Mechanism of glutamate-induced neurotoxicity in HT22 mouse hippocampal cells.
Glutamate is an endogenous excitatory neurotransmitter. At high concentrations, it is neurotoxic and contributes to the development of certain neurodegenerative diseases. There is considerable controversy in the literature with regard to whether glutamate-induced cell death in cultured HT22 cells (an immortalized mouse hippocampal cell line) is apoptosis, necrosis, or a new form of cell death. The present study focused on investigating the mechanism of glutamate-induced cell death. We found that glutamate induced, in a time-dependent manner, both necrosis and apoptosis in HT22 cells. At relatively early time points (8-12 h), glutamate induced mostly necrosis, whereas at late time points (16-24 h), it induced mainly apoptosis. Glutamate-induced mitochondrial oxidative stress and dysfunction were crucial early events required for the induction of apoptosis through the release of the mitochondrial apoptosis-inducing factor (AIF), which catalyzed DNA fragmentation (an ATP-independent process). Glutamate-induced cell death proceeded independently of the Bcl-2 family proteins and caspase activation. The lack of caspase activation likely resulted from the lack of intracellular ATP when the mitochondrial functions were rapidly disrupted by the mitochondrial oxidative stress. In addition, it was observed that activation of JNK, p38, and ERK signaling molecules was also involved in the induction of apoptosis by glutamate. In conclusion, glutamate-induced apoptosis is AIF-dependent but caspase-independent, and is accompanied by DNA ladder formation but not chromatin condensation.
Fukui
Masayuki
M
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Song
Ji-Hoon
JH
Choi
Jinyoung
J
Choi
Hye Joung
HJ
Zhu
Bao Ting
BT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D009498:Neurotoxins; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases