Excitotoxic protection by polyanionic polysaccharide: evidence of a cell survival pathway involving AMPA receptor-MAPK Interactions.
Growing numbers of studies indicate that polysaccharides influence signaling events important for brain function. It has been speculated that such polysaccharide modulation of neuronal signals can promote synaptogenesis and cell maintenance. Here, we tested whether dextran sulfate, a polyanion that mimics natural mucopolysaccharides, protects hippocampal neurons against excitotoxic insults. An excitotoxin was applied to primary hippocampal cultures in the absence or presence of a large 500-kDa dextran sulfate (DS-L), a smaller 5-8-kDa species (DS-S), or sulfate-free dextran of 500 kDa. Only DS-L prevented neuronal damage as determined by a membrane permeability assay and phase contrast morphology. The sulfate and size dependence is also characteristic of DS-L's modulatory action on the channel activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors. The extent of neuroprotection correlates with the level of modulation of AMPA responses, and DS-L exhibits comparable EC(50) values for the two effects (3-7 nM). DS-L also modulates the link between AMPA receptors and mitogen-activated protein kinase (MAPK) involving extracellular signal-regulated protein kinase (ERK), well known for its involvement in cell survival and repair. Correspondingly, protection against N-methyl-D-aspartate (NMDA) excitotoxicity was evident in hippocampal slice cultures when DS-L was applied 30 min postinsult. These findings suggest that polysaccharides elicit neuroprotection in the brain, including enhanced repair responses through the AMPA receptor-MAPK axis.
Chicoine
Linda M
LM
Cognetix, Inc., Salt Lake City, Utah, USA.
Bahr
Ben A
BA
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016264:Dextran Sulfate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D009924:Organ Culture Techniques; D000071228:Polyelectrolytes; D011108:Polymers / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D016264:Dextran Sulfate; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D020929:Mitogen-Activated Protein Kinase Kinases; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D000071228:Polyelectrolytes; D011108:Polymers; D011134:Polysaccharides; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid