Potential neuroprotective drugs in cerebral ischemia: new saturated and polyunsaturated lipids coupled to hydrophilic moieties: synthesis and biological activity.
The ganglioside GM1 has neuroprotective effects but is not of therapeutic value because of its lack of bioavailability. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized 19 small GM1-like analogues whose simplified structure includes a hydrophobic saturated or unsaturated moiety linked to a hydrophilic moiety. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells. We found that several analogues protected the HT22 cells from death at concentrations ranging from 2 to 5 microM. Additional neuroprotective assays using cortical slices injured by glutamate confirmed these results. Since members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the GM1-like analogues. Interestingly, the results indicate that the compounds provide neuroprotection through distinct mechanisms of action.
Biraboneye
Alain César
AC
Laboratoire de Chimie Biomoléculaire, CNRS, IBDML-UMR-6216, Campus de Luminy Case 907 13288, Marseille Cedex 09, France.
Madonna
Sébastien
S
Laras
Younes
Y
Krantic
Slavica
S
Maher
Pamela
P
Kraus
Jean-Louis
JL
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives*; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D005231:Fatty Acids, Unsaturated; D018696:Neuroprotective Agents; D005677:G(M1) Ganglioside