Neuroprotective effects of the novel brain-penetrating pyrrolopyrimidine antioxidants U-101033E and U-104067F against post-ischemic degeneration of nigrostriatal neurons.
A 10-min period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers a delayed retrograde degeneration of 35-40% of dopaminergic nigrostriatal (NS) neurons. The mechanism of the NS degeneration is believed to involve oxygen radical formation secondary to a postischemic increase in dopamine turnover (monoamine oxidase, MAO). If the oxygen radical increase is sufficiently severe, lipid peroxidative injury to the striatal NS terminals is followed by retrograde degeneration of the NS cell bodies. In the present study, we examined whether the novel brain-penetrating lipid antioxidant pyrrolopyrimidine, U-101033E, and its aromatized analog, U-104067F, could attenuate dopaminergic neurodegeneration in this model. Male Mongolian gerbils were dosed with U-101033E (1.5, 5, or 15 mg/kg, by mouth, twice daily) or U-104067F (5 or 15 mg/kg, by mouth, twice daily) for 27 days beginning on the day of the 10-min ischemic insult. Preservation of NS neurons was assessed by tyrosine hydroxylase immunohistochemistry at 28 days. In vehicle (40% hydroxypropyl-beta-cyclodextrin)-treated animals, there was a 42% loss of NS neurons. In contrast, gerbils that received 5 or 15 mg/kg U-101033E twice daily had only a 23% or 28% loss of NS neurons, respectively (P < 0.002 vs. vehicle). U-104067F showed little effect at sparing neurons at the 10 mg/kg dose, but did significantly attenuate neuronal loss to only 20% at the 30 mg/kg dose (P < 0.01 vs. vehicle). The results show that both the pyrrolopyrimidines (U-101033E and U-104067F) significantly attenuate the postischemic loss of NS dopaminergic neurons and further support the involvement of a dopamine metabolism-derived, oxygen radical-induced lipid peroxidative mechanism.
Andrus
P K
PK
CNS Diseases Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Fleck
T J
TJ
Oostveen
J A
JA
Hall
E D
ED
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D012016:Reference Values; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D000975:Antioxidants; D015415:Biomarkers; D018696:Neuroprotective Agents; D011743:Pyrimidines; D011759:Pyrrolidines; C101923:U 101033E; C096239:U 104067; D014446:Tyrosine 3-Monooxygenase