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Protection by cholesterol‐extracting cyclodextrins: a role for N ‐methyl‐ d ‐aspartate receptor redistribution
Author(s) -
Abulrob Abedelnasser,
Tauskela Joseph S.,
Mealing Geoff,
Brunette Eric,
Faid Karim,
Stanimirovic Danica
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03001.x
Subject(s) - nmda receptor , neuroprotection , glutamate receptor , postsynaptic potential , chemistry , biochemistry , postsynaptic density , receptor , biophysics , biology , pharmacology
Cyclodextrins (CDs) are cyclic oligosaccharides composed of a lipophilic central cavity and a hydrophilic outer surface. Some CDs are capable of extracting cholesterol from cell membranes and can affect function of receptors and proteins localized in cholesterol‐rich membrane domains. In this report, we demonstrate the neuroprotective activity of some CD derivatives against oxygen–glucose deprivation (OGD), N ‐methyl‐ d ‐aspartic acid (NMDA) and glutamate in cortical neuronal cultures. Although all CDs complexed with NMDA or glutamate, only β‐, methylated β‐ and sulfated β‐CDs displayed neuroprotective activity and lowered cellular cholesterol. Only CDs that lowered cholesterol levels redistributed the NMDA receptor NR2B subunit, PSD‐95 (postsynaptic density protein 95 kDa) and neuronal nitric oxide synthase (nNOS) from Triton X‐100 insoluble membrane domains to soluble fractions. Cholesterol repletion counteracted the ability of methylated β‐CD to protect against NMDA toxicity, and reversed NR2B, PSD‐95 and nNOS localization to Triton X‐100 insoluble membrane fraction. Surprisingly, neuroprotective CDs had minimal effect on NMDA receptor‐mediated increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ), but did suppress OGD‐induced increases in [Ca 2+ ] i . β‐CD, but not Mβ‐CD, also caused a slight block of NMDA‐induced currents, suggesting a minor contribution to neuroprotection by direct action on NMDA receptors. Taken together, data suggest that cholesterol extraction from detergent‐resistant microdomains affects NMDA receptor subunit distribution and signal propagation, resulting in neuroprotection of cortical neuronal cultures against ischemic and excitotoxic insults. Since cholesterol‐rich membrane domains exist in neuronal postsynaptic densities, these results imply that synaptic NMDA receptor subpopulations underlie excitotoxicity, which can be targeted by CDs without affecting overall neuronal Ca 2+ levels.