Kaempferol attenuates the glutamate-induced oxidative stress in mouse-derived hippocampal neuronal HT22 cells

Abstract

It is thought that the neuronal cell loss caused by oxidative stress is the primary mechanism underlying the pathogenesis of several neurodegenerative disorders. Glutamate is an endogenous neurotransmitter, but at high concentrations it can act as a neurotoxicant by increasing the intracellular levels of reactive oxygen species (ROS). Therefore, the development of factors that can attenuate glutamate-induced oxidative stress in neuronal cells is a good strategy by which new drugs could be discovered that may treat or prevent neurodegenerative diseases. Here, the neuroprotective effects of kaempferol (KF) isolated from the stems of butterbur (Petasites japonicus) were examined in glutamate-treated hippocampal neuronal cells (HT22). The administration of KF (25 μM) resulted in a significant increase in cell viability (105.18 ± 7.48%) compared with the control (100.00 ± 3.05%), while glutamate (5 mM) reduced cell viability by 39.94 ± 1.61%. The glutamate-induced calcium (Ca(2+)) influx (1.93 ± 0.08-fold) was significantly reduced by 0.89 ± 0.02-fold following the administration of 25 μM KF. Additionally, when HT22 cells were stressed with excessive glutamate, there was a 3.70 ± 0.01-fold increase in intracellular ROS generation, even though this was effectively attenuated by KF (25 μM, 0.72 ± 0.01-fold). The protective effects of KF in HT22 cells were later confirmed using a lactate dehydrogenase (LDH) assay and a FITC-annexin V/propidium iodide double staining procedure. These findings also revealed that the neuroprotective effects of KF are a result of the regulation of the expression levels of proteins, such as Bcl-2, Bid, apoptosis-inducing factor (AIF), and mitogen-activated protein kinase (MAPK). This is the first report to investigate the neuroprotective influence of KF in glutamate-treated HT22 cells. These data demonstrate that KF may be a useful candidate for pharmacological therapies that can prevent and treat neurodegenerative diseases such as Alzheimer's disease (AD).

Huperzine A Alleviates Oxidative Glutamate Toxicity in Hippocampal HT22 Cells via Activating BDNF/TrkB-Dependent PI3K/Akt/mTOR Signaling Pathway

“…Actually, oxidative injury was previously reported to be triggered in HT22 cells under glutamate stimulation, and the medicinal herb Gastrodia elata remarkably prevented oxidative glutamate toxicity (Han et al 2014). Besides, several previous investigations illustrated that suppression of ROS production by various substances such as kaempferol (Yang et al 2014), acetogenin A (Lee et al 2015), pinacidil (Shukry et al 2015), or herbal mixture (Ahn et al 2015) could remarkably attenuate cell apoptosis in mouse hippocampal HT22 cells. Similarly, results from our current study illustrated that HupA pretreatment dramatically suppressed ROS accumulation and subsequent neuronal damage in HT22 cells.…”

Selenium suppresses glutamate-induced cell death and prevents mitochondrial morphological dynamic alterations in hippocampal HT22 neuronal cells

“…However, excessive ROS can be detrimental to cells as a result of induction of oxidative stress and cellular damage [41]. Earlier studies describing the chronic effect of glutamate exposure in cellular toxicity point to the crucial role of oxidative stress-induced ROS as a major stimulus of glutamate-induced cell death [17, 42–45]. It has been reported that excessive concentrations of extracellular glutamate antagonize the glutamate/cystine-antiporter and inhibit cystine uptake.…”

Delivery of a protein transduction domain-mediated Prdx6 protein ameliorates oxidative stress-induced injury in human and mouse neuronal cells

“…Paraquat has been reported to cause brain damage via formation of oxygen-free radicals (60), leading to neuronal cell death that finally causes disease. Glutamate, an endogenous neurotransmitter, in high concentrations acts as a neurotoxicant by increasing intracellular ROS levels (62). Glutamate-induced oxidative stress plays an im- portant role in neuronal cell injury and degeneration in many brain disorders (16,33).…”