Tags

Type your tag names separated by a space and hit enter

Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution.
J Neurochem. 2005 Mar; 92(6):1477-86.JN

Abstract

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 beta-, methylated beta- and sulfated beta-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 beta-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). beta-CD, but not Mbeta-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.

Authors+Show Affiliations

Cerebrovascular Research Group, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, Ottawa, Ontario, K!A 0R6, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15748165

Citation

Abulrob, Abedelnasser, et al. "Protection By Cholesterol-extracting Cyclodextrins: a Role for N-methyl-D-aspartate Receptor Redistribution." Journal of Neurochemistry, vol. 92, no. 6, 2005, pp. 1477-86.
Abulrob A, Tauskela JS, Mealing G, et al. Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. J Neurochem. 2005;92(6):1477-86.
Abulrob, A., Tauskela, J. S., Mealing, G., Brunette, E., Faid, K., & Stanimirovic, D. (2005). Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. Journal of Neurochemistry, 92(6), 1477-86.
Abulrob A, et al. Protection By Cholesterol-extracting Cyclodextrins: a Role for N-methyl-D-aspartate Receptor Redistribution. J Neurochem. 2005;92(6):1477-86. PubMed PMID: 15748165.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. AU - Abulrob,Abedelnasser, AU - Tauskela,Joseph S, AU - Mealing,Geoff, AU - Brunette,Eric, AU - Faid,Karim, AU - Stanimirovic,Danica, PY - 2005/3/8/pubmed PY - 2005/4/23/medline PY - 2005/3/8/entrez SP - 1477 EP - 86 JF - Journal of neurochemistry JO - J Neurochem VL - 92 IS - 6 N2 - 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 beta-, methylated beta- and sulfated beta-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 beta-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). beta-CD, but not Mbeta-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. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15748165/Protection_by_cholesterol_extracting_cyclodextrins:_a_role_for_N_methyl_D_aspartate_receptor_redistribution_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03001.x DB - PRIME DP - Unbound Medicine ER -