Protective effect of the antioxidant 6-ethoxy-2,2-pentamethylen-1,2-dihydroquinoline (S 33113) in models of cerebral neurodegeneration.
In a previous study Dorey et al. [Bio. Org. Chem. Lett., 10 (2000) 935] a series of novel dihydroquinoline compounds were developed, based on the potent antioxidant 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin), and permitted the selection of the analogue 6-ethoxy-2,2-pentamethylen-1,2-dihydroquinoline (S 33113) lacking the hypothermic effects associated with ethoxyquin at equivalent doses. Herein, an extensive investigation of the neuroprotective capacity of S 33113 in different in vitro and in vivo paradigms of oxidative stress-mediated cellular degeneration was undertaken. In vitro S 33113 was a potent inhibitor (IC(50) = 0.29 microM) of Fenton-reaction-induced lipid peroxidation in mouse cortical membranes. Administration of S 33113 either intraperitoneally (< or =150 mg/kg i.p.) or orally (< or =600 mg/kg p.o.) did not significantly modify body temperature in NMRI mice. Furthermore, S 33113 (150 mg/kg i.p. or 600 mg/kg p.o.) markedly reduced the lethality induced by an intracerebroventricular injection of t-butylhydroperoxide in NMRI (naval medical research institute) mice for up to 5 h. Oral administration of S 33113, significantly attenuated alloxan-mediated hyperglycaemia in NMRI mice at 400 and 600 mg/kg (60%; P < 0.001). Administration of S 33113 (150 mg/kg i.p.) 30 min before transient global ischaemia significantly prevented delayed neuronal cell death in the CA1 region of the rat hippocampal formation, 7 days post-ischaemia (33% cell loss vs. 88% in ischaemia controls; P < 0.001). Similarly, a single pre-administration of S 33113 (150 mg/kg i.p.) prevented kainic acid-induced cell death in the CA3 hippocampal region at 7 days post-exposure (17% cell loss vs. 52% in kainate-treated controls; P < 0.01). Furthermore, D-methamphetamine-mediated dopamine depletion in the striatum of C57BL/6 mice (39-46%) was significantly prevented with S 33113 administered at either (2 x 150mg/kg i.p.) (11%; P < 0.01) or (2x150 mg/kg p.o.) (17%; P < 0.001). In conclusion, S 33113 represents a novel dihydroquinoline compound with potential for the treatment of cerebral pathologies implicating chronic neurodegeneration.
Division of Cerebral Pathology, Servier, 125, Chemin de ronde, 78290 Croissy-sur-Seine, France. Brian.lockhart@fr.netgrs.com
B
B
Lockhart
N
N
Bonhomme
A
A
Roger
G
G
Dorey
P
P
Casara
P
P
Lestage
D000496:Alloxan / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000401:mortality / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum; D015996:Survival Rate; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
C431003:6-ethoxy-2,2-pentamethylen-1,2-dihydroquinoline; D000975:Antioxidants; D011804:Quinolines; D008694:Methamphetamine; D000496:Alloxan; D020122:tert-Butylhydroperoxide; D007608:Kainic Acid; D004298:Dopamine