The effects of the 21-aminosteroid U-74389G on spatial orientation in rats after a cerebral oligemic episode and iron-induced oxidative stress

Oligemic episodes and increased iron concentration have both been proposed as being involved in neurodegenerative diseases. In animal models, a combination of both of these might therefore mimic the clinical pathology in humans. In rats, intrastriatal injections of ferric chloride, FeCl3, one week after a 60-minute oligemic episode, produced by bilateral clamping of the carotid arteries under pentobarbital anaesthesia (BCCA) impaired the animals' learning ability in a water maze task. Median adult rats, after intrastriatal 0.3 μg FeCl3, are impaired when challenged during the first three trial blocks, while after 0.06 μg FeCl3, an impairment is seen during the process of habituation to the challenge. Two-year-old animals do not show any learning effect at all after the combination of BCCA and intrastriatal FeCl3. Lazaroid U-74389G, a potent inhibitor of iron-induced lipid peroxidation, totally prevents the learning impairments in both median adult and aged animals, suggesting that iron-induced lipid peroxidation may be responsible for the late learning deficiencies. However, when U-74389G is applied one week after the oligemic episode but without the additional injection of iron, U-74389G on its own also impairs the animals' learning ability. The present animal model, when applied to clinical studies of lazaroids in humans, does seem able to give reliable information concerning the neuroprotective properties of such drugs.