Amphiphilic alpha-tocopherol analogues as inhibitors of brain lipid peroxidation.
Neurological disorders, such as stroke, trauma, tardive dyskinesia, Alzheimer's and Parkinson's diseases, may be partially attributed to excessive exposition of the nervous tissue to oxygen-derived radicals. A novel water-soluble alpha-tocopherol analogue, 2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methylpiperazino) methyl-1-benzofuran-5-ol dihydrochloride (MDL), is a potent radical scavenger. Following subcutaneous administration to mice, MDL inhibited the lipid peroxidation induced in the 100-fold diluted brain homogenates, with an ID50 of 8 mg/kg. Rapid brain penetration, within 30-60 min postadministration, and even distribution into different brain areas were observed. MDL was also detected after oral administration. In brain homogenate undergoing lipid peroxidation, MDL prevented the consumption of an equal amount of alpha-tocopherol, while inhibiting the concomitant malondialdehyde formation. The radical scavenging capacity of MDL was superior to that of alpha-tocopherol, although the peak and half-peak potentials were not significantly different. However, MDL was much less lipophilic, the partition coefficient (log P) at the octanol/water interface being 1.91. Although it is yet unknown, whether the applied criteria sufficiently predict its usefulness, beneficial effects of MDL may be expected in the above mentioned disorders.
Bolkenius
F N
FN
Marion Merrell Dow Research Institute, Strasbourg, France. FrankBolkenius@mmd.com
Verne-Mismer
J
J
Wagner
J
J
Grisar
J M
JM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014810:Vitamin E / Q000031:analogs & derivatives*
D000975:Antioxidants; D001572:Benzofurans; C101402:MDL 74,180; D018696:Neuroprotective Agents; D010879:Piperazines; D014810:Vitamin E