxidant Nrf2/ ARE pathway confers neuroprotective effects against pentylenetetrazole-or pilocarpine-induced brain damage in vivo and Mg 2+ free-induced seizure-like neuron injury [10,15,16,19]. In this study, the suppressed activity of the PI3K/Akt pathway and activated Nrf2/HO-1 pathway were observed, as indicated by decreased PI3K expression and Akt phosphorylation, as well as increased Nrf-2 nuclear translocation and HO-1 expression.…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, significant levels of free radicals and oxidative damage have been observed in the brain during seizures [11,12]. As one of the most important antioxidant pathways [13,14], the nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) (Nrf2/HO-1) pathway has been recently shown to exert a significantly neuroprotective role in epilepsy [15,16]. Under normal conditions, Nrf2 is located in the cytoplasm as an inactive complex bound to the repressor protein named as Kelch-like ECH-associated protein 1 (Keap1); Under oxidative/electrophilic stress, Nrf2 dissociates from Keap1, then translocates to the nucleus where it binds to the antioxidant response element (ARE) to regulate the transcription of numerous antioxidant and cytoprotective genes, such as HO-1 and superoxide dismutase 1 (SOD1) [17,18].…”
Section: Introductionmentioning
confidence: 99%
“…Under normal conditions, Nrf2 is located in the cytoplasm as an inactive complex bound to the repressor protein named as Kelch-like ECH-associated protein 1 (Keap1); Under oxidative/electrophilic stress, Nrf2 dissociates from Keap1, then translocates to the nucleus where it binds to the antioxidant response element (ARE) to regulate the transcription of numerous antioxidant and cytoprotective genes, such as HO-1 and superoxide dismutase 1 (SOD1) [17,18]. It has been recently reported that activation of Nrf2/ARE pathway conferred neuroprotective effects against pentylenetetrazoleor pilocarpine-induced brain damage in vivo and Mg 2+ free-induced seizure-like neuron injury [10,15,16,19].…”
Dynorphins act as endogenous anticonvulsants via activation of kappa opioid receptor (KOR). However, the mechanism underlying the anticonvulsant role remains elusive. This study aims to investigate whether the potential protection of KOR activation by dynorphin against epilepsy was associated with the regulation of PI3K/Akt/Nrf2/HO-1 pathway. Here, a pilocarpine-induced rat model of epilepsy and Mg 2+-free-induced epileptiform hippocampal neurons were established. Decreased prodynorphin (PDYN) expression, suppressed PI3K/Akt pathway, and activated Nrf2/ HO-1 pathway were observed in rat epileptiform hippocampal tissues and in vitro neurons. Furthermore, dynorphin activation of KOR alleviated in vitro seizure-like neuron injury via activation of PI3K/Akt/Nrf2/HO-1 pathway. Further in vivo investigation revealed that PDYN overexpression by intra-hippocampus injection of PDYN-overexpressing lentiviruses decreased hippocampal neuronal apoptosis and serum levels of inflammatory cytokines and malondialdehyde (MDA) content, and increased serum superoxide dismutase (SOD) level, in pilocarpine-induced epileptic rats. The protection of PDYN in vivo was associated with the activation of PI3K/Akt/Nrf2/HO-1 pathway. In conclusion, dynorphin activation of KOR protects against epilepsy and seizureinduced brain injury, which is associated with activation of the PI3K/Akt/Nrf2/HO-1 pathway.
