Iron is a potential key mediator of glutamate excitotoxicity in spinal cord motor neurons.
Threohydroxyaspartate (THA)-induced glutamate excitotoxicity in organotypic culture of rat spinal cord is a well-known model of motor neuron degeneration. THA causes accumulation of synaptic glutamate and over stimulation of the postsynaptic receptor by inhibiting glutamate uptake. This model has also been used to identify agents that inhibit glutamate excitotoxicity by increasing the expression of glutamate transporter. We now show that THA also increases iron level in rat spinal cord tissue, with concomitant modulation of key iron transport and storage proteins, including transferrin receptor, divalent metal-ion transporter 1 and ferritin. More significantly, iron chelator deferoxamine (DFO) was able to completely prevent THA-induced motor neuron degeneration. The protective effect of DFO did not involve enhancing glutamate uptake. These data provide new mechanistic insight into THA-induced glutamate excitotoxicity and suggest that blocking THA-induced iron rise alone may be sufficient for prevention of glutamate excitotoxicity.
Yu
Jixu
J
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.
Guo
Yansu
Y
Sun
Mengmeng
M
Li
Bin
B
Zhang
Yuesheng
Y
Li
Chunyan
C
D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D027682:Cation Transport Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000099236:Solute Carrier Family 11, Member 2
D001224:Aspartic Acid; D027682:Cation Transport Proteins; D003676:Deferoxamine; D005293:Ferritins; D018698:Glutamic Acid; D007501:Iron; D007502:Iron Chelating Agents; D007770:L-Lactate Dehydrogenase; D009498:Neurotoxins; D011990:Receptors, Transferrin; D000099236:Solute Carrier Family 11, Member 2; C011274:3-hydroxyaspartic acid