Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2/ARE Signaling

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 (MDA) and glutathione (GSH) were measured by the 2-thiobarbituric acid methods and the DTNB-GSSG reductase recycling methods. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Neuronal apoptosis was measured by Annexin V-FITC and propidium iodide (PI) staining. Immunohistochemistry and immunofluorescence staining were performed to evaluate Nrf2 and HO-1 expressions. Expression of Nrf2, HO-1, Bcl-2, iNOS and LC3 were evaluated by western blot. Results: The PTZ-injured rats presented longer seizure duration and shorter seizure latency. Rb1 ameliorated these effects, as well as the cognitive deficits caused by PTZ exposure. Besides, Rb1 dose-dependently increased GSH levels, decreased MDA levels and alleviated neuronal damage in PTZ-treated rats. In vitro, Rb1 increased cell viability and decreased neuronal apoptosis in a dose-dependent manner under Mg²⁺ free condition. Moreover, in vivo and in vitro, Rb1 enhanced both the Nrf2 and HO-1 expressions. Furthermore, upregulation of the expression of Bcl-2 and downregulation of the expression of iNOS and LC3 were observed. However, knockdown of Nrf2 adversely affected the protective effects of Rb1 in epileptic hippocampal neurons. Conclusion: Rb1 conferred neuroprotective effects against PTZ-induced brain damage and Mg²⁺ free-induced neuron injury by activating Nrf2/ARE signaling.

Dynorphin activation of kappa opioid receptor protects against epilepsy and seizure-induced brain injury via 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.…”

“…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].…”

“…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].…”

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

“…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.…”

Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

“…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].…”