“…Activation of the PI3K/Akt signaling pathway can alter neuronal apoptosis and attenuates the severity of seizures in experimental epilepsy-induced rats [20][21][22]. On the other hand, activation of the antioxidant Nrf2/ ARE pathway confers neuroprotective effects against pentylenetetrazole-or pilocarpine-induced brain damage in vivo and Mg 2+ free-induced seizure-like neuron injury [10,15,16,19]. In this study, the suppressed activity of the PI3K/Akt pathway and activated Nrf2/HO-1 pathway were observed, as indicated by decreased PI3K expression and Akt phosphorylation, as well as increased Nrf-2 nuclear translocation and HO-1 expression.…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, significant levels of free radicals and oxidative damage have been observed in the brain during seizures [11,12]. As one of the most important antioxidant pathways [13,14], the nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) (Nrf2/HO-1) pathway has been recently shown to exert a significantly neuroprotective role in epilepsy [15,16]. Under normal conditions, Nrf2 is located in the cytoplasm as an inactive complex bound to the repressor protein named as Kelch-like ECH-associated protein 1 (Keap1); Under oxidative/electrophilic stress, Nrf2 dissociates from Keap1, then translocates to the nucleus where it binds to the antioxidant response element (ARE) to regulate the transcription of numerous antioxidant and cytoprotective genes, such as HO-1 and superoxide dismutase 1 (SOD1) [17,18].…”
Section: Introductionmentioning
confidence: 99%
“…Under normal conditions, Nrf2 is located in the cytoplasm as an inactive complex bound to the repressor protein named as Kelch-like ECH-associated protein 1 (Keap1); Under oxidative/electrophilic stress, Nrf2 dissociates from Keap1, then translocates to the nucleus where it binds to the antioxidant response element (ARE) to regulate the transcription of numerous antioxidant and cytoprotective genes, such as HO-1 and superoxide dismutase 1 (SOD1) [17,18]. It has been recently reported that activation of Nrf2/ARE pathway conferred neuroprotective effects against pentylenetetrazoleor pilocarpine-induced brain damage in vivo and Mg 2+ free-induced seizure-like neuron injury [10,15,16,19].…”
Dynorphins act as endogenous anticonvulsants via activation of kappa opioid receptor (KOR). However, the mechanism underlying the anticonvulsant role remains elusive. This study aims to investigate whether the potential protection of KOR activation by dynorphin against epilepsy was associated with the regulation of PI3K/Akt/Nrf2/HO-1 pathway. Here, a pilocarpine-induced rat model of epilepsy and Mg 2+-free-induced epileptiform hippocampal neurons were established. Decreased prodynorphin (PDYN) expression, suppressed PI3K/Akt pathway, and activated Nrf2/ HO-1 pathway were observed in rat epileptiform hippocampal tissues and in vitro neurons. Furthermore, dynorphin activation of KOR alleviated in vitro seizure-like neuron injury via activation of PI3K/Akt/Nrf2/HO-1 pathway. Further in vivo investigation revealed that PDYN overexpression by intra-hippocampus injection of PDYN-overexpressing lentiviruses decreased hippocampal neuronal apoptosis and serum levels of inflammatory cytokines and malondialdehyde (MDA) content, and increased serum superoxide dismutase (SOD) level, in pilocarpine-induced epileptic rats. The protection of PDYN in vivo was associated with the activation of PI3K/Akt/Nrf2/HO-1 pathway. In conclusion, dynorphin activation of KOR protects against epilepsy and seizureinduced brain injury, which is associated with activation of the PI3K/Akt/Nrf2/HO-1 pathway.
“…3). Recent findings based on animal models studies have shown the neuroprotective effects of many compounds, such as the triterpene Ginsenoside Rb1 [95] and the alkaloid Glaucocalyxin B [96] as well as endogenous metabolites like alpha-lipoic acid [97] and estradiol [98], all involved in the activation of the Nrf2/ARE signaling. Aging is the main risk factor for neurodegeneration and is associated with enhanced ROS/RNS levels and lower antioxidant capacity.…”
Section: Cellular Physiology and Biochemistrymentioning
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.
“…Several studies have shown that gRb1 can protect neurons through activation of the Nrf2/ARE pathway in human SK-N-SH dopaminergic cells, SH-SY5Y cells, and neural progenitor cells [38][39][40]. Shi et al indicated that gRb1 protected the brain from neural injury through Nrf2 activation, and that the knockdown of Nrf2 counteracted the neuroprotective effect of gRb1 [41]. Liu et al indicated that gRb1 protected the spinal cord from oxidative stress by activating the Nrf2/ARE signal pathway [42].…”
Section: Effects Of Rg On Brain Ischemiamentioning
Red ginseng, as an effective herbal medicine, has been traditionally and empirically used for the treatment of neuronal diseases. Many studies suggest that red ginseng and its ingredients protect the brain and spinal cord from neural injuries such as ischemia, trauma, and neurodegeneration. This review focuses on the molecular mechanisms underlying the neuroprotective effects of red ginseng and its ingredients. Ginsenoside Rb1 and other ginsenosides are regarded as the active ingredients of red ginseng; the anti-apoptotic, anti-inflammatory, and anti-oxidative actions of ginsenosides, together with a series of bioactive molecules relevant to the above actions, appear to account for the neuroprotective effects in vivo and/or in vitro. Moreover, in this review, the possibility is raised that more effective or stable neuroprotective derivatives based on the chemical structures of ginsenosides could be developed. Although further studies, including clinical trials, are necessary to confirm the pharmacological properties of red ginseng and its ingredients, red ginseng and its ingredients could be promising candidate drugs for the treatment of neural injuries.
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