Protective effect of the antioxidant 6-ethoxy-2,2-pentamnethylen-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 s eries of novel dihydroquinoline compounds were developed, based on the pote nt 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 n europrotective capacity of S 33113 in different in vitro and in vivo paradi gms of oxidative stress-mediated cellular degeneration was undertaken. In v itro S 33113 was a potent inhibitor (IC50 = 0.29 muM) of Fenton-reaction-in duced lipid peroxidation in mouse cortical membranes. Administration of S 3 3113 either intraperitoneally ( less than or equal to 150 mg/kg i.p.) or or ally (less than or equal to 600 mg/kg p.o.) did not significantly modify bo dy temperature in NMRI mice. Furthermore, S 33113 (less than or equal to 15 0 mg/kg i.p. or 600 mg/kg p.o.) markedly reduced the lethality induced by a n intracerebroventricular injection of t-butylhydroperoxide in NMRI (naval medical research institute) mice for up to 5 h. Oral administration of S 33 113, 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 del ayed neuronal cell death in the CAI 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.) p revented 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 st riatum of C57BL/6 mice (39-46%) was significantly prevented with S 33113 ad ministered at either (2 X 150mg/kg i.p.) (11%; P < 0.01) or (2 X 150 mg/kg p.o.) (17%; P < 0.001). In conclusion, S 33113 represents a novel dihydroqu inoline compound with potential for the treatment of cerebral pathologies i mplicating chronic neurodegeneration. <(c)> 2001 Published by Elsevier Scie nce B.V.