In vivo neuroprotective effects of the novel imidazolyl nitrone free-radical scavenger (Z)-alpha-[2-thiazol-2-yl)imidazol-4-yl]-N-tert-butylnitrone (S34176).
Herein, we report an extensive investigation of the neuroprotective effects of the compound (Z)-alpha-[2-thiazol-2-yl)imidazol-4-yl]-N-tert-butylnitrone (S34176) and the prototypic nitrone alpha-phenyl-N-tert-butylnitrone (PBN), in different in vivo paradigms of neuronal degeneration. Administration of S34176 (75 mg/kg i.p.) 30 min before transient (10 min) global ischaemia in Wistar rats significantly prevented delayed neuronal cell death in the hippocampal CA1 area 7 days post-ischaemia (24% vs. 73% in ischaemia control; P<0.05) whereas PBN was inactive under similar conditions. Furthermore, oral administration of S34176 (30 mg/kg) 60 min before and during (1 x 30 mg/kg p.o.) 6 days post-ischaemia, in combination with an acute post-ischaemia sub-protective dose (3 x 10 mg/kg i.p.) of the glutamate receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), resulted in an increased neuroprotective action (29% cell loss in drug-treated vs. 84% in ischaemia control P<0.001) compared to either compound alone. S34176 (20 mg/kg i.p.) also partially prevented kainic acid-induced neuronal cell death at 7 days post-exposure in the CA1 (41% in drug-treated vs. 74% for kainate-treated controls; P<0.01) and CA3 hippocampal region (22% vs. 53%; P<0.01). Under similar conditions, S34176 administered orally (40 mg/kg) produced a more marked protection against kainate-induced neuronal cell loss in the CA1 (13% in drug-treated vs. 82%; P<0.001) and CA3 areas (10% vs. 52%; P<0.001). Sub-chronic oral administration of S34176 (10 mg/kg) also partially reduced kainate-induced hippocampal cell death in the CA1 (53% vs. 77%; P<0.01) and CA3 (23% vs. 53%; P<0.01) areas. Dopamine depletion in the striatum of C57BL/6 mice induced by systemic D-methamphetamine injection was significantly reduced by S34176 (40+/-5% vs. 11.5+/-8%; P<0.001) (150 mg/kg i.p.) whereas PBN was inactive under similar conditions. S34176 represents a new centrally acting nitrone-based radical scavenger with neuroprotective properties in in vivo models of delayed neuronal cell death, and supports the therapeutic potential of this class of compound for the treatment of cerebral pathologies implicating chronic neurodegeneration.
Lockhart
Brian
B
Division of Cerebral Pathology, 125, Chemin de ronde, 78290 Croissy-sur-Seine, France. Brian.lockhart@fr.netgrs.com
Roger
Anita
A
Bonhomme
Norbert
N
Goldstein
Solo
S
Lestage
Pierre
P
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C502304:(2-thiazol-2-yl)imidazol-4-yl-N-tert-butylnitrone; D016166:Free Radical Scavengers; D007093:Imidazoles; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011810:Quinoxalines; C015388:nitrones; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D008694:Methamphetamine; D007608:Kainic Acid; D004298:Dopamine